Sex differences in trends and outcomes of acute myocardial infarction with mechanical complications in the United States.

BACKGROUND: Mechanical complications (MC) are rare but significant sequelae of acute myocardial infarction (AMI). Current data on sex differences in AMI with MC is limited. METHODS: We queried the National Inpatient Sample database to identify adult patients with the primary diagnosis of AMI and MC. The main outcome of interest was sex difference in-hospital mortality. Secondary outcomes were sex differences in the incidence of acute kidney injury (AKI), major bleeding, use of inotropes, permanent pacemaker implantation (PPMI), performance of percutaneous coronary intervention (PCI), coronary artery bypass grafting (CABG), surgery (VSD repair and MV surgery), pericardiocentesis, use of mechanical circulatory support (MCS), ischemic stroke, and mechanical ventilation. RESULTS: Among AMI-MC cohort, in-hospital mortality was higher among females compared to males (41.24% vs 28.13%: aOR 1.39. 95% CI 1.079-1.798; p = 0.01). Among those who had VSD, females also had higher in-hospital mortality compared to males (56.7% vs 43.1%: aOR 1.74, 95% CI 1.12-2.69; p = 0.01). Females were less likely to receive CABG compared to males (12.03% vs 20%: aOR 0.49 95% CI 0.345-0.690; p < 0.001). CONCLUSION: Despite the decreasing trend in AMI admission, females had higher risk of MC and associated mortality. Significant sex disparities still exist in AMI treatment.

End-Of-Life Care for Patients With End-Stage Heart Failure, Comparisons of International Guidelines.

Heart failure (HF) is a chronic, debilitating condition associated with significant morbidity, mortality, and socioeconomic burden. Patients with end-stage HF (ESHF) who are not a candidate for advanced therapies will continue to progress despite standard medical therapy. Thus, the focus of care shifts from prolonging life to controlling symptoms and improving quality of life through palliative care (PC). Because the condition and prognosis of HF patients evolve and can rapidly deteriorate, it is imperative to begin the discussion on end-of-life (EOL) issues early during HF management. These include the completion of an advance directive, do-not-resuscitate orders, and policies on device therapy and discontinuation as part of advance care planning (ACP). ESHF patients who do not have indications for advanced therapies or those who wish not to have a left ventricular assist device (LVAD) or heart transplant (HT) often experience high symptom burden despite adequate medical management. The proper identification and assessment of symptoms such as pain, dyspnea, nausea, depression, and anxiety are essential to the management of ESHF and may be underdiagnosed and undertreated. Psychological support and spiritual care are also crucial to improving the quality of life during EOL. Caregivers of ESHF patients must also be provided supportive care to prevent compassion fatigue and improve resilience in patient care. In this narrative review, we compare the international guidelines and provide an overview of end-of-life and palliative care for patients with ESHF.

A review of the impact, pathophysiology, and management of atrial fibrillation in patients with heart failure with preserved ejection fraction.

Patients with heart failure with preserved ejection fraction (HFpEF) and atrial fibrillation (AF) have increased mortality and increased risk of stroke. Due to the heterogeneous nature of both disease processes, it is difficult to ascertain whether the diagnosis and progression of AF is the cause of deterioration or if it is a symptom of worsening heart failure. This presents physicians with a clinical conundrum of whether optimizing their heart failure will decrease the overall AF burden or if restoration of sinus rhythm is necessary to optimize patients with HFpEF. In this paper, we will review the impact of AF in patients with HFpEF, the pathophysiology and heterogeneity of HFpEF and AF, and the management of these patients. As HFpEF and AF become more prevalent, managing these disease processes needs standardization to improve outcomes. Further research is needed to understand the complex interplay between AF and HFpEF to help determine the best management strategy.

Association between number of vasopressors and mortality in COVID-19 patients.

