A Report of the American College of Cardiology Appropriate Use Criteria Task Force, American Academy of Pediatrics, American Heart Association, American Society of Echocardiography, Heart Rhythm ...Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, Society for Cardiovascular Magnetic Resonance, and Society of Pediatric Echocardiography Rating Panel Robert M. Campbell, MD, FACC, FAHA, FAAP, FHRS, Chairlow * Pamela S. Douglas, MD, MACC, FAHA, FASE, Moderatorlow * Louis I. Bezold, MD, FACC, FAAP, FASEdagger William B. Blanchard, MD, FACC, FAHA, FAAPlow * Jeffrey R. Boris, MD, FACClow * Bryan Cannon, MDdouble dagger Gregory J. Ensing, MD, FACC, FASE§ Craig E. Fleishman, MD, FACC, FASE|| Mark A. Fogel, MD, FACC, FAHA, FAAP¶ B. Kelly Han, MD, FACC# Shabnam Jain, MD, MPH, FAAPlow * Mark B. Lewin, MD|| Richard Lockwood, MDlow *low * G. Paul Matherne, MD, MBA, FACC, FAHAdaggerdagger David Nykanen, MD, FACCdouble daggerdouble dagger Catherine L. Webb, MD, FACC, FAHA, FASEdaggerdagger Robert Wiskind, MD, FAAPlow *American College of Cardiology representative.American Academy of Pediatrics representative.Heart Rhythm Society representative.American Society of Echocardiography representative.Society of Pediatric Echocardiography representative.Society for Cardiovascular Magnetic Resonance representative.Society of Cardiovascular Computed Tomography representative.Health Plan representative.American Heart Association representative.Society for Cardiovascular Angiography and Interventions representative.
Summary Background The anti-programmed-death-receptor-1 (PD-1) antibody pembrolizumab has shown potent antitumour activity at different doses and schedules in patients with melanoma. We compared the ...efficacy and safety of pembrolizumab at doses of 2 mg/kg and 10 mg/kg every 3 weeks in patients with ipilimumab-refractory advanced melanoma. Methods In an open-label, international, multicentre expansion cohort of a phase 1 trial, patients (aged ≥18 years) with advanced melanoma whose disease had progressed after at least two ipilimumab doses were randomly assigned with a computer-generated allocation schedule (1:1 final ratio) to intravenous pembrolizumab at 2 mg/kg every 3 weeks or 10 mg/kg every 3 weeks until disease progression, intolerable toxicity, or consent withdrawal. Primary endpoint was overall response rate (ORR) assessed with the Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1) by independent central review. Analysis was done on the full-analysis set (all treated patients with measurable disease at baseline). This study is registered with ClinicalTrials.gov , number NCT01295827. Findings 173 patients received pembrolizumab 2 mg/kg (n=89) or 10 mg/kg (n=84). Median follow-up duration was 8 months. ORR was 26% at both doses—21 of 81 patients in the 2 mg/kg group and 20 of 76 in the 10 mg/kg group (difference 0%, 95% CI −14 to 13; p=0·96). Treatment was well tolerated, with similar safety profiles in the 2 mg/kg and 10 mg/kg groups and no drug-related deaths. The most common drug-related adverse events of any grade in the 2 mg/kg and 10 mg/kg groups were fatigue (29 33% vs 31 37%), pruritus (23 26% vs 16 19%), and rash (16 18% vs 15 18%). Grade 3 fatigue, reported in five (3%) patients in the 2 mg/kg pembrolizumab group, was the only drug-related grade 3 to 4 adverse event reported in more than one patient. Interpretation The results suggest that pembrolizumab at a dose of 2 mg/kg or 10 mg/kg every 3 weeks might be an effective treatment in patients for whom there are few effective treatment options. Funding Merck Sharp and Dohme.
