Background Fractional flow reserve (FFR) measured by coronary computed tomography angiography (FFRCT ) has been validated against invasive FFR. However, there are no data on how the use of FFRCT ...affects patient care and outcomes. The aim of this study is to compare standard practice guided by usual care testing to FFRCT -guided management in symptomatic subjects with suspected coronary artery disease (CAD). Methods In this prospective nonrandomized trial, symptomatic patients with suspected CAD will be enrolled in 2 consecutive cohorts: a usual care-guided pathway (cohort 1) and an FFRCT -guided pathway (cohort 2). Each cohort is divided into 2 groups according to whether noninvasive or invasive diagnostic testing was planned before enrollment. In all subjects, the patient's clinical team will review all diagnostic test results and determine a treatment strategy. A total sample size of 580 subjects will be enrolled and followed up for 12 months. Results The primary end point is the comparison of the percentage of patients with planned invasive testing who have a catheterization (invasive coronary angiography) within 90 days from initial assessment, which does not show a significant stenosis (defined as coronary artery stenosis >50% or invasive FFR ≤0.80). Secondary end points include the rate of invasive coronary angiography without obstructive CAD in those with planned noninvasive testing and, in all groups, noninferiority of resource use, quality of life, medical radiation exposure, and major adverse cardiac events up to 365 days of follow-up. Conclusions The study compares clinical and economic outcomes based on diagnostic evaluation using FFRCT with that based on standard diagnostic strategies
The PROXIMAL Trial: Proximal Protection During Saphenous Vein Graft Intervention Using the Proxis Embolic Protection System: A Randomized, Prospective, Multicenter Clinical Trial Laura Mauri, David ...Cox, James Hermiller, Joseph Massaro, Joyce Wahr, Sew Wah Tay, Michael Jonas, Jeffrey J. Popma, Jim Pavliska, Dennis Wahr, Campbell Rogers We compared an embolic protection device placed proximal to the target lesion to distal embolic protection devices in 594 patients undergoing saphenous vein graft stenting. Intention-to-treat analysis showed that the composite of death, myocardial infarction, or target vessel revascularization at 30 days occurred in 9.2% of the test arm (proximal protection when possible, distal when not) and 10.0% of the control arm (distal protection when possible); noninferiority p = 0.0061. A treatment strategy that included proximal embolic protection whenever possible during treatment of saphenous vein graft lesions produced outcomes similar to those observed with a strategy using only distal embolic protection.
Abstract Background Coronary computed tomographic angiography (CTA) plus estimation of fractional flow reserve using CTA (FFRCT ) safely and effectively guides initial care over 90 days in patients ...with stable chest pain. Longer-term outcomes are unknown. Objectives The study sought to determine the 1-year clinical, economic, and quality-of-life (QOL) outcomes of using FFRCT instead of usual care. Methods Consecutive patients with stable, new onset chest pain were managed by either usual testing (n = 287) or CTA (n = 297) with selective FFRCT (submitted in 201, analyzed in 177); 581 of 584 (99.5%) completed 1-year follow-up. Endpoints were adjudicated major adverse cardiac events (MACE) (death, myocardial infarction, unplanned revascularization), total medical costs, and QOL. Results Patients averaged 61 years of age with a mean 49% pre-test probability of coronary artery disease. At 1 year, MACE events were infrequent, with 2 in each arm of the planned invasive group and 1 in the planned noninvasive cohort (usual care strategy). In the planned invasive stratum, mean costs were 33% lower with CTA and selective FFRCT ($8,127 vs. $12,145 usual care; p < 0.0001); in the planned noninvasive stratum, mean costs did not differ when using an FFRCT cost weight of zero ($3,049 FFRCT vs. $2,579; p = 0.82), but were higher when using an FFRCT cost weight equal to CTA. QOL scores improved overall at 1 year (p < 0.001), with similar improvements in both groups, apart from the 5-item EuroQOL scale scores in the noninvasive stratum (mean change of 0.12 for FFRCT vs. 0.07 for usual care; p = 0.02). Conclusions In patients with stable chest pain and planned invasive coronary angiography, care guided by CTA and selective FFRCT was associated with equivalent clinical outcomes and QOL, and lower costs, compared with usual care over 1-year follow-up. (The PLATFORM Study: Prospective LongitudinAl Trial of FFRct: Outcome and Resource IMpacts PLATFORM; NCT01943903 )
