Posttraumatic Stress Disorder After Spontaneous Coronary Artery Dissection: A Report of the International Spontaneous Coronary Artery Dissection Registry.

BACKGROUND: Myocardial infarction secondary to spontaneous coronary artery dissection (SCAD) can be traumatic and potentially trigger posttraumatic stress disorder (PTSD). In a large, multicenter, registry-based cohort, we documented prevalence of lifetime and past-month SCAD-induced PTSD, as well as related treatment seeking, and examined a range of health-relevant correlates of SCAD-induced PTSD. METHODS AND RESULTS: Patients with SCAD were enrolled in the iSCAD (International SCAD) Registry. At baseline, site investigators completed medical report forms, and patients reported demographics, medical/SCAD history, psychosocial factors (including SCAD-induced PTSD symptoms), health behaviors, and health status via online questionnaires. Of 1156 registry patients, 859 patients (93.9% women; mean age, 52.3 years) completed questionnaires querying SCAD-induced PTSD. Nearly 35% (n=298) of patients met diagnostic criteria for probable SCAD-induced PTSD in their lifetime, and 6.4% (n=55) met criteria for probable past-month PTSD. Of 811 patients ever reporting any SCAD-induced PTSD symptoms, 34.8% indicated seeking treatment for this distress. However, 46.0% of the 298 patients with lifetime probable SCAD-induced PTSD diagnoses reported never receiving trauma-related treatment. Younger age at first SCAD, fewer years since SCAD, being single, unemployed status, more lifetime trauma, and history of anxiety were associated with greater past-month PTSD symptom severity in multivariable regression models. Greater past-month SCAD-induced PTSD symptoms were associated with greater past-week sleep disturbance and worse past-month disease-specific health status when adjusting for various risk factors. CONCLUSIONS: Given the high prevalence of SCAD-induced PTSD symptoms, efforts to support screening for these symptoms and connecting patients experiencing distress with empirically supported treatments are critical next steps. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04496687.

Non-atherosclerotic acute cardiac syndromes: spontaneous coronary artery dissection and Takotsubo syndrome. Comparison of long-term clinical outcomes.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) and Takotsubo syndrome (TTS) constitute two common causes of nonatherosclerotic acute cardiac syndrome particularly frequent in women. Currently, there is no information comparing long-term clinical outcomes in unselected patients with these conditions. METHODS: We compared the baseline characteristics, in-hospital outcomes, and the 12-month and long-term clinical outcomes of two large prospective registries on SCAD and TTS. RESULTS: A total of 289 SCAD and 150 TTS patients were included; 89% were women. TTS patients were older with a higher prevalence of cardiovascular risk factors. Precipitating triggers were more frequent in TTS patients, while emotional triggers and depressive disorders were more common in the SCAD group. Left ventricular ejection fraction was lower in TTS patients, but SCAD patients showed higher cardiac biomarkers. In-hospital events (43.3% vs. 5.2%, P <0.01) occurred more frequently in TTS patients. TTS patients also presented more frequent major adverse events at 12-month (14.7% vs. 7.1%, HR 5.3, 95% CI: 2.4-11.7, P <0.01) and long-term (median 36 vs. 31 months, P =0.41) follow-up (25.8% vs. 9.6%, HR 4.5, 95% CI: 2.5-8.2, P <0.01). Atrial fibrillation was also more frequent in TTS patients. Moreover, TTS patients presented a higher 12-month and long-term mortality (5.6% vs. 0.7%, P =0.01; and 12.6% vs. 0.7%, P <0.01) mainly driven by noncardiovascular deaths. CONCLUSION: Compared to SCAD, TTS patients are older and present more cardiovascular risk factors but less frequent depressive disorder or emotional triggers. TTS patients have a worse in-hospital, mid-term, and long-term prognosis with higher noncardiac mortality than SCAD patients.