Study objective: Study the clinical outcomes associated with the number of concomitant vasopressors used in critically ill COVID-19 patients. Design: A single-center retrospective cohort study was conducted on patients admitted with COVID-19 to the intensive care unit (ICU) between March and October 2020. Setting: Rush University Medical Center, United States. Participants: Adult patients at least 18 years old with COVID-19 with continuous infusion of any vasopressors were included. Main outcome measures: 60-day mortality in COVID-19 patients by the number of concurrent vasopressors received. Results: A total of 637 patients met our inclusion criteria, of whom 338 (53.1 %) required the support of at least one vasopressor. When compared to patients with no vasopressor requirement, those who required 1 vasopressor (V1) (adjusted odds ratio [aOR] 3.27, 95 % confidence interval (CI) 1.86-5.79, p < 0.01) (n = 137), 2 vasopressors (V2) (aOR 4.71, 95 % CI 2.54-8.77, p < 0.01) (n = 86), 3 vasopressors (V3) (aOR 26.2, 95 % CI 13.35-53.74 p < 0.01) (n = 74), and 4 or 5 vasopressors(V4-5) (aOR 106.38, 95 % CI 39.17-349.93, p < 0.01) (n = 41) were at increased risk of 60-day mortality. In-hospital mortality for patients who received no vasopressors was 6.7 %, 22.6 % for V1, 27.9 % for V2, 62.2 % for V3, and 78 % for V4-V5. Conclusion: Critically ill patients with COVID-19 requiring vasopressors were associated with significantly higher 60-day mortality.

Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19.

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (ß=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Clinical outcomes of COVID-19 infection in patients with pre-existing cardiovascular disease.

Introduction: Patients with pre-existing cardiovascular disease may carry a higher risk for mortality from COVID-19. This study examined the association between individuals with pre-existing cardiovascular disease admitted for COVID-19 and their clinical outcomes. Methods: A retrospective cohort study was conducted on patients admitted with COVID-19 to Rush University System for Health (RUSH) to identify cardiovascular risk factors associated with increased mortality and major adverse cardiovascular events (MACE; a composite of cardiovascular death, stroke, myocardial injury, and heart failure exacerbation). Multivariable logistic regression was used to adjust for demographic data and comorbid conditions. Results: Of the 1682 patients who met inclusion criteria, the median age was 59. Patients were predominantly African American (34.4 %) and male (54.5 %). Overall, 202 (12 %) patients suffered 60-day mortality. In the multivariable model that assessed risk factors for 60-day mortality, age 60-74 (adjusted odds ratio [aOR] 3.30 [CI: 1.23-10.62]; p < 0.05) and age 75-100 (aOR 4.52 [CI: 1.46-16.15]; p < 0.05) were significant predictors when compared to those aged 19 to 39. This model also showed that those with past medical histories of atrial fibrillation (aOR 2.47 [CI: 1.38-4.38]; p < 0.01) and venous thromboembolism (aOR 2.00 [CI: 1.12-3.50]; p < 0.05) were at higher risk of 60-day mortality. Conclusion: In this cohort, patients over 60 years old with a pre-existing history of atrial fibrillation and venous thromboembolism were at increased risk of mortality from COVID-19.

Hyperdynamic left ventricular ejection fraction is associated with higher mortality in COVID-19 patients.

Study objective: To compare the characteristics and outcomes of COVID-19 patients with a hyperdynamic LVEF (HDLVEF) to those with a normal or reduced LVEF. Design: Retrospective study. Setting: Rush University Medical Center. Participants: Of the 1682 adult patients hospitalized with COVID-19, 419 had a transthoracic echocardiogram (TTE) during admission and met study inclusion criteria. Interventions: Participants were divided into reduced (LVEF < 50%), normal (≥50% and <70%), and hyperdynamic (≥70%) LVEF groups. Main outcome measures: LVEF was assessed as a predictor of 60-day mortality. Logistic regression was used to adjust for age and BMI. Results: There was no difference in 60-day mortality between patients in the reduced LVEF and normal LVEF groups (adjusted odds ratio [aOR] 0.87, p = 0.68). However, patients with an HDLVEF were more likely to die by 60 days compared to patients in the normal LVEF group (aOR 2.63 [CI: 1.36-5.05]; p < 0.01). The HDLVEF group was also at higher risk for 60-day mortality than the reduced LVEF group (aOR 3.34 [CI: 1.39-8.42]; p < 0.01). Conclusion: The presence of hyperdynamic LVEF during a COVID-19 hospitalization was associated with an increased risk of 60-day mortality, the requirement for mechanical ventilation, vasopressors, and intensive care unit.