Abstract Background Fractional flow reserve estimated using computed tomography (FFRCT ) might improve evaluation of patients with chest pain. Objectives The authors sought to determine the effect on ...cost and quality of life (QOL) of using FFRCT instead of usual care to evaluate stable patients with symptoms suspicious for coronary disease. Methods Symptomatic patients without known coronary disease were enrolled into 2 strata based on whether invasive or noninvasive diagnostic testing was planned. In each stratum, consecutive observational cohorts were evaluated with either usual care or FFRCT . The number of diagnostic tests, invasive procedures, hospitalizations, and medications during 90-day follow-up were multiplied by U.S. cost weights and summed to derive total medical costs. Changes in QOL from baseline to 90 days were assessed using the Seattle Angina Questionnaire, the EuroQOL, and a visual analog scale. Results In the 584 patients, 74% had atypical angina, and the pre-test probability of coronary disease was 49%. In the planned invasive stratum, mean costs were 32% lower among the FFRCT patients than among the usual care patients ($7,343 vs. $10,734 p < 0.0001). In the noninvasive stratum, mean costs were not significantly different between the FFRCT patients and the usual care patients ($2,679 vs. $2,137; p = 0.26). In a sensitivity analysis, when the cost weight of FFRCT was set to 7 times that of computed tomography angiography, the FFRCT group still had lower costs than the usual care group in the invasive testing stratum ($8,619 vs. $ 10,734; p < 0.0001), whereas in the noninvasive testing stratum, when the cost weight of FFRCT was set to one-half that of computed tomography angiography, the FFRCT group had higher costs than the usual care group ($2,766 vs. $2,137; p = 0.02). Each QOL score improved in the overall study population (p < 0.0001). In the noninvasive stratum, QOL scores improved more in FFRCT patients than in usual care patients: Seattle Angina Questionnaire 19.5 versus 11.4, p = 0.003; EuroQOL 0.08 versus 0.03, p = 0.002; and visual analog scale 4.1 versus 2.3, p = 0.82. In the invasive cohort, the improvements in QOL were similar in the FFRCT and usual care patients. Conclusions An evaluation strategy based on FFRCT was associated with less resource use and lower costs within 90 days than evaluation with invasive coronary angiography. Evaluation with FFRCT was associated with greater improvement in quality of life than evaluation with usual noninvasive testing. (Prospective Longitudinal Trial of FFRCT : Outcomes and Resource Impacts PLATFORM; NCT01943903 )
BACKGROUND: Previous clinical studies have demonstrated that injectable gold salts and the oral gold compound, auranofin, possess significant steroid-sparing effects in the treatment of asthma.
...OBJECTIVES: The objectives of this investigation were to determine whether auranofin could reduce oral corticosteroid requirements and to evaluate the safety of auranofin in the treatment of chronic corticosteroid-dependent asthma.
METHODS: Patients with asthma were eligible if they required at least 10 mg of prednisone per day for control and prevention of asthma exacerbations. Two hundred seventy-nine patients with chronic corticosteroid-dependent asthma (requiring ≥ 10 mg/day) were randomized to receive auranofin, 3 mg twice daily, or placebo during an 8-month clinical trial, which was divided into three phases including: a 4-week baseline period (phase I), a 6-month double-blind treatment and steroid reduction period (phase II), and a 4-week posttreatment observation period during which steroid and auranofin doses or placebo doses were maintained at levels achieved by the end of phase II (phase III). The primary efficacy variable was “therapeutic success” or reduction of daily corticosteroid use by 50% or more.
RESULTS: The proportion of patients in the auranofin group achieving therapeutic success (41%) was significantly higher than that in the placebo group (27%) (
p = 0.01). This effect was greatest in patients requiring 10 to 19 mg of oral prednisone per day at baseline (
p < 0.001). In all treated patients, including those who did and did not complete the trial, significant reduction (≥50% of baseline) in oral corticosteroid dosage was achieved in the auranofin group (60%) compared with the placebo group (32%) (
p < 0.001). There were no significant differences between treatment groups in symptoms, concomitant medication use, or lung function. Mean serum total IgE levels decreased significantly from baseline in the auranofin group (-44.63 IU/ml) compared with the placebo group (
p = 0.001). Gastrointestinal and cutaneous adverse events were greater in the auranofin group.
