Sebastian Carballo

β-Lactam Monotherapy vs β-Lactam-Macrolide Combination Treatment in Moderately Severe Community-Acquired Pneumonia A Randomized Noninferiority Trial

IMPORTANCE The clinical benefit of adding a macrolide to a β-lactam for empirical treatment of moderately severe community-acquired pneumonia remains controversial. OBJECTIVE To test noninferiority of a β-lactam alone compared with a β-lactam and macrolide combination in moderately severe community-acquired pneumonia. DESIGN, SETTING, AND PARTICIPANTS Open-label, multicenter, noninferiority, randomized trial conducted from January 13, 2009, through January 31, 2013, in 580 immunocompetent adult patients hospitalized in 6 acute care hospitals in Switzerland for moderately severe community-acquired pneumonia. Follow-up extended to 90 days. Outcome assessors were masked to treatment allocation. INTERVENTIONS Patients were treated with a β-lactam and a macrolide (combination arm) or with a β-lactam alone (monotherapy arm). Legionella pneumophila infection was systematically searched and treated by addition of a macrolide to the monotherapy arm. MAIN OUTCOMES AND MEASURES Proportion of patients not reaching clinical stability (heart rate <100/min, systolic blood pressure >90 mm Hg, temperature <38.0°C, respiratory rate <24/min, and oxygen saturation >90% on room air) at day 7. RESULTS After 7 days of treatment, 120 of 291 patients (41.2%) in the monotherapy arm vs 97 of 289 (33.6%) in the combination arm had not reached clinical stability (7.6% difference, P = .07). The upper limit of the 1-sided 90% CI was 13.0%, exceeding the predefined noninferiority boundary of 8%. Patients infected with atypical pathogens (hazard ratio [HR], 0.33; 95% CI, 0.13-0.85) or with Pneumonia Severity Index (PSI) category IV pneumonia (HR, 0.81; 95% CI, 0.59-1.10) were less likely to reach clinical stability with monotherapy, whereas patients not infected with atypical pathogens (HR, 0.99; 95% CI, 0.80-1.22) or with PSI category I to III pneumonia (HR, 1.06; 95% CI, 0.82-1.36) had equivalent outcomes in the 2 arms. There were more 30-day readmissions in the monotherapy arm (7.9% vs 3.1%, P = .01). Mortality, intensive care unit admission, complications, length of stay, and recurrence of pneumonia within 90 days did not differ between the 2 arms. CONCLUSIONS AND RELEVANCE We did not find noninferiority of β-lactam monotherapy in patients hospitalized for moderately severe community-acquired pneumonia. Patients infected with atypical pathogens or with PSI category IV pneumonia had delayed clinical stability with monotherapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00818610.

Elevated endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity.

AIMS Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. METHODS AND RESULTS Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with (13)N-ammonia PET/CT. Study participants (n = 77) were divided into three groups based on their body mass index (BMI, kg/m(2)): control group 20 ≤ BMI <25 (n = 21); overweight group, 25 ≤ BMI <30 (n = 26); and obese group, BMI ≥ 30 (n = 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P = 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P = 0.806)]. The endothelium-related change in MBF during CPT from rest (ΔMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (-0.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P = 0.010 and P = 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P = 0.007 and P = 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with ΔMBF to CPT (r = -0.37, P = 0.046 and r = -0.48, P = 0.008) and hyperaemic MBFs (r = -0.38, P = 0.052 and r = -0.45, P = 0.017), respectively. CONCLUSIONS Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.

Coronary Vasomotor Control in Obesity and Morbid Obesity: Contrasting Flow Responses With Endocannabinoids, Leptin, and Inflammation