Objective The short-term outcomes were evaluated in patients treated for tricuspid valve endocarditis using a novel extracellular matrix (ECM) cylinder reconstruction technique. Methods Patients with ...clinically significant tricuspid regurgitation whose valves were not repairable by conventional techniques underwent valve replacement with a cylindrical construct sewn out of CorMatrix ECM (CorMatrix Cardiovascular, Roswell, Ga). The cylinders were sized to the native valve dimensions and attached distally to the papillary muscles using polypropylene sutures and ECM pledgets, and proximally to the annulus using a running suture. Patient data were collected retrospectively. Results From November 2011 to October 2013, 12 surgeons performed 19 tricuspid valve cylinder reconstructions in 8 men and 10 women (age range, 19-53 years). Of the 19 patients, 11 had active and 5 had treated endocarditis. One case was robotic-assisted. No deaths occurred, and no new cases of heart block developed. The papillary attachments were disrupted intraoperatively in 1 patient and after 7 days in another; both were successfully revised. A third patient experienced recurrent disruption of the implant at 13 and 22 months and ultimately received a pericardial valve. Fungal infection occurred in 1 cylinder at 6 months; a second ECM cylinder was implanted. Follow-up data were available for 13 patients at 1 to 2 months, 8 at 6 months, and 3 at 12 and 18 months. Other than patients undergoing reoperation, all showed well-functioning tricuspid valves with no to mild regurgitation. Conclusions Cylinder reconstruction with ECM could be a suitable technique for replacing the tricuspid valve while preserving annuloventricular continuity in patients with infective endocarditis not repairable by conventional techniques.
Objective Patients with Marfan syndrome with aortic root aneurysms undergo elective aortic root replacement to avoid the life-threatening outcomes of aortic dissection and emergency repair. The ...long-term implications of failed aortic surveillance leading to acute dissection and emergency repair are poorly defined. We compared the long-term clinical courses of patients with Marfan syndrome who survive emergency versus elective proximal aortic surgery. Methods The Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions Registry is a National Institutes of Health–funded multicenter database and biorepository that enrolls patients with genetically triggered thoracic aortic aneurysms. Of the 635 patients with Marfan syndrome enrolled as of March 2011, 194 had undergone proximal aortic replacement. Patients were grouped according to emergency (n = 47) or elective (n = 147) status at the time of surgery. Results Patients in the emergency group were more likely to have incomplete proximal aortic resection; 83% of emergency procedures included aortic root replacement, compared with 95% of elective procedures. At long-term follow-up (mean, >6 years), the emergency group had a higher incidence of chronic dissection of the distal aorta and significantly larger diameters in distal aortic segments than elective patients. Patients in the emergency group had undergone more operations (1.31 vs 1.11 procedures/patient; P = .01) and had lower activity scores on a health-related quality of life survey. Conclusions For patients with Marfan syndrome, failed aortic surveillance and consequent emergency dissection repair have important long-term implications with regard to the status of the distal aorta, need for multiple procedures, and quality of life. These findings emphasize the importance of aortic surveillance and timely elective aortic root aneurysm repair for patients with Marfan syndrome.
Abstract Hyponatremia is a serious, but often overlooked, electrolyte imbalance that has been independently associated with a wide range of deleterious changes involving many different body systems. ...Untreated acute hyponatremia can cause substantial morbidity and mortality as a result of osmotically induced cerebral edema, and excessively rapid correction of chronic hyponatremia can cause severe neurologic impairment and death as a result of osmotic demyelination. The diverse etiologies and comorbidities associated with hyponatremia pose substantial challenges in managing this disorder. In 2007, a panel of experts in hyponatremia convened to develop the Hyponatremia Treatment Guidelines 2007: Expert Panel Recommendations that defined strategies for clinicians caring for patients with hyponatremia. In the 6 years since the publication of that document, the field has seen several notable developments, including new evidence on morbidities and complications associated with hyponatremia, the importance of treating mild to moderate hyponatremia, and the efficacy and safety of vasopressin receptor antagonist therapy for hyponatremic patients. Therefore, additional guidance was deemed necessary and a panel of hyponatremia experts (which included all of the original panel members) was convened to update the previous recommendations for optimal current management of this disorder. The updated expert panel recommendations in this document represent recommended approaches for multiple etiologies of hyponatremia that are based on both consensus opinions of experts in hyponatremia and the most recent published data in this field.