CONCLUSIONS: Auranofin demonstrated a steroid-sparing effect without concomitant worsening of symptoms or lung function and appeared to be more effective in patients dependent on 10 to 19 mg of prednisone per day. Therefore this study has demonstrated that auranofin is useful as a steroid-sparing agent in the treatment of chronic corticosteroid-dependent asthma. (J A
LLERGY C
LIN I
MMUNOL 1996;98:317-24.)
Abstract Background Patients perceive different symptoms of heart failure decompensation. It is not known whether the nature of the worst symptom relates to hemodynamic profile, response to therapy, ...or improvement in clinical trials. Methods and Results Patients in the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness trial were hospitalized with advanced heart failure, ejection fraction ≤30%, and at least 1 sign and 1 symptom of elevated filling pressures. Visual analog scales (VAS) for symptoms were completed by 371 patients, who selected their worst symptom as difficulty breathing, fatigue, abdominal discomfort, or body swelling and also scored breathing and global condition at baseline and discharge. The dominant symptom identified was difficulty breathing by 193 (52%) patients, fatigue by 118 (32%), and abdominal discomfort and swelling each by 30 (8%) patients, combined as right-sided congestion for analysis. Clinical and hemodynamic assessments were not different between groups except that right-sided congestion was associated with more hepatomegaly, ascites, third heart sounds, and jugular venous distention. This group also had greater reduction in jugular venous distention and trend toward higher blood urea nitrogen after therapy. By discharge, average improvements in worst symptom and global score were 28 points and 24 points. For those with ≥10 points in improvement in worst symptom, 84% also improved global assessment ≥10 points. Initial fatigue was associated with less improvement ( P = .002) during and after hospitalization, but improvements in symptom scores were sustained when re-measured during 6 months after discharge. Conclusion In most patients hospitalized with clinical congestion, therapy will improve symptoms regardless of the worst symptom perceived, with more evidence of baseline fluid retention and reduction during therapy for worst symptoms of abdominal discomfort or edema. Improvement in trials should be similar when tracking worst symptom, dyspnea, or global assessment.
Abstract Background The aim of the Building on Existing Tools to Improve Chronic Disease Prevention and Screening in Family Practice (BETTER) randomized controlled trial is to improve the primary ...prevention of and screening for multiple conditions (diabetes, cardiovascular disease, cancer) and some of the associated lifestyle factors (tobacco use, alcohol overuse, poor nutrition, physical inactivity). In this article, we describe how we harmonized the evidence-based clinical practice guideline recommendations and patient tools to determine the content for the BETTER trial. Methods We identified clinical practice guidelines and tools through a structured literature search; we included both indexed and grey literature. From these guidelines, recommendations were extracted and integrated into knowledge products and outcome measures for use in the BETTER trial. End-users (family physicians, nurse practitioners, nurses and dieticians) were engaged in reviewing the recommendations and tools, as well as tailoring the content to the needs of the BETTER trial and family practice. Results In total, 3–5 high-quality guidelines were identified for each condition; from these, we identified high-grade recommendations for the prevention of and screening for chronic disease. The guideline recommendations were limited by conflicting recommendations, vague wording and different taxonomies for strength of recommendation. There was a lack of quality evidence for manoeuvres to improve the uptake of guidelines among patients with depression. We developed the BETTER clinical algorithms for the implementation plan. Although it was difficult to identify high-quality tools, 180 tools of interest were identified. Interpretation The intervention for the BETTER trial was built by integrating existing guidelines and tools, and working with end-users throughout the process to increase the intervention’s utility for practice. Trial registration: ISRCTN07170460