Echocardiographic predictors of mortality and morbidity in COVID-19 disease using focused cardiovascular ultrasound.

BACKGROUND: Focused transthoracic echocardiography (fTTE) has emerged as a critical diagnostic tool during the COVID-19 pandemic, allowing for efficient cardiac imaging while minimizing staff exposure. The utility of fTTE in predicting clinical outcomes in COVID-19 remains under investigation. METHODS: We conducted a retrospective study of 2,266 hospitalized patients at Rush University Medical Center with COVID-19 infection between March and November 2020 who received a fTTE. fTTE data were analyzed for association with primary adverse outcomes (60-day mortality) and with secondary adverse outcomes (need for renal replacement therapy, need for invasive ventilation, shock, and venous thromboembolism). RESULTS: Of the 427 hospitalized patients who had a fTTE performed (mean 62 years, 43% female), 109 (26%) had died by 60 days. Among patients with an available fTTE measurement, right ventricular (RV) dilation was noted in 34% (106/309), 43% (166/386) had RV dysfunction, and 17% (72/421) had left ventricular (LV) dysfunction. In multivariable models accounting for fTTE data, RV dilation was significantly associated with 60-day mortality (OR 1.93 [CI 1.13-3.3], p = 0.016). LV dysfunction was not significantly associated with 60-day mortality (OR 0.95 [CI: 0.51-1.78], p = 0.87). CONCLUSIONS: Abnormalities in RV echocardiographic parameters are adverse prognosticators in COVID-19 disease. Patients with RV dilation experienced double the risk for 60-day mortality due to COVID-19. To our knowledge, this is the largest study to date that highlights the adverse prognostic implications of RV dilation as determined through fTTE in hospitalized COVID-19 patients.

Prognostic value of H2FPEF score in COVID-19.

STUDY OBJECTIVE: This study sought to assess the predictive value of H2FPEF score in patients with COVID-19. DESIGN: Retrospective study. SETTING: Rush University Medical Center. PARTICIPANTS: A total of 1682 patients had an echocardiogram in the year preceding their COVID-19 admission with a preserved ejection fraction (≥50%). A total of 156 patients met inclusion criteria. INTERVENTIONS: Patients were divided into H2FPEF into low (0-2), intermediate (3-5), and high (6-9) score H2FPEF groups and outcomes were compared. MAIN OUTCOME MEASURES: Adjusted multivariable logistic regression models evaluated the association between H2FPEF score group and a composite outcome for severe COVID-19 infection consisting of (1) 60-day mortality or illness requiring (2) intensive care unit, (3) intubation, or (4) non-invasive positive pressure ventilation. RESULTS: High H2FPEF scores were at increased risk for severe COVID-19 infection when compared intermediate to H2FPEF score groups (OR 2.18 [CI: 1.01-4.80]; p = 0.049) and low H2FPEF score groups (OR 2.99 [CI: 1.22-7.61]; p < 0.05). There was no difference in outcome between intermediate H2FPEF scores (OR 1.34 [CI: 0.59-3.16]; p = 0.489) and low H2FPEF score. CONCLUSIONS: Patients with a high H2FPEF score were at increased risk for severe COVID-19 infection when compared to patients with an intermediate or low H2FPEF score regardless of regardless of coronary artery disease and chronic kidney disease.

Cardiovascular findings on chest computed tomography associated with COVID-19 adverse clinical outcomes.