Twenty-five-year trends in incidence, angiographic appearance, and management of spontaneous coronary artery dissection.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) has been described as an infrequent cause of acute coronary syndrome (ACS). Knowledge about the disease is still limited and SCAD might still be underdiagnosed. OBJECTIVES: Trends in incidence, presentation, angiographic appearance, management, and outcomes of SCAD over 25 years were analyzed. METHODS: Patients with SCAD between 1997 and 2021 at the University Hospital Zurich, Switzerland, were included. Incidences were assessed as total numbers and proportions of ACS cases. Clinical data were collected from medical records and angiographic findings were reviewed. Major adverse cardiac events (MACE) were defined as the composite of all-cause death, cardiac arrest, SCAD recurrence or progression, other myocardial infarction, and stroke. RESULTS: One hundred fifty-six SCAD cases were included in this study. The incidence increased significantly in total (p < 0.001) and relative to ACS cases (p < 0.001). This was based on an increase of shorter lesions (p = 0.004), SCAD type 2 (p < 0.001), and lesions in side branches (p = 0.014), whereas lesions in the left main coronary artery and proximal segments were decreasing (p-values 0.029 and < 0.001, respectively). There was an increase in conservative therapy (p < 0.001). The rate of MACE (24%) was stable, however, there was a reduced proportion of patients with a need for intensive care treatment (p = 0.017). CONCLUSIONS: SCAD represents an important entity of ACS that still might be underappreciated. The increasing incidence of SCAD is likely based on better awareness and familiarity with the disease. A lower need for intensive care treatment suggests positive effects of the increasing implementation of conservative management.

Spontaneous Coronary Artery Dissection Across the Health Care Pathway: A National, Multicenter, Patient-Informed Investigation.

BACKGROUND: Clinical practice guidelines for the management and convalescence of patients with spontaneous coronary artery dissection (SCAD) have yet to be developed. The targeted content, delivery, and outcomes of interventions that benefit this population remain unclear. Patient-informed data are required to substantiate observational research and provide evidence to inform and standardize clinical activities. METHODS AND RESULTS: Patients diagnosed with SCAD (N=89; 86.5% women; mean age, 53.2 years) were purposively selected from 5 large tertiary care hospitals. Patients completed sociodemographic and medical questionnaires and participated in an interview using a patient-piloted semistructured interview guide. Interviews were transcribed and subjected to framework analysis using inductive and then deductive coding techniques. Approximately 1500 standard transcribed pages of interview data were collected. Emotional distress was the most commonly cited precipitating factor (56%), with an emphasis on anxiety symptoms. The awareness and detection of SCAD as a cardiac event was low among patients (35%) and perceived to be moderate among health care providers (55%). Health care providers' communication of the prognosis and self-management of SCAD were perceived to be poor (79%). Postevent psychological disorders among patients were evident (30%), and 73% feared recurrence. Short- and longer-term follow-up that was tailored to patients' needs was desired (72%). Secondary prevention programming was recommended, but there were low completion rates of conventional cardiac rehabilitation (48%), and current programming was deemed inadequate. CONCLUSIONS: This early-stage, pretrial research has important implications for the acute and long-term management of patients with SCAD. Additional work is required to validate the hypotheses generated from this patient-oriented research.

Venous compression syndromes in females: A descriptive review.

Venous compression syndromes have been described, yet the role of sex is poorly understood. Although iliac vein compression has been discussed more often with the advent of newer technologies, research has fallen short on defining epidemiology, best practices for evaluation and treatment, and differences in responses to treatment between men and females. The authors report on iliac vein compression, nonthrombotic renal vein compression, and other venous compression syndromes in females. Literature searches of PubMed were performed using the following keywords: females/females and May Thurner, venous stenting, venous outcomes, deep venous disease, deep venous compression, venous stenting, renal vein compression, renal vein surgery/stent, popliteal vein entrapment, venous thoracic vein entrapment, and popliteal vein entrapment. The articles prompted the authors to research further as the referenced articles were reviewed. Sex representation has not been addressed adequately in the research of venous compression syndromes, making the discussion of best treatment options and long-term outcomes difficult. More specific understanding of epidemiology and response to interventions will only come from research that addresses these issues directly, understanding that some of these syndromes occur rarely.

The Patient Experience After Spontaneous Coronary Artery Dissection.