OBJECTIVES This study sought to investigate abnormalities in coronary circulatory function in 2 different disease entities of obese (OB) and morbidly obese (MOB) individuals and to evaluate whether these would differ in severity with different profiles of endocannabinoids, leptin, and C-reactive protein (CRP) plasma levels. BACKGROUND There is increasing evidence that altered plasma levels of endocannabinoids, leptin, and CRP may affect coronary circulatory function in OB and MOB. METHODS Myocardial blood flow (MBF) responses to cold pressor test from rest and during pharmacologically induced hyperemia were measured with N-13 ammonia positron emission tomography/computed tomography. Study participants (n = 111) were divided into 4 groups based on their body mass index (BMI) (kg/m(2)): 1) control group (BMI: 20 to 24.9, n = 30); 2) overweight group (BMI: 25 to 29.9, n = 31), 3) OB group (BMI: 30 to 39.9, n = 25); and 4) MOB group (BMI ≥40, n = 25). RESULTS The cold pressor test-induced change in endothelium-related MBF response (ΔMBF) progressively declined in overweight and OB groups when compared with the control group [median: 0.19 (interquartile range [IQR] 0.08, 0.27) and 0.11 (0.03, 0.17) vs. 0.27 (0.23, 0.38) ml/g/min; p ≤ 0.01, respectively], whereas it did not differ significantly between OB and MOB groups [median: 0.11 (IQR: 0.03, 0.17) and 0.09 (-0.01, 0.19) ml/g/min; p = 0.93]. Compared with control subjects, hyperemic MBF subjects comparably declined in the overweight, OB, and MOB groups [median: 2.40 (IQR 1.92, 2.63) vs. 1.94 (1.65, 2.30), 2.05 (1.67, 2.38), and 2.14 (1.78, 2.76) ml/g/min; p ≤ 0.05, respectively]. In OB individuals, ΔMBF was inversely correlated with increase in endocannabinoid anandamide (r = -0.45, p = 0.044), but not with leptin (r = -0.02, p = 0.946) or with CRP (r = -0.33, p = 0.168). Conversely, there was a significant and positive correlation among ΔMBF and elevated leptin (r = 0.43, p = 0.031) and CRP (r = 0.55, p = 0.006), respectively, in MOB individuals that was not observed for endocannabinoid anandamide (r = 0.07, p = 0.740). CONCLUSIONS Contrasting associations of altered coronary endothelial function with increases in endocannabinoid anandamide, leptin, and CRP plasma levels identify and characterize OB and MOB as different disease entities affecting coronary circulatory function.

Prognosis of Patients With Familial Hypercholesterolemia After Acute Coronary Syndromes

BACKGROUND: Patients with heterozygous familial hypercholesterolemia (FH) and coronary heart disease have high mortality rates. However, in an era of high-dose statin prescription after acute coronary syndrome (ACS), the risk of recurrent coronary and cardiovascular events associated with FH might be mitigated. We compared coronary event rates between patients with and without FH after ACS. METHODS: We studied 4534 patients with ACS enrolled in a multicenter, prospective cohort study in Switzerland between 2009 and 2013 who were individually screened for FH on the basis of clinical criteria according to 3 definitions: the American Heart Association definition, the Simon Broome definition, and the Dutch Lipid Clinic definition. We used Cox proportional models to assess the 1-year risk of first recurrent coronary events defined as coronary death or myocardial infarction and adjusted for age, sex, body mass index, smoking, hypertension, diabetes mellitus, existing cardiovascular disease, high-dose statin at discharge, attendance at cardiac rehabilitation, and the GRACE (Global Registry of Acute Coronary Events) risk score for severity of ACS. RESULTS: At the 1-year follow-up, 153 patients (3.4%) had died, including 104 (2.3%) of fatal myocardial infarction. A further 113 patients (2.5%) experienced nonfatal myocardial infarction. The prevalence of FH was 2.5% with the American Heart Association definition, 5.5% with the Simon Broome definition, and 1.6% with the Dutch Lipid Clinic definition. Compared with patients without FH, the risk of coronary event recurrence after ACS was similar in patients with FH in unadjusted analyses, although patients with FH were >10 years younger. However, after multivariable adjustment including age, the risk was greater in patients with FH than without, with an adjusted hazard ratio of 2.46 (95% confidence interval, 1.07–5.65; P=0.034) for the American Heart Association definition, 2.73 (95% confidence interval, 1.46–5.11; P=0.002) for the Simon Broome definition, and 3.53 (95% confidence interval, 1.26–9.94; P=0.017) for the Dutch Lipid Clinic definition. Depending on which clinical definition of FH was used, between 94.5% and 99.1% of patients with FH were discharged on statins and between 74.0% and 82.3% on high-dose statins. CONCLUSIONS: Patients with FH and ACS have a >2-fold adjusted risk of coronary event recurrence within the first year after discharge than patients without FH despite the widespread use of high-intensity statins.

