Journal Club

JULY 2015

Screening for Occult Cancer in Unprovoked Venous Thromboembolism

M. Carrier, A. Lazo‑Langner, S Shivakumar et al.

Department of Medicine, Ottawa Hospital Research Institute

NEJM 22nd June 2015

Venous thromboembolism (VTE) can be a may be a sign of underlying malignancy and as such screening for occult cancer in a patient with unprovoked VTE is often undertaken. However there is a large diversity in practice. The aim of this study was to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked VTE.

This was a multicenter, open-label, randomized, controlled trial in which patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period.

854 patients randomised of which 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up. 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P = 0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P = 1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P = 0.88) or in cancer-related mortality (1.4% and 0.9%, P = 0.75).

The authors conclude that routine screening with CT of the abdomen and pelvis in these patients did not provide a clinically significant benefit.
The prevalence of occult cancer was low (3.9%) among patients with a first unprovoked venous thromboembolism in this study. Previous studies have suggested it may be as high as 10% and that 60% of occult cancers are detected in the first few months after a diagnosis of VTE.
The authors note that at best the number needed to screen to detect one missed occult cancer was 91 and that multiphasic CT of the abdomen and pelvis is associated with a median effective dose of radiation exposure of 31 millisieverts which is equivalent to 442 chest radiographs, whilst the estimated number of patients undergoing multiphasic CT of the abdomen and pelvis required for the development of one radiation induced cancer is 460 for women 40 years of age and 498 for men 40 years of age.

APRIL 2015


Antibiotic Treatment Strategies for Community-Acquired Pneumonia in Adults

D. F.Postma, C. H. van Werkhoven, L. J.R. van Elden et al

N Engl J Med April 2, 2015. 372:1312-1323

This study investigated empirical antibiotic treatment for patients with suspected community-acquired pneumonia (CAP) admitted to general hospital wards in a cluster-randomized, crossover trial with strategies rotated in 4-month periods. They tested the noninferiority of beta-lactam monotherapy (656 patients) to beta-lactam–macrolide combination (739 patients) and to fluoroquinolone monotherapy (888) strategies with respect to 90-day mortality, in an intention-to-treat analysis, using a noninferiority margin of 3 percentage points and a two-sided 90% confidence interval.
The median age of the patients was 70 years. The crude 90-day mortality was 9.0% (59 patients), 11.1% (82 patients), and 8.8% (78 patients), respectively, during these strategy periods. In the intention-to-treat analysis, the risk of death was higher by 1.9 percentage points (90% confidence interval [CI], −0.6 to 4.4) with the beta-lactam–macrolide strategy than with the beta-lactam strategy and lower by 0.6 percentage points (90% CI, −2.8 to 1.9) with the fluoroquinolone strategy than with the beta-lactam strategy. The median length of hospital stay was 6 days for all strategies, and the median time to starting oral treatment was 3 days (interquartile range, 0 to 4) with the fluoroquinolone strategy and 4 days (interquartile range, 3 to 5) with the other strategies.
They conclude that a strategy of preferred empirical treatment with beta-lactam monotherapy was noninferior to strategies with a beta-lactam–macrolide combination or fluoroquinolone monotherapy with regard to 90-day mortality.

The current UK National Institute for Health and Clinical Excellence (NICE) evidence based guidelines on Pneumonia; Diagnosis and management of community and hospital acquired pneumonia in adults, recommend a 5-day course of a single antibiotic to patients with low-severity community-acquired pneumonia with amoxicillin used in preference to a macrolide or a tetracycline and that a fluoroquinolone or dual antibiotic therapy should not be used. Dual antibiotic therapy with amoxicillin and a macrolide for patients is recommended only in moderate-severity CAP and dual antibiotic therapy with a beta-lactamase stable beta-lactam and a macrolide in high severity CAP.


P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study

R Abdulqawi, R Dockry and K Holt et al

Lancet 28 March 2015. Volume 385, No. 9974, p1198–1205.