OBJECTIVE: There is considerable burden of anxiety, depression, and post-traumatic stress disorder in patients with spontaneous coronary artery dissection (SCAD), yet research is limited on the experience and impact of SCAD from the patient perspective. This literature review sought to describe the current state of the literature on the patient experience of SCAD and consequences for patients following a SCAD event from the patient perspective. To better understand how people's experiences of SCAD affect their wellbeing, quality of life, lifestyles, and identity, and what would be useful from the patient perspective, an integrative review was performed. METHODS: An integrative literature review was conducted to understand the experience of SCAD and the post-event implications. Five databases were searched. Search terms included 'spontaneous coronary artery dissection', 'SCAD', 'patient', 'experience', 'perspective', and 'opinion'. English-language, peer-reviewed primary research in people with a diagnosis of SCAD that reflected the patient experience was included. Data indicating the SCAD experience including distress prevalence were extracted into an Excel spreadsheet, and narrative synthesis of included studies followed. FINDINGS: From 325 identified studies, five were included for review, yielding a combined sample of 447 participants. Patients with SCAD reported a lack of information about SCAD and the recovery process, and use of the internet for obtaining information. Patients with SCAD reported challenges in recovery including anxiety associated with fear of recurrence and uncertainty, and a need for greater support. A wide range of negative emotions was reported during and after the SCAD event. Participants reported participating in support groups, with mixed reviews of their appropriateness and effectiveness.

[French National registry of spontaneous coronary artery dissections : ''DISCO registry'']. / Registre national des dissections coronaires spontanées : le registre DISCO.

AIM: Spontaneous coronary artery dissection (SCAD) is a form of acute coronary syndrome (ACS). The aim of this registry is to assess the clinical and angiographic features of SCAD, to describe the therapeutic management and prognosis, and to identify links with other vascular diseases. METHOD: From 2016 to 2018, 424 patients with a diagnosis of SCAD were included prospectively and retrospectively in 51 French cardiology centres. RESULTS: 373 patients with confirmed SCAD were included. The mean age was 51.5±10.3 years with 90.6% women. 54.7% of patients had <2 cardiovascular risk factors. ACS occurred in 96.2% of patients. 84.2% of patients were managed conservatively, 15.5% interventionally and 0.3% surgically. At 1-year follow-up, recurrence of SCAD occurred in 3.3%. No deaths occurred. The association with fibro-muscular dysplasia was found in 45% of cases and genetic analysis confirmed a strong relationship between the occurrence of SCAD and gene variations at the PHACTR1 locus. CONCLUSION: The DISCO registry is the largest European cohort of SCAD. It confirms that this disease mainly affects young women with few cardiovascular risk factors, and that there is a strong association with the presence of fibromuscular dysplasia (45%). Conservative management should be preferred, with a favourable prognosis (no deaths at 1 year; recurrence rate of 3.3%).

Characteristics and treatment of nonagenarian patients with vascular disease admitted to internal medicine services. NONAVASC-2 registry.

INTRODUCTION: Vascular disease (VD) is the most frequent cause of morbidity and mortality and its prevalence increases with age. Old patients are not included in studies on VD, their characteristics and treatments being unknown. OBJECTIVE: Know the clinical characteristics of nonagenarian patients hospitalized in Internal Medicine services with a diagnosis of established VD and the adequacy of their pharmacological management. MATERIAL AND METHODS: The NONAVASC-2 registry is an observational, prospective, multicentre study. Hospitalized patients for any cause were included. Data collection was carried out through an anonymous online database with sociodemographic, clinical, analytical, therapeutic and evolutionary parameters. RESULTS: One thousand forty-nine patients with a mean age of 93.14 years (57.8% women) were included. The prevalence of risk factors and VD was high: hypertension (84.9%), dyslipidemia (50.9%) and diabetes mellitus (29.4%). 33.4% presented severe-total dependency. 82.9% received antithrombotic treatment (53.7% antiplatelets, 25.4% anticoagulation and 3.8% double therapy). Only 38.2% received statins. The percentage of severe dependence (39.2% vs 24.1%; p = 0.00) and severe cognitive impairment (30.8% vs 13.8%; p = 0.00) was significantly higher among patients who did not receive them. 19% died during admission. CONCLUSIONS: Nonagenarian patients with VD present high comorbidity, dependence and mortality. Despite being in secondary prevention, 17% did not receive antithrombotics and only 38% received statins. The underprescription is conditioned, among other factors, by the functional status. More studies are necessary to determine the impact of this issue on their prognosis.

[Knowledge of chronic venous disease among healthcare professionals in Spain]. / Conocimiento de la enfermedad venosa crónica en los profesionales sanitarios en España.

