Scott Hetzel

Prevalence and Significance of Alterations in Cardiac Structure and Function in Patients With Heart Failure and a Preserved Ejection Fraction

Background— The purpose of this study was to examine the prevalence of abnormalities in cardiac structure and function present in patients with heart failure and a preserved ejection fraction (HFPEF) and to determine whether these alterations in structure and function were associated with cardiovascular morbidity and mortality. Methods and Results— The Irbesartan in HFPEF trial (I-PRESERVE) enrolled 4128 patients; echocardiographic determination of left ventricular (LV) volume, mass, left atrial (LA) size, systolic function, and diastolic function were made at baseline in 745 patients. The primary end point was death or protocol-specific cardiovascular hospitalization. A secondary end point was the composite of heart failure death or heart failure hospitalization. Associations between baseline structure and function and patient outcomes were examined using univariate and multivariable Cox proportional hazard analyses. In this substudy, LV hypertrophy or concentric remodeling was present in 59%, LA enlargement was present in 66%, and diastolic dysfunction was present in 69% of the patients. Multivariable analyses controlling for 7 clinical variables (including log N-terminal pro-B–type natriuretic peptide) indicated that increased LV mass, mass/volume ratio, and LA size were independently associated with an increased risk of both primary and heart failure events (all P<0.05). Conclusions— Left ventricular hypertrophy or concentric remodeling, LA enlargement, and diastolic dysfunction were present in the majority of patients with HFPEF. Left ventricular mass and LA size were independently associated with an increased risk of morbidity and mortality. The presence of structural remodeling and diastolic dysfunction may be useful additions to diagnostic criteria and provide important prognostic insights in patients with HFPEF. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Mode of Death in Patients With Heart Failure and a Preserved Ejection Fraction Results From the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) Trial

Background— The mode of death has been well characterized in patients with heart failure and a reduced ejection fraction; however, less is known about the mode of death in patients with heart failure and a preserved ejection fraction (HFPEF). The purpose of this study was to examine the mode of death in patients with HFPEF enrolled in the Irbesartan in Heart Failure With Preserved Ejection Fraction Study (I-Preserve) trial and to determine whether irbesartan altered the distribution of mode of death in HFPEF. Methods and Results— All deaths were reviewed by a clinical end-point committee, and the mode of death was assigned by consensus of the members. The annual mortality rate was 5.2% in the I-Preserve trial. There were no significant differences in mortality rate between the placebo and irbesartan groups. The mode of death was cardiovascular in 60% (including 26% sudden, 14% heart failure, 5% myocardial infarction, and 9% stroke), noncardiovascular in 30%, and unknown in 10%. There were no differences in the distribution of mode-specific mortality rates between placebo and irbesartan. Conclusions— Sixty percent of the deaths in patients with HFPEF were cardiovascular, with sudden death and heart failure death being the most common. Treatment with irbesartan did not affect overall mortality or the distribution of mode-specific mortality rates. Clinical Trial Registration— URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.

Factors Associated with Outcome in Heart Failure with Preserved Ejection Fraction: Findings from the Irbesartan in Heart Failure with Preserved Ejection Fraction Study (I-PRESERVE)

Background—The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results—We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions—In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.Background— The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results— We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions— In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration— URL: . Unique identifier: [NCT00095238][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00095238&atom=%2Fcirchf%2F4%2F1%2F27.atom

Factors Associated With Outcome in Heart Failure With Preserved Ejection FractionClinical Perspective