Preclinical studies suggest that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons so could mediate sensitisation of the cough reflex, leading to chronic cough.
They investigated the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in patients with refractory chronic cough in a double-blind, placebo-controlled, two-period, crossover study at one UK centre. The primary analysis used a mixed effects model with the intention-to-treat population.
They randomly assigned 24 patients (mean age 54·5 years; SD 11·1). Cough frequency was reduced by 75% when patients were allocated to AF-219 compared when allocated to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219.
They conclude P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity. Antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives

Chronic cough is a common complaint that that can be difficult to manage in practice. Current guidelines stress the identification and management of underlying causes such as gastrooesphageal reflux diseaseCur

MARCH 2015


The Prognostic Value of Undetectable Highly Sensitive Cardiac Troponin I in Patients With Acute Pulmonary Embolism

Emad U. Hakemi, Tareq Alyousef, Geetanjali Dang, et al.

Chest. March 2015;147(3):685-694.

Acute pulmonary embolism (PE) is a major cause of mortality, morbidity, and hospitalization worldwide. Current evidence-based treatment guidelines are clear for patients for instance who are in hemodynamic shock, but for those who stable there is increasing interest in managing these patients as outpatients, particularly since the introduction of new oral anticoagulant agents. The crucial issue therefore is to select those patients who are at low risk of an adverse early outcome. A number of risk prediction models have been developed, the PESI score being the most extensively validated and widely used. This doesn’t include biomarkers such as cardiac troponin, yet elevated levels of these have been shown to be associated with adverse outcomes in patients with acute PE. However, few data address the management implications of undetectable cardiac troponin I (cTnI) using a highly sensitive assay.
This study hypothesized that undetectable cTnI (cTnI -, <0.012ng/ml) predicts very low in-hospital adverse event rates. In 298 consecutive patients with confirmed acute PE, 161 (55%) were cTnI+ and 137 (45%) cTnI−. No deaths, CPR or thrombolysis occurred in the cTnI− group vs fifteen (9%) in the cTnI+ group (P = 0.001) [6% deaths]. and no No hard events were observed in the cTnI− group vs 15 (9%) in the cTnI+ group (P < .001). Other events (ICU admisiion, IVC filter etc) were observed at a lower rate in the cTnI– group (21[15%] vs 69 [43%], P < .001). cTnI provided incremental prognostic value beyond clinical (PESI score), ECG, and imaging data (P < .001). They conclude that highly sensitive cTnI assay provides an excellent prognostic negative predictive value and may identifying candidates for out-of-hospital treatment of acute PE.

Sleep disordered breathing and enlargement of the right heart after myocardial infarction

Stefan Buchner, Michael Eglseer and Kurt Debl et al.

ERJ March 1, 2015 vol. 45 no. 3 680-690

Sleep Disordered breathing (SDB) is associated with cardiovascular disease and in long-term studies, SDB in patients with coronary artery disease was associated with a significant increase in the composite end point of death, myocardial infarction, and cerebrovascular events at a 5-year median follow-up interval.
The objective of this study was to assess the impact of SDB on structure and function of the right heart early after AMI, which is important in the prognosis after acute myocardial infarction (AMI). 54 patients underwent cardiovascular magnetic resonance 3–5 days and 12 weeks after AMI, and were stratified according to the presence of SDB, defined as an apnoea–hypopnoea index of ≥15 events·h−1. The results showed that 12 weeks after AMI, end-diastolic volume of the right ventricle had increased significantly in patients with SDB (n=27) versus those without (n=25) (mean±sd 14±23% versus 0±17%, p=0.020) and using multivariable linear regression analysis that the apnoea–hypopnoea index was significantly associated with right ventricular end-diastolic volume (B-coefficient 0.315 (95% CI 0.013–0.617); p=0.041). From baseline to 12 weeks, right atrial diastolic area increased more in patients with SDB (2.9±3.7 cm2 versus 1.0±2.4 cm2, p=0.038; when adjusted for left ventricular end systolic volume, p=0.166). The authors conclude therefore that SDB diagnosed shortly after AMI predicts an increase of right ventricular end-diastolic volume and possibly right atrial area over the following 12 weeks and therefore SDB may contribute to enlargement of the right heart after AMI.