Quality of Care after Acute Coronary Syndromes in a Prospective Cohort with Reasons for Non-Prescription of Recommended Medications

Background Adherence to guidelines is associated with improved outcomes of patients with acute coronary syndrome (ACS). Clinical registries developed to assess quality of care at discharge often do not collect the reasons for non-prescription for proven efficacious preventive medication in Continental Europe. In a prospective cohort of patients hospitalized for an ACS, we aimed at measuring the rate of recommended treatment at discharge, using pre-specified quality indicators recommended in cardiologic guidelines and including systematic collection of reasons for non-prescription for preventive medications. Methods In a prospective cohort with 1260 patients hospitalized for ACS, we measured the rate of recommended treatment at discharge in 4 academic centers in Switzerland. Performance measures for medication at discharge were pre-specified according to guidelines, systematically collected for all patients and included in a centralized database. Results Six hundred and eighty eight patients(54.6%) were discharged with a main diagnosis of STEMI, 491(39%) of NSTEMI and 81(6.4%) of unstable angina. Mean age was 64 years and 21.3% were women. 94.6% were prescribed angiotensin converting enzyme inhibitors/angiotensin II receptor blockers at discharge when only considering raw prescription rates, but increased to 99.5% when including reasons non-prescription. For statins, rates increased from 98% to 98.6% when including reasons for non-prescription and for beta-blockers, from 82% to 93%. For aspirin, rates further increased from 99.4% to 100% and from to 99.8% to 100% for P2Y12 inhibitors. Conclusions We found a very high adherence to ACS guidelines for drug prescriptions at discharge when including reasons for non-prescription to drug therapy. For beta-blockers, prescription rates were suboptimal, even after taking into account reason for non-prescription. In an era of improving quality of care to achieve 100% prescription rates at discharge unless contra-indicated, pre-specification of reasons for non-prescription for cardiovascular preventive medication permits to identify remaining gaps in quality of care at discharge. Trial Registration ClinicalTrials.gov NCT01000701

Improved risk stratification of patients with acute coronary syndromes using a combination of hsTnT, NT-proBNP and hsCRP with the GRACE score.

Background: Clinical scores and biomarkers improve risk stratification of patients with acute coronary syndromes. However, little is known about their value in patients referred for coronary angiography. Methods: Consecutive patients admitted at four Swiss university hospitals with a diagnosis of acute coronary syndrome were enrolled into the SPUM-ACS Biomarker Cohort between 2009 and 2012. Patients were followed at 30 days and 1 year with assessment of adjudicated events including all-cause mortality and the composite of all-cause mortality or non-fatal recurrent myocardial infarction. Results: Events and biomarkers were analysed in 1892 patients (52.4% with ST-segment elevation myocardial infarction, 43.3% with non-ST-segment elevation myocardial infarction and 4.3% with unstable angina). Death at 30 days occurred in 35 patients (1.9%) and at 1 year in 80 patients (4.3%). The choice of troponin assay (conventional versus high sensitivity) to calculate the Global Registry of Acute Coronary Events (GRACE) score did not affect risk prediction. The prognostic accuracy of the GRACE score was improved when combined with three individual biomarkers including high sensitivity troponin T (hsTnT), N-terminal-pro B-type natriuretic peptide (NT-proBNP) and high sensitivity C-reactive protein (hsCRP) to yield a 9% increment (C-statistic 0.73–>0.82) for the discrimination of short-term risk for all-cause mortality. In contrast, the novel biomarkers placental growth factor (PlGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and the ratio sFlt-1/PlGF did not improve risk stratification. Conclusions: In patients with acute coronary syndrome referred for coronary angiography, combinations of biomarkers including hsTnT, NT-proBNP and hsCRP with the GRACE score enhanced risk discrimination. Clinical Trials Registration: NCT01000701

Acute Respiratory and Cardiovascular Admissions after a Public Smoking Ban in Geneva, Switzerland

Background Many countries have introduced legislations for public smoking bans to reduce the harmful effects of exposure to tobacco smoke. Smoking bans cause significant reductions in admissions for acute coronary syndromes but their impact on respiratory diseases is unclear. In Geneva, Switzerland, two popular votes led to a stepwise implementation of a state smoking ban in public places, with a temporary suspension. This study evaluated the effect of this smoking ban on hospitalisations for acute respiratory and cardiovascular diseases. Methods This before and after intervention study was conducted at the University Hospitals of Geneva, Switzerland, across 4 periods with different smoking legislations. It included 5,345 patients with a first hospitalisation for acute coronary syndrome, ischemic stroke, acute exacerbation of chronic obstructive pulmonary disease, pneumonia and acute asthma. The main outcomes were the incidence rate ratios (IRR) of admissions for each diagnosis after the final ban compared to the pre-ban period and adjusted for age, gender, season, influenza epidemic and secular trend. Results Hospitalisations for acute exacerbation of chronic obstructive pulmonary disease significantly decreased over the 4 periods and were lowest after the final ban (IRR = 0.54 [95%CI: 0.42–0.68]). We observed a trend in reduced admissions for acute coronary syndromes (IRR = 0.90 [95%CI: 0.80–1.00]). Admissions for ischemic stroke, asthma and pneumonia did not significantly change. Conclusions A legislative smoking ban was followed by a strong decrease in hospitalisations for acute exacerbation of chronic obstructive pulmonary disease and a trend for reduced admissions for acute coronary syndrome. Smoking bans are likely to be very beneficial for patients with chronic obstructive pulmonary disease.