INTRODUCTION: Chronic venous disease (CVD) is classified as the most prevalent vascular disease in humans. It has been associated with an increased incidence of cardiovascular diseases and is a strong predictor of all-cause mortality, representing a public health problem of the first magnitude. The objective of this study was to analyze the actions in the management of CVD in the daily clinical practice of health professionals in Spain. MATERIAL AND METHODS: Observational, descriptive and cross-sectional study with data collection through an opinion survey of 22 questions completed electronically through a Google® form for professionals involved in chronic venous disease care. Three hundred surveys were analyzed. The quantitative variables were represented with means and standard deviation and the qualitative ones with percentages and confidence intervals. RESULTS: Three hundred surveys analyzed. 65.3% were women. The most participatory age group was over 55 years of age. 85% of those surveyed considered that CVD is an underdiagnosed and undertreated disease, with an added negative impact in terms of follow-up during the Covid-19 pandemic, since 91.7% considered that it had not been adequate. 47% of the participants did not know the CEAP classification and 56.3% did not know the venous clinical severity scale (VCSS). 92.7% of physicians prescribed compression stockings and 74.7% phlebotonic drugs. Hidrosmine was the best known and most prescribed venoactive drug (51.7%). 73% of the doctors recognized that they did not use any algorithm or protocol for the diagnosis, treatment and monitoring of CVD in their usual clinical practice and 91% stated that they were not trained in their workplaces. 54.3% of the physicians believed that one of the main limitations that made follow-up of the disease difficult was the lack of coordination with the vascular surgeons. CONCLUSIONS: Updating and responding to the training needs of professionals regarding CVD is essential to guarantee quality care continuity in the care of our patients.

Prevalence, management and efficacy of treatment in portal vein obstruction after paediatric liver transplantation: protocol of the retrospective international multicentre PORTAL registry.

INTRODUCTION: Portal vein obstruction (PVO) consists of anastomotic stenosis and thrombosis, which occurs due to a progression of the former. The aim of this large-scale international study is to assess the prevalence, current management practices and efficacy of treatment in patients with PVO. METHODS AND ANALYSIS: The Portal vein Obstruction Revascularisation Therapy After Liver transplantation registry will facilitate an international, retrospective, multicentre, observational study, with 25 centres around the world already actively involved. Paediatric patients (aged <18 years) with a diagnosed PVO between 1 January 2001 and 1 January 2021 after liver transplantation will be eligible for inclusion. The primary endpoints are the prevalence of PVO, primary and secondary patency after PVO intervention and current management practices. Secondary endpoints are patient and graft survival, severe complications of PVO and technical success of revascularisation techniques. ETHICS AND DISSEMINATION: Medical Ethics Review Board of the University Medical Center Groningen has approved the study (METc 2021/072). The results of this study will be disseminated via peer-reviewed publications and scientific presentations at national and international conferences. TRIAL REGISTRATION NUMBER: Netherlands Trial Register (NL9261).

Cutaneous lupus erythematosus is associated with an increased risk of cardiac and vascular diseases: a large-scale, propensity-matched global retrospective cohort study.

BACKGROUND: Autoimmune skin diseases can expedite various systemic sequelae involving other organs. Although limited to the skin, cutaneous lupus erythematosus (CLE) was noted to be associated with thromboembolic diseases. However, small cohort sizes, partially discrepant outcomes, missing data on CLE subtypes, and incomplete risk assessment limits these findings. METHODS: The Global Collaborative Network of TriNetX provides access to medical records of more than 120 million patients worldwide. We used TriNetX to elucidate the risk for cardiac and vascular diseases after diagnosis of CLE, and its subtypes chronic discoid (DLE) and subacute cutaneous lupus erythematosus (SCLE). We included 30,315 CLE, 27,427 DLE, and 1613 SCLE patients. We performed propensity-matched cohort studies determining the risk to develop cardiac and vascular diseases (ICD10CM:I00-99) following diagnosis of CLE, DLE, or SCLE. Patients with systemic lupus erythematosus were excluded. FINDINGS: We document that CLE and its subtype DLE but less so SCLE are associated with a higher risk for various cardiac and vascular diseases. This included predominantly thromboembolic events such as pulmonary embolism, cerebral infarction, and acute myocardial infarction, but also peripheral vascular disease and pericarditis. For example, the hazard ratio of arterial embolism and thrombosis was 1.399 (confidence interval: 1.230-1.591, p < 0.0001) following CLE diagnosis. The study is limited by retrospective data collection and reliance on ICD10-disease classification. INTERPRETATION: CLE and its major subtype DLE are associated with an increased risk for the development of a wide range of cardiac and vascular diseases. FUNDING: This research was funded by Deutsche Forschungsgemeinschaft (EXC 2167, CSSL/CS01-2022) and the Excellence-Chair Program of the State of Schleswig-Holstein.