Abstract Background To determine the predictive value of volumetrically measured lung perfusion defects (PDvol) and right ventricular dysfunction on dual-energy computed tomography angiography ...(DE-CTA) for predicting all cause mortality in patients suspected of pulmonary embolism (PE) but without evident thromboembolic clot on CTA. Methods 448 patients underwent DE-CTA on a 64-channel DSCT system between January 2007 and December 2012 for suspected PE, of which 115 were without detectable thromboembolic clot on CTA. Diagnostic performance for identifying patients at risk of dying was evaluated using ROC analysis. All-cause mortality was assessed via the hospital electronic medical records and/or consultation of the patient or the patient's primary care physician via phone call interviews. Sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and area under the curve (AUC) were determined for PDvol (volume of perfusion defects/total lung volume), transverse right ventricular to left ventricular diameter ratios (RV/LV) and for the combination of both tests. Results Mortality was 38% within the investigated time period of 6 months. Patients who died had significantly higher PDvol (PDvol 28 ± 13% vs. 19 ± 12%, p < 0.001) and a non-significant difference in transverse RV/LV ratio (1.14 ± 0.37 vs. 1.06 ± 0.22, p = 0.159). The AUC was 0.71 for PDvol, 0.53 for RV/LV ratio, and 0.67 for the combination of PDvol and RV/LV ratio. PDvol remained a significant predictor after correcting for age. Conclusions In the absence of thromboembolic clots, PDvol at DE-CTA appears to be predictive for all cause mortality.
Between 43,000 and 47,000 people die annually in the United States from diseases of the aorta and its branches and continues to increase. For the thoracic aorta, these diseases are increasingly ...treated by stent-grafting. No prospective randomized study exists comparing stent-grafting and open surgical treatment, including for disease subgroups. Currently, one stent-graft device is approved by the Food and Drug Administration for descending thoracic aortic aneurysms although two new devices are expected to obtain FDA approval in 2008. Stent-graft devices are used “off label” or under physician Investigational Device Exemption studies for other indications such as traumatic rupture of the aorta and aortic dissection. Early first-generation devices suffered from problems such as stroke with insertion, ascending aortic dissection or aortic penetration from struts, vascular injury, graft collapse, endovascular leaks, graft material failure, continued aneurysm expansion or rupture, and migration or kinking; however, the newer iterations coming to market have been considerably improved. Although the devices have been tested in pulse duplicators out to 10 years, long-term durability is not known, particularly in young patients. The long-term consequences of repeated computed tomography scans for checking device integrity and positioning on the risk of irradiation-induced cancer remains of concern in young patients. This document (1) reviews the natural history of aortic disease, indications for repair, outcomes after conventional open surgery, currently available devices, and insights from outcomes of randomized studies using stent-grafts for abdominal aortic aneurysm surgery, the latter having been treated for a longer time by stent-grafts; and (2) offers suggestions for treatment.
Noninvasive fractional flow reserve (FFR) from coronary computed tomography angiography (cCTA) correlates well with invasive FFR and substantially improves the detection of obstructive coronary ...artery disease. However, with current algorithms, computed tomography (CT)–based FFR is derived off-site in an involved time-consuming manner. We sought to investigate the diagnostic performance of a novel CT-based FFR algorithm, developed for time-efficient in-hospital evaluation of hemodynamically indeterminate coronary lesions. In a blinded fashion, CT-based FFR was assessed in 67 coronary lesions of 53 patients. Pressure guidewire–based FFR <0.80 served as the reference standard to define hemodynamically significant stenosis and assess the diagnostic performance of CT-based FFR compared with standard evaluation of cCTA (luminal diameter stenosis of ≥50%). We recorded the time needed for derivation of CT-based FFR. On a per-lesion and per-patient basis, CT-based FFR resulted in a sensitivity of 85% and 94%, a specificity of 85% and 84%, a positive predictive value of 71% and 71%, and a negative predictive value of 93% and 97%, respectively. The area under the receiver operating characteristic curve on a per-lesion basis was significantly greater for CT-based FFR compared with standard evaluation of cCTA (0.92 vs 0.72, p = 0.0049). A similar trend, albeit not statistically significant, was observed on per-patient analysis (0.91 vs 0.78, p = 0.078). Mean total time for CT-based FFR was 37.5 ± 13.8 minutes. In conclusion, the CT-based FFR algorithm evaluated here outperforms standard evaluation of cCTA for the detection of hemodynamically significant stenoses while allowing on-site application within clinically viable time frames.