STUDY OBJECTIVE: Chest computed tomography (chest CT) is routinely obtained to assess disease severity in COVID-19. While pulmonary findings are well-described in COVID-19, the implications of cardiovascular findings are less well understood. We evaluated the impact of cardiovascular findings on chest CT on the adverse composite outcome (ACO) of hospitalized COVID-19 patients. SETTING/PARTICIPANTS: 245 COVID-19 patients who underwent chest CT at Rush University Health System were included. DESIGN: Cardiovascular findings, including coronary artery calcification (CAC), aortic calcification, signs of right ventricular strain [right ventricular to left ventricular diameter ratio, pulmonary artery to aorta diameter ratio, interventricular septal position, and inferior vena cava (IVC) reflux], were measured by trained physicians. INTERVENTIONS/MAIN OUTCOME MEASURES: These findings, along with pulmonary findings, were analyzed using univariable logistic analysis to determine the risk of ACO defined as intensive care admission, need for non-invasive positive pressure ventilation, intubation, in-hospital and 60-day mortality. Secondary endpoints included individual components of the ACO. RESULTS: Aortic calcification was independently associated with an increased risk of the ACO (odds ratio 1.86, 95% confidence interval (1.11-3.17) p < 0.05). Aortic calcification, CAC, abnormal septal position, or IVC reflux of contrast were all significantly associated with 60-day mortality and major adverse cardiovascular events. IVC reflux was associated with in-hospital mortality (p = 0.005). CONCLUSION: Incidental cardiovascular findings on chest CT are clinically important imaging markers in COVID-19. It is important to ascertain and routinely report cardiovascular findings on CT imaging of COVID-19 patients as they have potential to identify high risk patients.

The prognostic value of cardiac troponin for 60 day mortality and major adverse events in COVID-19 patients.

BACKGROUND: The variability of coronavirus disease 2019 (COVID-19) illness severity has puzzled clinicians and has sparked efforts to better predict who would benefit from rapid intervention. One promising biomarker for in-hospital morbidity and mortality is cardiac troponin (cTn). METHODS: A retrospective study of 1331 adult patients with COVID-19 admitted to the Rush University System in Illinois, USA was performed. Patients without cTn measurement during their admission or a history of end stage renal disease or stage 5 chronic kidney disease were excluded. Using logistic regression adjusted for baseline characteristics, pre-existing comorbidities, and other laboratory markers of inflammation, cTn was assessed as a predictor of 60-day mortality and severe COVID-19 infection, consisting of a composite of 60-day mortality, need for intensive care unit, or requiring non-invasive positive pressure ventilation or intubation. RESULTS: A total of 772 patients met inclusion criteria. Of these, 69 (8.9%) had mild cTn elevation (> 1 to < 2x upper limit of normal (ULN)) and 46 (6.0%) had severe cTn elevation (≥ 2x ULN). Regardless of baseline characteristics, comorbidities, and initial c-reactive protein, lactate dehydrogenase, and ferritin, when compared to the normal cTn group, mild cTn elevation and severe cTn elevation were predictors of severe COVID-19 infection (adjusted OR [aOR] aOR 3.00 [CI: 1.51 - 6.29], P < 0.01; aOR 9.96 [CI: 2.75 - 64.23], P < 0.01, respectively); severe cTn elevation was a predictor of in-hospital mortality (aOR 2.42 [CI: 1.10 - 5.21], P < 0.05) and 60-day mortality (aOR 2.45 [CI: 1.13 - 5.25], P < 0.05). CONCLUSION: In our cohort, both mild and severe initial cTn elevation were predictors of severe COVID-19 infection, while only severe cTn elevation was predictive of 60-day mortality. First cTn value on hospitalization is a valuable longitudinal prognosticator for COVID-19 disease severity and mortality.

Impact of pre-existing heart failure on 60-day outcomes in patients hospitalized with COVID-19.