Background—The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results—We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions—In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00095238.Background— The determinants of prognosis in patients with heart failure and preserved ejection fraction (HF-PEF) are poorly documented. Methods and Results— We evaluated data from 4128 patients in the I-PRESERVE trial (Irbesartan in Heart Failure with Preserved Ejection Fraction Study). Multivariable Cox regression models were developed using 58 baseline demographic, clinical, and biological variables to model the primary outcome of all-cause mortality or cardiovascular hospitalization (1505 events), all-cause mortality (881 events), and HF death or hospitalization (716 events). Log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and previous hospitalization for HF were the most powerful factors associated with the primary outcome and with the HF composite. For all-cause mortality, log N-terminal pro–B-type natriuretic peptide, age, diabetes mellitus, and left ventricular EF were the strongest independent factors. Other independent factors associated with poor outcome included quality of life, a history of chronic obstructive lung disease, log neutrophil count, heart rate, and estimated glomerular filtration rate. The models accurately stratified the actual 3-year rate of outcomes from 8.1% to 59.9% (primary outcome) 2.7% to 36.5% (all-cause mortality), and 2.1% to 38.9% (HF composite) for the lowest to highest septiles of predicted risks. Conclusions— In a large sample of elderly patients with HF and preserved EF enrolled in I-Preserve, simple clinical, demographic, and biological variables were associated with outcome and identified subgroups at very high and very low risk of events. Clinical Trial Registration— URL: . Unique identifier: [NCT00095238][1]. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00095238&atom=%2Fcirchf%2F4%2F1%2F27.atom

The Effect of Lace-up Ankle Braces on Injury Rates in High School Basketball Players

Background: Ankle injuries are the most common injury in basketball players. However, no prospective studies have been performed to determine if wearing lace-up ankle braces will reduce the incidence of ankle injuries in high school athletes. Purpose: This trial was undertaken to determine if lace-up ankle braces reduce the incidence and severity of acute first-time and recurrent ankle injuries sustained by high school basketball players. Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 1460 male and female basketball players from 46 high schools were randomly assigned to a braced or control group. The braced group players wore lace-up ankle braces during the 2009-2010 basketball season. Athletic trainers recorded brace compliance, athlete exposures, and injuries. Cox proportional hazards models (adjusted for demographic covariates), accounting for intracluster correlation, were utilized to compare time to first acute ankle injury between groups. Injury severity (days lost) was tested with the Wilcoxon rank-sum test. Results: The rate of acute ankle injury (per 1000 exposures) was 0.47 in the braced group and 1.41 in the control group (Cox hazard ratio [HR] 0.32; 95% confidence interval [CI] 0.20, 0.52; P < .001). The median severity of acute ankle injuries was similar (P = .23) in the braced (6 days) and control group (7 days). For players with a previous ankle injury, the incidence of acute ankle injury was 0.83 in the braced group and 1.79 in the control group (Cox HR 0.39; 95% CI 0.17, 0.90; P = .028). For players who did not report a previous ankle injury, the incidence of acute ankle injury was 0.40 in the braced group and 1.35 in the control group (Cox HR 0.30; 95% CI 0.17, 0.52, P < .001). Conclusion: Use of lace-up ankle braces reduced the incidence but not the severity of acute ankle injuries in male and female high school basketball athletes both with and without a previous history of an ankle injury.

Clinical and Morphological Changes Following 2 Rehabilitation Programs for Acute Hamstring Strain Injuries: A Randomized Clinical Trial

STUDY DESIGN Randomized, double-blind, parallel-group clinical trial. OBJECTIVES To assess differences between a progressive agility and trunk stabilization rehabilitation program and a progressive running and eccentric strengthening rehabilitation program in recovery characteristics following an acute hamstring injury, as measured via physical examination and magnetic resonance imaging (MRI). BACKGROUND Determining the type of rehabilitation program that most effectively promotes muscle and functional recovery is essential to minimize reinjury risk and to optimize athlete performance. METHODS Individuals who sustained a recent hamstring strain injury were randomly assigned to 1 of 2 rehabilitation programs: (1) progressive agility and trunk stabilization or (2) progressive running and eccentric strengthening. MRI and physical examinations were conducted before and after completion of rehabilitation. RESULTS Thirty-one subjects were enrolled, 29 began rehabilitation, and 25 completed rehabilitation. There were few differences in clinical or morphological outcome measures between rehabilitation groups across time, and reinjury rates were low for both rehabilitation groups after return to sport (4 of 29 subjects had reinjuries). Greater craniocaudal length of injury, as measured on MRI before the start of rehabilitation, was positively correlated with longer return-to-sport time. At the time of return to sport, although all subjects showed a near-complete resolution of pain and return of muscle strength, no subject showed complete resolution of injury as assessed on MRI. CONCLUSION The 2 rehabilitation programs employed in this study yielded similar results with respect to hamstring muscle recovery and function at the time of return to sport. Evidence of continuing muscular healing is present after completion of rehabilitation, despite the appearance of normal physical strength and function on clinical examination. LEVEL OF EVIDENCE Therapy, level 1b-.