Treatment with fatostatin, a small molecule inhibitor of sterol regulatory element-binding protein (SREBP) function that decreases the expression of MVK6 (see Fig E3, A, in this article's Online ...Repository at www.jacionline.org), enhanced the prenylation defect in MVA LCLs at 37°C and 40°C (Fig E3, B). Methods Cell isolation and culture Human PBMCs were isolated from buffy coat preparations of fresh blood samples, obtained with informed consent and with approval from the St Vincent's Hospital Human Research Ethics Committee. MVK mRNA expression was measured by quantitative PCR as previously described.E1 In vitro prenylation assay Cell lysates were prepared as previously describedE1 and 10 to 50 μg of protein were used for in vitro prenylation assays with recombinant GGTase I or with GGTase II and REP-1.E2In vitro prenylated (ie, biotinylated) proteins were detected on polyvinylidene difluoride blots using streptavidin-680RD (LiCOR).E2 Blots were also analyzed for unprenylated Rap1A using goat anti-Rap1A (Santa Cruz Biotechnology, Dallas, Tex; sc-1482).E2 Rab14 was detected in 2 μg of PBMC lysates using a 1/200 dilution of rabbit polyclonal anti-Rab14 (H-55, Santa Cruz Biotechnology), 1/5000 peroxidase-conjugated goat anti-rabbit (Pierce), and SuperSignal West Femto ECL reagent (ThermoFisher Scientific, Waltham, Mass). Patient Age (y) Sex Current statin use Approximate duration of statin treatment (y) 1 82 F Atorvastatin 10 2 78 F Rosuvastatin 20 3 71 M Rosuvastatin 0.25∗ 4 64 M Atorvastatin 5 5 74 M Rosuvastatin 10 6 58 M Atorvastatin 10 7 71 M Atorvastatin 14 8 88 F Atorvastatin 5 9 58 M Pravastatin 2 1 A. Simon, H.P. Kremer, R.A. Wevers, H. Scheffer, J.G. De Jong, J.W. Van Der Meer, Mevalonate kinase deficiency: evidence for a phenotypic continuum, Neurology, Vol. 62, 2004, 994-997 2 C.C. Palsuledesai, M.D. Distefano, Protein prenylation: enzymes, therapeutics, and biotechnology applications, ACS Chem Biol, Vol. 10, 2015, 51-62 3 Y.H. Park, G. Wood, D.L. Kastner, J.J. Chae, Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS, Nat Immunol, Vol. 17, 2016, 914-921 4 M.K. Akula, M. Shi, Z. Jiang, C.E. Foster, D. Miao, A.S. Li, Control of the innate immune response by the mevalonate pathway, Nat Immunol, Vol. 17, 2016, 922-929 5 N. Ali, J. Jurczyluk, G. Shay, Z. Tnimov, K. Alexandrov, M.A. Munoz, A highly sensitive prenylation assay reveals in vivo effects of bisphosphonate drug on the Rab prenylome of macrophages outside the skeleton, Small GTPases, Vol. 6, 2015, 202-211 6 J. Jurczyluk, M.A. Munoz, O.P. Skinner, R. Chai, N. Ali, U. Palendira, Mevalonate kinase deficiency leads to decreased prenylation of Rab GTPases, Immunol Cell Biol, Vol. 94, 2016, 994-999 7 M.J. Rogers, J.C. Crockett, F.P. Coxon, J. Monkkonen, Biochemical and molecular mechanisms of action of bisphosphonates, Bone, Vol. 49, 2011, 34-41 8 L. Messer, G. Alsaleh, P. Georgel, R. Carapito, H.R. Waterham, N. Dali-Youcef, Homozygosity for the V377I mutation in mevalonate kinase causes distinct clinical phenotypes in two sibs with hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS), RMD Open, Vol. 2, 2016, e000196 9 S.M. Houten, J. Frenkel, G.T. Rijkers, R.J. Wanders, W. Kuis, H.R. Waterham, Temperature dependence of mutant mevalonate kinase activity as a pathogenic factor in hyper-IgD and periodic fever syndrome, Hum Mol Genet, Vol. 11, 2002, 3115-3124
Summary Diagnostic yield of endomyocardial biopsy is low, particularly in disease that affects the myocardium in a nonuniform distribution. The authors hypothesized that real-time MRI guidance could ...improve the yield through targeted biopsy of focal myocardial pathology. They tested this hypothesis in an animal model of focal myocardial pathology using intracoronary ethanol and microspheres. The authors compared real-time MRI-guided endomyocardial biopsy in swine using a custom actively visualized MRI bioptome against x-ray–guided biopsy using a commercial bioptome by skilled operators. Real-time MRI guidance significantly increased the diagnostic yield of endomyocardial biopsy.
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