Cardiac surgery is the largest consumer of blood products in medicine; although believed life saving, transfusion carries substantial adverse risks. This study characterizes the relationship between ...transfusion and risk of major infection after cardiac surgery. In all, 5,158 adults were prospectively enrolled to assess infections after cardiac surgery. The most common procedures were isolated coronary artery bypass graft surgery (31%) and isolated valve surgery (30%); 19% were reoperations. Infections were adjudicated by independent infectious disease experts. Multivariable Cox modeling was used to assess the independent effect of blood and platelet transfusions on major infections within 60 ± 5 days of surgery. Red blood cells (RBC) and platelets were transfused in 48% and 31% of patients, respectively. Each RBC unit transfused was associated with a 29% increase in crude risk of major infection ( p < 0.001). Among RBC recipients, the most common infections were pneumonia (3.6%) and bloodstream infections (2%). Risk factors for infection included postoperative RBC units transfused, longer duration of surgery, and transplant or ventricular assist device implantation, in addition to chronic obstructive pulmonary disease, heart failure, and elevated preoperative creatinine. Platelet transfusion decreased the risk of infection ( p = 0.02). Greater attention to management practices that limit RBC use, including cell salvage, small priming volumes, vacuum-assisted venous return with rapid autologous priming, and ultrafiltration, and preoperative and intraoperative measures to elevate hematocrit could potentially reduce occurrence of major postoperative infections.
Jeffries et al. (2018) investigated testing for a treatment difference in the setting of a randomized clinical trial with a single outcome measured longitudinally over a series of common follow‐up ...times while adjusting for covariates. That paper examined the null hypothesis of no difference at any follow‐up time versus the alternative of a difference for at least one follow‐up time. We extend those results here by considering multivariate outcome measurements, where each individual outcome is examined at common follow‐up times. We consider the case where there is interest in first testing for a treatment difference in a global function of the outcomes (e.g., weighted average or sum) with subsequent interest in examining the individual outcomes, should the global function show a treatment difference. Testing is conducted for each follow‐up time and may be performed in the setting of a group sequential trial. Testing procedures are developed to determine follow‐up times for which a global treatment difference exists and which individual combinations of outcome and follow‐up time show evidence of a difference while controlling for multiplicity in outcomes, follow‐up, and interim analyses. These approaches are examined in a study evaluating the effects of tissue plasminogen activator on longitudinally obtained stroke severity measurements.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
In a randomized trial involving patients undergoing mitral-valve surgery for degenerative mitral regurgitation, the addition of tricuspid repair resulted in a lower risk of the primary outcome, a ...composite of reoperation for tricuspid regurgitation, progression of tricuspid regurgitation, or death. Tricuspid repair resulted in more frequent permanent pacemaker implantation.
After 2 years of follow-up in a randomized trial involving 301 patients with moderate ischemic mitral regurgitation undergoing CABG, the addition of mitral-valve repair did not improve left ...ventricular function or remodeling.
Ischemic mitral regurgitation of moderate severity develops in approximately 10% of patients after myocardial infarction.
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Mitral regurgitation is caused by the displacement of papillary muscle, leaflet tethering, reduced closing forces, and annular dilatation. Over time, the condition has an adverse effect on the rate of survival free of heart failure.
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Because most patients with ischemic mitral regurgitation have multivessel coronary artery disease requiring revascularization, surgeons have to consider whether to add mitral-valve repair to coronary-artery bypass grafting (CABG).
The appropriate surgical management of moderate ischemic mitral regurgitation at the time of CABG remains controversial. Some experts advocate revascularization alone . . .
BACKGROUND—Allogeneic mesenchymal precursor cells (MPCs) injected during left ventricular assist device (LVAD) implantation may contribute to myocardial recovery. This trial explores the safety and ...efficacy of this strategy.
METHODS AND RESULTS—In this multicenter, double-blind, sham-procedure controlled trial, 30 patients were randomized (2:1) to intramyocardial injection of 25 million MPCs or medium during LVAD implantation. The primary safety end point was incidence of infectious myocarditis, myocardial rupture, neoplasm, hypersensitivity reaction, and immune sensitization (90 days after randomization). Key efficacy end points were functional status and ventricular function while temporarily weaned from LVAD support (90 days after randomization). Patients were followed up until transplant or 12 months after randomization, whichever came first. Mean age was 57.4 (±13.6) years, mean left ventricular ejection fraction was 18.1%, and 66.7% were destination therapy LVADs. No safety events were observed. Successful temporary LVAD weaning was achieved in 50% of MPC and 20% of control patients at 90 days (P=0.24); the posterior probability that MPCs increased the likelihood of successful weaning was 93%. At 90 days, 3 deaths (30%) occurred in control patients, and none occurred in MPC patients. Mean left ventricular ejection fraction after successful wean was 24.0% (MPC=10) and 22.5% (control=2; P=0.56). At 12 months, 30% of MPC patients and 40% of control patients were successfully temporarily weaned from LVAD support (P=0.69), and 6 deaths (30%) occurred in MPC patients. Donor-specific HLA sensitization developed in 2 MPC and 3 control patients and resolved by 12 months.