Vacuum-mixing significantly changes antibiotic elution characteristics of commercially available antibiotic-impregnated bone cements.

BACKGROUND Evidence-based medicine indicates the use of antibiotic-impregnated polymethylmethacrylate bone cement during hip and knee replacement reduces the rate of prosthetic joint infection. In the United States, so-called off-label use of antibiotic-impregnated polymethylmethacrylate for primary joint replacement is increasing and multiple antibiotic-containing polymethylmethacrylate products are commercially available. However, there are sparse published data comparing the antibiotic elution characteristics of these bone cement products and the effect that vacuum-mixing has on antibiotic elution from these products. This study compares the antibiotic elution characteristics of six commercially available antibiotic polymethylmethacrylate formulations mixed under atmospheric pressure and vacuum conditions. METHODS The antibiotic-impregnated polymethylmethacrylate products were mixed with use of a commonly employed intraoperative technique at atmospheric pressure and clinically relevant vacuum conditions. A standard Kirby-Bauer bioassay technique was subsequently used to quantify antibiotic elution from the products. An international infectious disease database was mined to determine antibiotic susceptibility of common bacteria causing prosthetic joint infection and to define the gentamicin concentration above which optimal antibiotic efficacy begins for these organisms. Statistical analyses incorporating the above susceptibility data were performed to compare antibiotic elution (1) among products mixed at atmospheric pressure, (2) among vacuum-mixed products, and (3) between atmospheric and vacuum-mixing for each individual product. RESULTS Comparisons of antibiotic-loaded polymethylmethacrylate products mixed at atmospheric pressure indicated that significant antibiotic elution differences exist among the products. Comparisons of vacuum-mixed antibiotic-loaded polymethylmethacrylate products indicated that significant antibiotic elution differences exist among the products. When mixing under atmospheric pressure was compared with vacuum-mixing for each individual antibiotic polymethylmethacrylate product, vacuum-mixing significantly increased the clinically relevant cumulative antibiotic elution from three products but significantly decreased antibiotic elution from three other products. CONCLUSIONS The method by which antibiotic-containing polymethylmethacrylate products are prepared significantly affects their antibiotic elution characteristics. The effect of vacuum-mixing on antibiotic elution is product-specific.

Altering the Proclivity towards Daptomycin Resistance in Methicillin-Resistant Staphylococcus aureus Using Combinations with Other Antibiotics

ABSTRACT Daptomycin (DAP) is increasingly used as a part of combination therapy, particularly in complex methicillin-resistant Staphylococcus aureus (MRSA) infections. While multiple studies have reported the potential for synergy between DAP and adjunctive anti-infectives, few have examined the influence of adjunctive therapy on the emergence of DAP resistance. This study examined eight adjunctive antimicrobial combinations with DAP in vitro and the emergence of DAP resistance over time (up to 4 weeks) using clinical isolates of DAP-susceptible MRSA (MIC, 0.5 μg/ml) in which DAP resistance subsequently developed during patient therapy (MIC, 3 μg/ml). In addition to DAP susceptibility testing, selected strains were examined for phenotypic changes associated with DAP resistance, including changes to cell wall thickness (CWT) and cell membrane alterations. The addition of either oxacillin or clarithromycin in medium containing DAP significantly inhibited the development of DAP resistance through the entirety of the 4-week exposure (10- to 32-fold MIC reduction from that of DAP alone). Combinations with rifampin or fosfomycin were effective in delaying the emergence of DAP resistance through the end of week one only (week one MIC, 0.5 μg/ml; week four MIC, 24 μg/ml). Cell wall thickening was observed for all antibiotic combinations regardless of their effect on the DAP MIC (14 to 70% increase in CWT), while changes in cell membrane fluidity were variable and treatment dependent. DAP showed reduced activity against strains with DAP MICs of 1 to 12 μg/ml, but cell membrane integrity was still disrupted at concentrations achieved with doses greater than 10 mg/kg of body weight. The emergence of DAP resistance in MRSA is strongly influenced by the presence of subinhibitory concentrations of adjunctive antimicrobials. These data suggest that combining DAP with oxacillin or clarithromycin may delay the development of DAP resistance in cases requiring prolonged antibiotic therapy.