BACKGROUND: In the coronavirus disease 2019 (COVID-19) global pandemic, patients with cardiovascular disease represent a vulnerable population with higher risk for contracting COVID-19 and worse prognosis with higher case fatality rates. However, the relationship between COVID-19 and heart failure (HF) is unclear, specifically whether HF is an independent risk factor for severe infection or if other accompanying comorbidities are responsible for the increased risk. METHODS: This is a retrospective analysis of 1331 adult patients diagnosed with COVID-19 infection between March and June 2020 admitted at Rush University System for Health (RUSH) in metropolitan Chicago, Illinois, USA. Patients with history of HF were identified by International Classification of Disease, Tenth Revision (ICD-10) code assignments extracted from the electronic medical record. Propensity score matching was utilized to control for the numerous confounders, and univariable logistic regression was performed to assess the relationship between HF and 60-day morbidity and mortality outcomes. RESULTS: The propensity score matched cohort consisted of 188 patients in both the HF and no HF groups. HF patients did not have lower 60-day mortality (OR 0.81; p = 0.43) compared to patients without HF. However, those with HF were more likely to require readmission within 60 days (OR 2.88; p < 0.001) and sustain myocardial injury defined as troponin elevation within 60 days (OR 3.14; p < 0.05). CONCLUSIONS: This study highlights the complex network of confounders present between HF and COVID-19. When balanced for these numerous factors, those with HF appear to be at no higher risk of 60-day mortality from COVID-19 but are at increased risk for morbidity.

COVID-19-associated takotsubo cardiomyopathy.

The novel COVID-19 has had an unprecedented and devastating spread internationally. COVID-19 infection can lead to a number of cardiovascular sequelae, including heart failure, which may portend worse clinical outcomes. Here, we report a rare case of a 57-year-old woman who developed acute left ventricular systolic dysfunction with apical ballooning consistent with takotsubo cardiomyopathy (TCM), and mixed cardiogenic and septic shock in the setting of COVID-19 disease. We briefly review the pathophysiology and diagnosis of TCM (also described as apical ballooning syndrome and stress-induced cardiomyopathy). Additionally, this case highlights the importance of a multidisciplinary approach to clinical decision-making and resource allocation in diagnosis and management of critical illness in the setting of the ongoing international COVID-19 pandemic.

Endocarditis Complicated by Severe Aortic Insufficiency in a Patient with COVID-19: Diagnostic and Management Implications.

A 38-year-old man presented with cough, shortness of breath, and fatigue. He was diagnosed with Coronavirus Disease-2019 (COVID-19) as well as Enterococcus faecalis bacteremia. Imaging revealed a subaortic membrane with aortic valve endocarditis and severe aortic insufficiency. He had successful aortic valve replacement with a mechanical prosthesis and subaortic membrane resection. This case highlights some of the diagnostic and therapeutic challenges presented by COVID-19 pandemic.

Tropical Endomyocardial Fibrosis.

Tropical endomyocardial fibrosis is a common cause of restrictive cardiomyopathy worldwide, but is relatively rare in developed countries. We present a case of tropical endomyocardial fibrosis with right ventricular involvement initially mistaken as Ebstein's anomaly. We highlight the need for timely and accurate diagnosis to ensure appropriate management. (Level of Difficulty: Intermediate.).

Sex Differences in Takotsubo Syndrome: A Narrative Review.

Takotsubo syndrome (TTS), or apical ballooning syndrome, is a transient and usually reversible form of cardiac dysfunction. It has classically been described in women with cardiac susceptibility when exposed to emotional or physical stress. Various hypotheses on the pathophysiology of TTS have been suggested, but the underlying mechanism remains unknown. There is increasing recognition of the sex differences in the presentation, triggers, severity, and complications of TTS. A literature review was conducted and found 75 relevant articles on PubMed Cochrane Library, and Google Scholar from 2001 to 2019 regarding TTS. We found remarkable sex differences existed in the underlying triggers, pathophysiology, illness severity, complications, and mortality. However, no sex differences were identified for baseline transthoracic echocardiogram findings, age at presentation, presenting symptoms, recurrence, and treatment approach. Much information regarding TTS remain lacking, but collaboration of national and international registries will be beneficial in addressing these gaps.

A Curious Case of Coronary Vasospasm with Cardiogenic Shock: Type 1 Kounis Syndrome Complicated by Eosinophilic Myocarditis.