Derivation and Validation of Spontaneous Coronary Artery Dissection Prediction Score in Patients With Myocardial Infarction.

Spontaneous coronary artery dissection (SCAD) is an important cause of acute myocardial infarction (AMI); however, the prevalence of SCAD and its predictors in AMI are unknown. We sought to derive and validate a simple score that can help predict SCAD in patients with AMI. We analyzed the Nationwide Readmissions Database and created a risk score for SCAD in patients with an index hospitalization for AMI. We used a multivariate logistic regression analysis to determine the independent predictors of SCAD, and each was assigned points proportional to its regression coefficient. Among 1,155,164 patients with AMI, 8,630 (0.75%) had SCAD. Based on the derivation cohort, the independent predictors of SCAD were fibromuscular dysplasia (odds ratio [OR] 67.0, 95% confidence interval [CI] 42.0 to 107.9, p <0.01), Marfan or Ehlers-Danlos syndrome (OR 4.7, 95% CI 1.7 to 12.5, p <0.01), polycystic ovarian syndrome (OR 5.4, 95% CI 3.0 to 9.8, p <0.01), female gender (OR 1.99, 95% CI 1.9 to 2.1, p <0.01), and aortic aneurysm (OR 1.41, 95% CI 1.1 to 1.7, p <0.01). The SCAD risk score included fibromuscular dysplasia (5 points), Marfan or Ehlers-Danlos syndrome (2 points), polycystic ovarian syndrome (2 points), female gender (1 point), and aortic aneurysm (1 point). The C-statistics of the score were 0.58 (derivation cohort) and 0.61 (validation cohort). In conclusion, the SCAD score is an easy bedside clinical tool that can help clinicians identify patients with AMI who are at risk for SCAD.

Precipitating factors in patients with spontaneous coronary artery dissection: Clinical, laboratoristic and prognostic implications.

BACKGROUND: Spontaneous coronary artery dissection (SCAD) often presents with acute coronary syndrome and underlying pathophysiology involves the interplay between predisposing factors and precipitating stressors, such as emotional and physical triggers. In our study we sought to compare clinical, angiographic and prognostic features in a cohort of patients with SCAD according to the presence and type of precipitating stressors. METHODS: Consecutive patients with angiographic evidence of SCAD were divided into three groups: patients with emotional stressors, patients with physical stressors and those without any stressor. Clinical, laboratoristic and angiographic features were collected for each patient. The incidence of major adverse cardiovascular events, recurrent SCAD and recurrent angina was assessed at follow-up. RESULTS: Among the total population (64 subjects), 41 [64.0%] patients presented with precipitating stressors, including emotional triggers (31 [48.4%] subjects) and physical efforts (10 [15.6%] subjects). As compared with the other groups, patients with emotional triggers were more frequently female (p = 0.009), had a lower prevalence of hypertension (p = 0.039] and dyslipidemia (p = 0.039), were more likely to suffer from chronic stress (p = 0.022) and presented with higher levels of C-reactive protein (p = 0.037) and circulating eosinophils cells (p = 0.012). At a median follow-up of 21 [7; 44] months, patients with emotional stressors experienced higher prevalence of recurrent angina (p = 0.025), as compared to the other groups. CONCLUSIONS: Our study shows that emotional stressors leading to SCAD may identify a SCAD subtype with specific features and a trend towards a worse clinical outcome.

Spontaneous Coronary Artery Dissection: A Review of Epidemiology, Pathophysiology and Principles of Management.