CONCLUSIONS—In this preliminary trial, administration of MPCs appeared to be safe, and there was a potential signal of efficacy. Future studies will evaluate the potential for higher or additional doses to enhance the ability to wean LVAD recipients off support.
CLINICAL TRIAL REGISTRATION—URLhttp://www.clinicaltrials.gov. Unique identifierNCT01442129.
Summary Background Friedreich's ataxia (FA) is a progressive, multisystem, degenerative disorder caused by a reduction in frataxin. Loss of frataxin results in mitochondrial dysfunction and oxidative ...damage in patients and model systems. Previous studies have indicated that the antioxidant idebenone (5 mg/kg daily) reduces cardiac hypertrophy, but definite improvement in neurological function has not been shown. Methods 48 genetically confirmed FA patients, aged 9–17 years, were enrolled in a 6-month, randomised, double-blind, placebo-controlled study. The patients received placebo or one of three doses of idebenone (∼5 mg/kg, 15 mg/kg, and 45 mg/kg), stratified by body weight. The primary endpoint was change from baseline in urinary 8-hydroxy-2′-deoxyguanosine (8OH2′dG), a marker of oxidative DNA damage. Secondary endpoints included changes in the international cooperative ataxia rating scale (ICARS), the FA rating scale (FARS), and a survey of activities of daily living (ADL). This study is registered with ClinicalTrials.gov , number NCT00229632. Findings Idebenone was generally well tolerated with similar numbers of adverse events in each group. One child receiving high-dose idebenone developed neutropenia after 6 months, which resolved after discontinuation of treatment. 8OH2′dG concentrations were not increased, and did not significantly change with idebenone treatment. Whereas an overall analysis did not show a significant difference in ICARS, FARS, or ADL total scores, there were indications of a dose-dependent response in the ICARS score. A second, pre-specified analysis, excluding patients who required wheelchair assistance, showed a significant improvement in ICARS (Bonferroni p=0·03) and suggested a dose-related response in ICARS, FARS, and ADL scores. Interpretation Treatment with higher doses of idebenone was generally well tolerated and associated with improvement in neurological function and ADL in patients with FA. The degree of improvement correlated with the dose of idebenone, suggesting that higher doses may be necessary to have a beneficial effect on neurological function.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary Background Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. Animal models have a ...neuromuscular deficit that is mitigated by androgen-reducing treatment. We aimed to assess the efficacy and safety of the 5α-reductase inhibitor dutasteride in patients with SBMA, and to identify outcome measures for use in future studies of the disease. Methods We undertook a randomised, double-blind, placebo-controlled, single-site clinical trial in ambulatory, symptomatic men with genetically confirmed SBMA. Participants were assigned by random number table to receive dutasteride (0·5 mg per day) or placebo orally for 24 months. Patients and investigators were masked to treatment allocation. The primary outcome measure was quantitative muscle assessment (QMA). The final efficacy analysis included all patients who were compliant with study treatment at 24 months. This trial was registered with ClinicalTrials.gov , NCT00303446. Findings 50 men were randomly assigned to treatment groups (25 dutasteride, 25 placebo), and 44 were included in the efficacy analysis (21 dutasteride, 23 placebo). At 24 months, the placebo group showed a decrease of 4·5% (−0·30 kg/kg) from baseline in weight-scaled muscle strength as indicated by QMA, and the dutasteride group had an increase in strength of 1·3% (0·14 kg/kg); the difference between groups (5·8%, 95% CI −5·9 to 17·6; p=0·28) was not significant. Prespecified secondary outcome measures of creatine kinase, muscle strength and function, motor nerve conduction, activities of daily living, and erectile function did not show a significant difference between the study groups in change from baseline. Quality of life, as measured by the physical component summary of the Medical Outcomes Study 36-item Short Form version 2, favoured dutasteride (change in score from baseline: placebo, −3·6%, vs dutasteride, 2·1%; p=0·01), whereas the mental component summary favoured placebo (3·3% vs −3·2%; p=0·03). The dutasteride group had fewer patients reporting falls than did the placebo group (9 vs 16; p=0·048); there were no other significant differences in reported adverse events. Interpretation Our study did not show a significant effect of dutasteride on the progression of muscle weakness in SBMA, although there were secondary indications of both positive and negative effects compared with placebo. A longer trial duration or larger number of patients might be needed to show an effect on disease progression. Performance testing, QMA, and quality of life measures were identified as potentially useful endpoints for future therapeutic trials. Funding US National Institutes of Health.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
To examine risk factors for new-onset postoperative atrial fibrillation (POAF) after cardiac surgery.