Objectives The ORBIT II (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions) trial evaluated the safety and efficacy of the coronary Orbital Atherectomy System ...(OAS) to prepare de novo, severely calcified coronary lesions for stent placement. Background Despite advances in interventional techniques, treatment of calcified coronary lesions remains a challenge. Stent placement in these lesions may result in stent underexpansion, malapposition, and procedural complications. Methods ORBIT II is a prospective, multicenter, nonblinded clinical trial that enrolled 443 consecutive patients with severely calcified coronary lesions at 49 U.S. sites from May 25, 2010, to November 26, 2012. Investigators used the centrifugal action of the OAS diamond-coated crown to modify calcified lesions prior to stent placement. Results The pre-procedure mean minimal lumen diameter of 0.5 mm increased to 2.9 mm after the procedure. The primary safety endpoint was 89.6% freedom from 30-day major adverse cardiac events compared with the performance goal of 83%. The primary efficacy endpoint (residual stenosis <50% post-stent without in-hospital major adverse cardiac events) was 88.9% compared with the performance goal of 82%. Stent delivery occurred successfully in 97.7% of cases with <50% stenosis in 98.6% of subjects. Low rates of in-hospital Q-wave myocardial infarction (0.7%), cardiac death (0.2%), and target vessel revascularization (0.7%) were reported. Conclusions The ORBIT II coronary OAS trial met both the primary safety and efficacy endpoints by significant margins. Preparation of severely calcified plaque with the OAS not only helped facilitate stent delivery, but improved both acute and 30-day clinical outcomes compared with the outcomes of historic control subjects in this difficult-to-treat patient population. (Evaluate the Safety and Efficacy of OAS in Treating Severely Calcified Coronary Lesions ORBIT II; NCT01092416 )
Background Mutations in signal transducer and activator of transcription (STAT) 1 cause a broad spectrum of disease, ranging from severe viral and bacterial infections (amorphic alleles) to mild ...disseminated mycobacterial disease (hypomorphic alleles) to chronic mucocutaneous candidiasis (CMC; hypermorphic alleles). The hypermorphic mutations are also associated with arterial aneurysms, autoimmunity, and squamous cell cancers. Objective We sought to investigate the role of STAT1 gain-of-function mutations in phenotypes other than CMC. Methods We initially screened patients with CMC and autoimmunity for STAT1 mutations. We functionally characterized mutations in vitro and studied immune profiles and regulatory T (Treg) cells. After our initial case identifications, we explored 2 large cohorts of patients with wild-type forkhead box protein 3 and an immune dysregulation–polyendocrinopathy–enteropathy–X-linked (IPEX)–like phenotype for STAT1 mutations. Results We identified 5 children with polyendocrinopathy, enteropathy, and dermatitis reminiscent of IPEX syndrome; all but 1 had a variety of mucosal and disseminated fungal infections. All patients lacked forkhead box protein 3 mutations but had uniallelic STAT1 mutations (c.629 G>T, p.R210I; c.1073 T>G, p.L358W, c.796G>A; p.V266I; c.1154C>T, T385M 2 patients). STAT1 phosphorylation in response to IFN-γ, IL-6, and IL-21 was increased and prolonged. CD4+ IL-17–producing T-cell numbers were diminished. All patients had normal Treg cell percentages in the CD4+ T-cell compartment, and their function was intact in the 2 patients tested. Patients with cells available for study had normal levels of IL-2–induced STAT5 phosphorylation. Conclusions Gain-of-function mutations in STAT1 can cause an IPEX-like phenotype with normal frequency and function of Treg cells.
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