Asthma and the Hygiene Hypothesis. Does Cleanliness Matter?

Juliane Weber, Sabina Illi, Dennis Nowak et al.

American Journal of Respiratory and Critical Care Medicine. 1st March 2015. Vol. 191, No. 5, pp. 522-529.

In 1989 David Strachan proposed an explanation for the rise in atopic disease which became know as the ‘hygiene hypothesis’. He reasoned that if allergic disease was prevented by infection in early childhood then improved standards of living and household amenities improving cleanliness and the decreasing size of the family reducing risk of infection by older siblings may account for the changes seen in allergic diseases. The aim of this study was to relate personal and home cleanliness to risk of asthma and allergies. Comprehensive questionnaire information on home or personal cleanliness and allergic health conditions at school age was collected in 399 participants of the urban Perinatale Asthma Umwelt Langzeit Allergie Studie (PAULA) birth cohort. Bacterial markers were assessed in floor and mattress dust and were related to cleanliness and allergic diseases.
The results showed personal cleanliness was inversely related to bacterial compounds on floors and mattresses, whereas home cleanliness effectively reduced dust amount but not microbial markers. Exposure to muramic acid related to a lower prevalence of school-age asthma (adjusted odds ratio, 0.59 [95% confidence interval, 0.39; 0.90]). Mattress endotoxin in the first year of life was inversely associated with atopic sensitization (0.73 [0.56–0.96]) and asthma at school age (0.72 [0.55–0.95]).
The authors conclude that bacterial exposure in house dust determined childhood asthma and allergies. Personal cleanliness, such as washing hands, and home cleanliness were objectively reflected by dust parameters in homes. However, neither personal nor home cleanliness was associated with a risk for asthma and allergies. Other microbial components in house dust not affected by personal hygiene are likely to play a role.

Randomized Trial of Peanut Consumption in Infants at Risk for Peanut Allergy

George Du Toit, Graham Roberts, Peter H. Sayre et al.

N Engl J Med February 26th 2015;372:803-13.

The prevalence of peanut allergy among children in Western countries has doubled in the past 10 years, is becoming increasingly common in Africa and Asia and is the commonest cause of anaphylaxis and death from food allergy.Peanut allergy develops early in life and is rarely outgrown. International guidelines recommended the exclusion of allergenic foods from the diets of infants at high risk for allergy and from the diets of their mothers during pregnancy and lactation. However, studies in which food allergens have been eliminated from the diet have consistently failed to show that elimination from the diet prevented the development of IgE-mediated food allergy.
In this study 640 infants between 4 and 11 months with severe eczema, egg allergy, or both were randomised to consume or avoid peanuts until 60 months of age. They were assigned to separate study cohorts on the basis of pre-existing sensitivity to peanut extract. The results showed the prevalence of peanut allergy at 60 months of age was 13.7% in the avoidance group and 1.9% in the consumption group (P<0.001). Among the 98 participants in the intention-to-treat population who initially had positive test results, the prevalence of peanut allergy was 35.3% in the avoidance group and 10.6% in the consumption group (P = 0.004). There was no significant difference in the incidence of serious adverse events. Increases in levels of peanut-specific IgG4 antibody occurred predominantly in the consumption group; a greater percentage of participants in the avoidance group had elevated titres of peanut-specific IgE antibody. A larger wheal on the skin-prick test and a lower ratio of peanut-specific IgG4:IgE were associated with peanut allergy. The authors conclude that the early sustained consumption of peanuts significantly decreased the frequency of the development of peanut allergy among high risk children and modulated immune responses to peanuts. This raises questions about the usefulness of deliberate avoidance of peanuts as a strategy to prevent allergy.