Spontaneous coronary artery dissection (SCAD) is a sudden rupture of coronary artery wall leading to false lumen and intramural hematoma formation. It commonly occurs in young and middle-aged women lacking typical cardiovascular risk factors. Fibromuscular dysplasia and pregnancy are strongly associated with SCAD. To date, the "inside-out" and "outside-in" are the 2 proposed hypothesis for the pathogenesis of SCAD. Coronary angiography is the gold standard and first line diagnostic test. Three types of SCAD have been described according to coronary angiogram. Intracoronary imaging modalities are reserved for patients with ambiguous diagnosis or to guide percutaneous coronary intervention view the increased risk of secondary iatrogenic dissection. The management of SCAD includes conservative approach, coronary revascularization strategies accounting for percutaneous coronary intervention and coronary artery bypass graft, and long-term follow-up. The overall prognosis of patients with SCAD is favorable marked by a spontaneous healing in a large proportion of cases.

Treatment strategy for spontaneous coronary artery dissection based on anatomical characteristics.

OBJECTIVES: To compare the clinical and angiographic characteristics of high-risk and low-risk spontaneous coronary artery dissection (SCAD) patients to determine the optimal treatment strategy. BACKGROUND: SCAD is a rare and emerging cause of acute coronary syndrome and sudden cardiac death, especially in young female patients. However, the indication of percutaneous coronary intervention (PCI) in patients with SCAD remains elusive. METHODS: We evaluated the clinical and angiographic characteristics of all SCAD patients admitted to our center from 2012 to 2020. The outcomes of the high-risk and low-risk SCAD patients according to the location of the lesion segment with dissection or intramural hematoma were compared. Further analyses were performed to evaluate the vessel healing or residual dissection in the patients receiving the follow-up angiography. RESULTS: A total of 81 SCAD patients were enrolled in the present study, in which 38 patients were categorized as high-risk group, defined as involvement of the left main artery or proximal segment of any main coronary artery. PCI was the more common treatment approach in the high-risk group (68.4%), while conservative treatment was more common in the low-risk group (62.8%). The incidence of major adverse cardiac events, defined as cardiac death, myocardial infarction, unstable angina pectoris, severe arrhythmias, or heat failure, within 1 year follow-up was similar between the two groups. 57 patients (70.4%) received the follow-up angiography after 1 year. The high- and low-risk groups had a similar rate of vessel healing among the PCI treatment patients. However, more patients achieved spontaneous healing in the low-risk group than the high-risk group among the conservative treatment patients (86.4% vs. 33.3%, p < 0.05). CONCLUSIONS: Conservative management remains the recommended treatment strategy for the low-risk SCAD patients. PCI could be considered in high-risk SCAD patients with favorable clinical outcomes and vessel healing. Characterization of lesion anatomy may be an important indicator for treatment decision.

Clinical characteristics and outcomes of patients with takotsubo syndrome versus spontaneous coronary artery dissection.

BACKGROUND: Takotsubo syndrome (TTS) and spontaneous coronary artery dissection (SCAD) are now increasingly recognized. Both conditions predominantly affect females; however, the exact pathophysiology remains unclear. Large multi-center databases can help elucidate the underlying mechanism and optimize treatments to improve outcomes by allowing us to compare features and outcomes of patients with TTS and patients with SCAD. METHODS: Takotsubo syndrome patients were enrolled from the International Takotsubo Registry and compared to SCAD patients from the Canadian Spontaneous Coronary Artery Dissection Cohort Study. In total 2098 TTS patients and 750 SCAD patients were included in the present study. RESULTS: More than 85% of patients in both groups were females. TTS patients were older compared to SCAD patients. Physical triggers were more common in TTS patients, while emotional triggers and non-identifiable triggering events were more common in SCAD patients. Left ventricular ejection fraction was more impaired in TTS compared to SCAD. TTS patients had more major cardiovascular risk factors, while SCAD patients had a higher rate of migraines and anxiety disorders than TTS patients. Thirty-day mortality was significantly higher in TTS patients, while 30-day stroke rates were comparable between groups. CONCLUSIONS: These findings suggest that women are at higher risk for TTS and SCAD compared to men, which should be considered in the differential diagnosis of those presenting with acute coronary syndrome. Additionally, emotional stressors play a significant role in triggering events particularly in younger women suffering from SCAD. The present findings may help clinicians better differentiate these two entities and aid in the appropriate risk stratification, diagnosis, and management. TRIAL REGISTRATION: ClinicalTrials.gov no. NCT01947621.