A Two-handed Jaw-thrust Technique Is Superior to the One-handed EC-clamp Technique for Mask Ventilation in the Apneic Unconscious Person

Background:Mask ventilation is considered a “basic” skill for airway management. A one-handed “EC-clamp” technique is most often used after induction of anesthesia with a two-handed jaw-thrust technique reserved for difficult cases. Our aim was to directly compare both techniques with the primary outcome of air exchange in the lungs. Methods:Forty-two elective surgical patients were mask-ventilated after induction of anesthesia by using a one-handed “EC-clamp” technique and a two-handed jaw-thrust technique during pressure-control ventilation in randomized, crossover fashion. When unresponsive to a jaw thrust, expired tidal volumes were recorded from the expiratory limb of the anesthesia machine each for five consecutive breaths. Inadequate mask ventilation and dead-space ventilation were defined as an average tidal volume less than 4 ml/kg predicted body weight or less than 150 ml/breath, respectively. Differences in minute ventilation and tidal volume between techniques were assessed with the use of a mixed-effects model. Results:Patients were (mean ± SD) 56 ± 18 yr old with a body mass index of 30 ± 7.1 kg/m2. Minute ventilation was 6.32 ± 3.24 l/min with one hand and 7.95 ± 2.70 l/min with two hands. The tidal volume was 6.80 ± 3.10 ml/kg predicted body weight with one hand and 8.60 ± 2.31 ml/kg predicted body weight with two hands. Improvement with two hands was independent of the order used. Inadequate or dead-space ventilation occurred more frequently during use of the one-handed compared with the two-handed technique (14 vs. 5%; P = 0.013). Conclusion:A two-handed jaw-thrust mask technique improves upper airway patency as measured by greater tidal volumes during pressure-controlled ventilation than a one-handed “EC-clamp” technique in the unconscious apneic person.

Azithromycin for Bronchial Asthma in Adults: An Effectiveness Trial

Background: Macrolides have antimicrobial and anti-inflammatory properties that may be useful in the treatment of chronic asthma. Methods: We performed a randomized, placebo-controlled, double-blinded effectiveness trial of 12 weekly doses of adjunctive azithromycin, with follow-up to 1 year after randomization, in adults with persistent asthma. Measurements included overall asthma symptoms, asthma quality of life (AQL), and asthma control. Eligible subjects who declined to participate in randomization were offered enrollment into a parallel open-label (OL) azithromycin treatment arm. Results: Of 304 adult asthma patients screened, 97 (32%) were enrolled: 38 were randomized to azithromycin, 37 were randomized to placebo, and 22 opted in as OL subjects. OL subjects had higher rates of severe persistent asthma compared with randomized subjects (32% vs 8%, respectively; P = .012). At 1 year, compared with the placebo arm, subjects randomized to azithromycin were more likely to have an AQL score ≥1 unit increase compared with baseline, but this difference was not statistically significant (36% vs 21% for placebo; P = .335). Compared with placebo, OL subjects had significant improvements in overall asthma symptoms from baseline (P = .0196), AQL (P = .0006), and asthma control (P = .0148). Conclusions: Adults with asthma who were randomized to azithromycin did not show statistically significant improvement in asthma outcomes, although the study was underpowered to detect clinical improvement in 15% (number needed to treat = 7). Adults with severe persistent asthma who elected OL treatment documented clinical improvements in asthma symptoms, AQL, and asthma control that persisted after completion of OL azithromycin (number needed to treat = 2).