Inclusion into a heart failure critical pathway reduces the risk of death or readmission after hospital discharge.

BACKGROUND Evidence-based therapies can lower the risk of death or hospital admission in heart failure (HF) patients, but are underprescribed. Critical pathways are one means of supporting systematic use of evidence-based recommendations. METHODS Patients admitted for HF in one hospital in 2009 and included in a critical pathway were compared with a control group of patients admitted in 2007. The primary endpoint was the risk of death or readmission within 90 days after discharge. The hazard ratio of death or readmission was evaluated in a multivariate Cox proportional hazard model adjusting for age, sex, co-morbidities, and length of stay. RESULTS Three hundred and sixty-three patients were evaluated (151 in the critical pathway and 212 in the control group). Adjusted hazard ratio for death or readmission at 90 days was 0.72 (95 CI 0.51-1.00, p=0.049). Adhesion to guidelines was significantly better for patients included in the critical pathway (p=0.004), with more frequent prescription of beta-blockers (70.9% (95% CI 62.9-78.0) vs. 56.6% (95% CI 49.6-63.4), p=0.006), and evaluation of left ventricular ejection fraction (LVEF, 73.5% (95% CI 65.7-80.3) vs. 57.5% (95% CI 50.6-64.3), p=0.002). Patients with reduced LVEF seem to have benefited the most from the inclusion in the critical pathway. CONCLUSIONS Implementation of a critical pathway for patients hospitalized for HF was associated with a 28% reduction of the relative risk of death or readmission and improved adhesion to guidelines.

Determining prognosis in acute exacerbation of COPD

Background Acute exacerbations are the leading causes of hospitalization and mortality in patients with COPD. Prognostic tools for patients with chronic COPD exist, but there are scarce data regarding acute exacerbations. We aimed to identify the prognostic factors of death and readmission after exacerbation of COPD. Methods This was a retrospective study conducted in the Department of Internal Medicine of Geneva University Hospitals. All patients admitted to the hospital with a diagnosis of exacerbation of COPD between 2008 and 2011 were included. The studied variables included comorbidities, Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity classification, and biological and clinical parameters. The main outcome was death or readmission during a 5-year follow-up. The secondary outcome was death. Survival analysis was performed (log-rank and Cox). Results We identified a total of 359 patients (195 men and 164 women, average age 72 years). During 5-year follow-up, 242 patients died or were hospitalized for the exacerbation of COPD. In multivariate analysis, age (hazard ratio [HR] 1.03, 95% CI 1.02–1.05; P<0.0001), severity of airflow obstruction (forced expiratory volume in 1 s <30%; HR 4.65, 95% CI 1.42–15.1; P=0.01), diabetes (HR 1.47, 95% CI 1.003–2.16; P=0.048), cancer (HR 2.79, 95% CI 1.68–4.64; P<0.0001), creatinine (HR 1.003, 95% CI 1.0004–1.006; P=0.02), and respiratory rate (HR 1.03, 95% CI 1.003–1.05; P=0.028) on admission were significantly associated with the primary outcome. Age, cancer, and procalcitonin were significantly associated with the secondary outcome. Conclusion COPD remains of ominous prognosis, especially after exacerbation requiring hospitalization. Baseline pulmonary function remains the strongest predictor of mortality and new admission. Demographic factors, such as age and comorbidities and notably diabetes and cancer, are closely associated with the outcome of the patient. Respiratory rate at admission appears to be the most prognostic clinical parameter. A prospective validation is, however, still required to enable the identification of patients at higher risk of death or readmission.

Present and future of secondary prevention after an acute coronary syndrome

Despite a marked improvement of in-hospital outcome of patients with Acute Coronary Syndrome (ACS), long-term outcome remains poor. There remains a high risk of complications, Non ST-Elevation ACS (NSTE-ACS) patients being at higher risk than those with ST-elevation ACS, in part due to more diffuse coronary artery disease. Whether with conservative medical management or an early invasive approach, of which they less frequently benefit, NSTE-ACS patients are less frequently treated according to guidelines. Therapeutic adhesion within the months following hospital discharge is low and associated with an increase in one-year mortality. The next step in the improvement of care of ACS patients will be to use multi-dimensional prevention programs that use didactic information tools and improve patient motivation, aimed at reinforcing the use of guidelines, promoting in-hospital therapeutic education, creating patient-health care provider partnerships and including discharge programs that ensure the prescription of recommended therapies.