Effect of roflumilast on exacerbations in patients with severe chronic obstructive pulmonary disease uncontrolled by combination therapy (REACT): a multicentre randomised controlled trial

Fernando J Martinez, Peter M A Calverley, Udo-Michael Goehring, Manja Brose, Leonardo M Fabbri, Klaus F Rabe

Lancet. 7 March 2015. Vol. 385, No. 9971, p857–866.

Roflumilast is a highly selective phosphodiesterase inhibitor approved in several countries for treatment of patients with severe chronic obstructive pulmonary disease (COPD). In the UK NICE guidance on Roflumilast issued in 2012is that it should only be used in the context of a clinical trial for adults with severe COPD associated with chronic bronchitis with a history of frequent exacerbations as an add-on to bronchodilator treatment. This study investigated whether Roflumilast would reduce exacerbations in patients with severe COPD at risk for exacerbations, even in combination with inhaled corticosteroid and longacting β2 agonist treatment. It was a one year double-blind, placebo-controlled, parallel group, multicentre, phase 3–4 trial. 1945 patients from 203 centres in 21 countries were enrolled. Eligible patients were 40 years of age or older with at least a 20 pack-years smoking history and a diagnosis of COPD with severe airflow limitation, symptoms of chronic bronchitis, and at least two exacerbations in the previous year. Patients were randomised to Roflumilast 500 μg or placebo given orally once daily together with a fixed inhaled corticosteroid and longacting β2 agonist combination. Background Tiotropium treatment was allowed. All patients and investigators were masked to group assignment.
The results showed the rate of moderate-to-severe COPD exacerbations was 13·2% lower in the Roflumilast group than in the placebo group according to a Poisson regression analysis (Roflumilast 0·805 vs placebo 0·927; rate ratio [RR] 0·868 [95% CI 0·753–1·002], p=0·0529), and 14·2% lower according to a predefined sensitivity analysis using negative binomial regression (0·823 vs 0·959; 0·858 [0·740–0·995], p=0·0424). Adverse events were reported by 648 (67%) of 968 patients receiving Roflumilast and by 572 (59%) of 967 patients in the placebo group; adverse event-associated patient withdrawal from the study was also more common in the Roflumilast group (104/968 [11%]) than in the placebo group (52/967 [5%]). The most frequently reported serious adverse events were COPD exacerbations and pneumonia. 17 (1·8%) deaths occurred in the Roflumilast group compared with 18 (1·9%) in the placebo group.
The authors conclude that Roflumilast reduces exacerbations and hospital admissions in patients with severe COPD and chronic bronchitis who are at risk of frequent and severe exacerbations despite inhaled corticosteroid and longacting β2 agonist therapy, even in combination with Tiotropium.



P2X3 receptor antagonist (AF-219) in refractory chronic cough: a randomised, double-blind, placebo-controlled phase 2 study

Rayid Abdulqawi, Rachel Dockry, Kimberley Holt et al.

The Lancet, 25 November 2014

Chronic cough, defined as a cough lasting longer than 8 weeks, may occur in up to 12% of patients, and whilst asthma, gastro-oesophageal reflux, and rhino-sinus disease is thought to account for most patients with cough and a normal chest X-ray and clinical assessment, it is now recognised that a significant proportion of these patients are refractory to treatment of any underlying disorders, despite careful investigation and trials of treatments. Few effective treatment options are available for these patients. Studies have suggested that P2X3 receptors are expressed by airway vagal afferent nerves and contribute to the hypersensitisation of sensory neurons. P2X3 receptors could mediate sensitisation of the cough reflex, leading to chronic cough.
In a double-blind, placebo-controlled, two-period, crossover study, the authors investigated the efficacy of a first-in-class oral P2X3 antagonist, AF-219, to reduce cough frequency in 24 patients (mean age 54·5 years; SD 11·1) with refractory chronic cough
Their results showed cough frequency was reduced by 75% when patients were allocated to AF-219 compared to placebo (p=0·0003). Daytime cough frequency fell from a mean 37 coughs per h (SD 32) to 11 (8) coughs per h after AF-219 treatment versus 65 (163) coughs per h to 44 (51) coughs per h after placebo. Six patients withdrew before the end of the study because of taste disturbances, which were reported by all patients taking AF-219.
The authors conclude that P2X3 receptors seem to have a key role in mediation of cough neuronal hypersensitivity and that antagonists of P2X3 receptors such as AF-219 are a promising new group of antitussives.