Patients enrolled in the Cardiothoracic Surgical Trials Network multicenter, randomized trial of ...rate control versus rhythm control for POAF were included. Predictors of POAF were determined using multivariable logistic regression.
Among the 2104 patients who were enrolled preoperatively, 695 developed POAF (33.0%). Rates of POAF were 28.1% after isolated coronary artery bypass grafting (CABG), 33.7% after isolated valve repair or replacement, and 47.3% after CABG plus valve repair or replacement. Baseline characteristics associated with an increased risk of POAF identified on multivariable analysis included older age (odds ratio OR 1.57; 95% confidence interval CI 1.42-1.73, per 10 y), White race or non-Hispanic ethnicity (OR 1.52; CI: 1.11-2.07), history of heart failure (OR 1.55; CI: 1.16-2.08), and history of hypothyroidism (OR 1.42; CI 1.04-1.94). The type of cardiac procedure was associated with an increased risk of POAF with both isolated valve repair or replacement (OR 1.33, CI 1.08-1.64) and combined CABG plus valve repair or replacement (OR 1.64, CI 1.24-2.17) having increased risk of POAF compared to isolated CABG. No preoperative cardiac medication was associated with POAF.
In this prospective cohort of patients, older age, a history of hypothyroidism, a history of heart failure, and valve repair or replacement, with or without CABG, and White non-Hispanic race were associated with an increased risk of POAF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Ambulatory patients with advanced heart failure (HF) are often considered for advanced therapies, including durable mechanical circulatory support (MCS). The Interagency Registry for Mechanically ...Assisted Circulatory Support (INTERMACS) profiles are a commonly used descriptor of disease severity in patients receiving MCS devices, but their role in defining the prognosis of ambulatory patients is less well established, especially for Profiles 6 and 7.
Registry Evaluation of Vital Information on Ventricular Assist Devices in Ambulatory Life is a prospective observational study of 400 outpatients from 21 MCS and cardiac transplant centers. Eligible patients had New York Heart Association Class II to IV symptoms despite optimal medical and electrical therapies with a recent HF hospitalization, heart transplant listing, or evidence of high neurohormonal activation.
The cohort included 33 INTERMACS Profile 4 (8%), 83 Profile 5 (21%), 155 Profile 6 (39%), and 129 Profile 7 (32%). Across INTERMACS profiles, there were no differences in age, gender, ejection fraction, blood pressure, or use of guideline-directed medical therapy. A lower INTERMACS profile was associated with more hospitalizations, greater frailty, and more impaired functional capacity and quality of life. The composite end point of death, durable MCS, or urgent transplant at 12 months occurred in 39%, 27%, 24%, and 14% subjects with INTERMACS Profiles 4, 5, 6, and 7, respectively (p = 0.004).
Among ambulatory patients with advanced HF, a lower INTERMACS profile was associated with a greater burden of HF across multiple dimensions and a higher composite risk of durable MCS, urgent transplant, or death. These profiles may assist in risk assessment and triaging ambulatory patients to advanced therapies.
In longitudinal studies comparing two treatments over a series of common follow-up measurements, there may be interest in determining if there is a treatment difference at any follow-up period when ...there may be a non-monotone treatment effect over time. To evaluate this question, Jeffries and Geller (2015) examined a number of clinical trial designs that allowed adaptive choice of the follow-up time exhibiting the greatest evidence of treatment difference in a group sequential testing setting with Gaussian data. The methods are applicable when a few measurements were taken at prespecified follow-up periods. Here, we test the intersection null hypothesis of no difference at any follow-up time versus the alternative that there is a difference for at least one follow-up time. Results of Jeffries and Geller (2015) are extended by considering a broader range of modeled data and the inclusion of covariates using generalized estimating equations. Testing procedures are developed to determine a set of follow-up times that exhibit a treatment difference that accounts for multiplicity in follow-up times and interim analyses.
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BFBNIB, DOBA, FSPLJ, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, UILJ, UKNU, UL, UM, UPUK
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