Kounis syndrome is a rare but life-threatening form of coronary vasospasm, defined by the co-occurrence of acute coronary syndrome and hypersensitivity reaction. We present a case of refractory coronary vasospasm with aborted sudden cardiac arrest secondary to type 1 Kounis syndrome, which was complicated by eosinophilic myocarditis and cardiogenic shock. A 29-year-old Hispanic woman with history of vasospastic angina, presented with recurrent episodes of angina at rest. Initial evaluation revealed hyper-eosinophilia, elevated troponin and diffuse ST segment depression on electrocardiogram (ECG). Suddenly, she developed bradycardia and had a sudden cardiac arrest. An urgent coronary angiogram after resuscitation revealed severe multifocal vasospasm which resolved following high doses of intracoronary vasodilators. Type 1 Kounis syndrome was suspected and she was initiated on intravenous corticosteroids and anti-histamines. Subsequently, she developed cardiogenic shock, and a cardiac magnetic resonance imaging (cMRI) showed diffuse subendocardial late gadolinium enhancement (LGE) suggestive of eosinophilic myocarditis. She was diagnosed with type 1 Kounis syndrome associated with eosinophilic myocarditis. Kounis syndrome should be suspected in patients with refractory vasospastic angina. When indicated, coronary angiography should be performed with administration of intracoronary vasodilators for diagnostic and therapeutic purposes. Although, definite diagnosis of eosinophilic myocarditis requires endomyocardial biopsy, cMRI can be a crucial non-invasive method for establishing the diagnosis.

Lactobacillus plantarum 299v Supplementation Improves Vascular Endothelial Function and Reduces Inflammatory Biomarkers in Men With Stable Coronary Artery Disease.

RATIONALE: A strong association has emerged between the gut microbiome and atherosclerotic disease. Our recent data suggest Lactobacillus plantarum 299v (Lp299v) supplementation reduces infarct size in male rats. Limited human data are available on the impact of Lp299v on the vasculature. OBJECTIVE: To determine whether oral Lp299v supplementation improves vascular endothelial function and reduces systemic inflammation in humans with stable coronary artery disease (CAD). METHODS AND RESULTS: Twenty men with stable CAD consumed a drink containing Lp299v (20 billion CFU) once daily for 6 weeks. After a 4-week washout, subjects were given an option of additionally participating in a 10-day study of oral liquid vancomycin (250 mg QID). Vascular endothelial function was measured by brachial artery flow-mediated dilation. Before and after Lp299v, plasma short-chain fatty acids, trimethylamine oxide, and adipokine levels were measured. Additional plasma samples underwent unbiased metabolomic analyses using liquid chromatography/mass spectroscopy. 16S rRNA sequencing was used to determine changes of the stool microbiome. Arterioles from patients with CAD were obtained, and endothelium-dependent vasodilation was measured by video microscopy after intraluminal incubation with plasma from Lp299v study subjects. Lp299v supplementation improved brachial flow-mediated dilation ( P=0.008) without significant changes in plasma cholesterol profiles, fasting glucose, or body mass index. Vancomycin did not impact flow-mediated dilation. Lp299v supplementation decreased circulating levels of IL (interleukin)-8 ( P=0.01), IL-12 ( P=0.02), and leptin ( P=0.0007) but did not significantly change plasma trimethylamine oxide concentrations ( P=0.27). Plasma propionate ( P=0.004) increased, whereas acetate levels decreased ( P=0.03). Post-Lp299v plasma improved endothelium-dependent vasodilation in resistance arteries from patients with CAD ( P=0.02).16S rRNA analysis showed the Lactobacillus genus was enriched in postprobiotic stool samples without other changes. CONCLUSIONS: Lp299v improved vascular endothelial function and decreased systemic inflammation in men with CAD, independent of changes in traditional risk factors and trimethylamine oxide. Circulating gut-derived metabolites likely account for these improvements and merit further study. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov . Unique identifier: NCT01952834.