A contemporary survival analysis of individuals with cystic fibrosis: a cohort study

Anne L. Stephenson, Melissa Tom, Yves Berthiaume et al.

Eur Resp J 2014. November 13

Median age of survival in cystic fibrosis (CF) has increased in recent years. Factors associated
with worse survival include female sex, malnutrition, low lung function, certain infections and CF-related diabetes (CFRD).
The objectives of this study were to identify risk factors associated with survival using contemporary
population-based data across the spectrum of disease severity and to identify those subgroups of CF patients
at highest risk for death. The authors undertook a population-based cohort study using the Canadian CF Registry (CCFR) containing data on 5787 Canadians with CF to evaluate survival between 1990 and 2012.
Their results median age of survival increased from 31.9 years (95% CI 28.3–35.2 years) in 1990 to 49.7 years (95% CI 46.1–52.2 years) in 2012.The annual rate of pulmonary exacerbations was the strongest variable associated with risk of death (HR 4.53 for o3 exacerbations per year, p,0.0001; HR 2.98 for 1–2 exacerbations/year, p,0.001). Malnutrition was associated with an increased risk of death, with a HR of 2.12. FEV1 remained an independent risk factor (higher FEV1 was associated with a lower risk of death).The adjusted risk of death in females was higher than in males (HR 1.28). Significantly more females had CFRD compared with males and they found a differential negative effect of having CFRD in females which may explain much of the sex gap in CF survival.

Predicting survival in malignant pleural effusion: development and validation of the LENT prognostic score

Amelia O Clive, Brennan C Kahan, Clare E Hooper et al.

Thorax 2014;69:1098–1104. November 11th

The aim of this study was to obtain contemporary data on survival by underlying tumour type in patients
with Malignant Pleural Effusion, identify prognostic indicators of overall survival and develop and validate a prognostic scoring system.
Based on the results of the international dataset of 789 patients from UK, Australia and Holland and the multivariable survival analysis, the LENT prognostic score (pleural fluid Lactate dehydrogenase, Eastern Cooperative Oncology Group (ECOG) performance score (PS), Neutrophil-to-lymphocyte ratio and Tumour type) was developed and subsequently validated using an independent data set.
The authors found that this new LENT score predicted survival with significantly better accuracy than ECOG Performance Status alone and concluded that it may aid clinical decision making in this diverse patient population.

Cost-Effectiveness of CT Screening in the National Lung Screening Trial

William C. Black, Ilana F. Gareen, Samir S. Soneji, et al.

N Engl J Med 2014; 371:1793-1802. November 6, 2014

The National Lung Screening Trial (NLST) reported that screening with low-dose computed tomography (CT) compared with chest radiography reduced reduced the risk of death from lung cancer by 20% among persons 55 to 74 years of age who had a smoking history of at least 30 pack-years and were current smokers or were former smokers who had quit within the previous 15 years.
The authors of this study examined the cost-effectiveness of screening with low-dose CT by estimating mean life-years, quality-adjusted life-years (QALYs), costs per person, and incremental cost-effectiveness ratios (ICERs) for three alternative strategies: screening with low-dose CT, screening with radiography, and no screening.
Their results showed that screening for lung cancer with low-dose CT would cost $81,000 per QALY gained, but that modest changes in their assumptions would greatly alter this figure. This raises questions as to whether screening outside will be cost-effective and will depend on how it is implemented.