Wouter D. van Dijk

The acute effect of cigarette smoking on the high-sensitivity CRP and fibrinogen biomarkers in chronic obstructive pulmonary disease patients

AIM The evidence on the acute effects of smoking on biomarkers is limited. Our aim was to study the acute effect of smoking on disease-related biomarkers. METHODS The acute effect of smoking on serum high sensitivity CRP (hs-CRP) and plasma fibrinogen and its association with disease severity was studied by challenging 31 chronic obstructive pulmonary disease patients with cigarette smoking and repeatedly measuring these biomarkers before and after smoking. RESULTS Fibrinogen and hs-CRP increased directly after smoking by 9.4 mg/dl (95% CI: 4.2-14.5) and 0.13 mg/l (95% CI: 0.03-0.23), respectively. Fibrinogen levels remained elevated after 35 min, whereas hs-CRP normalized. Pearsons correlation coefficient between the hs-CRP change and chronic obstructive pulmonary disease severity was 0.25 (p = 0.06). CONCLUSION Fibrinogen and hs-CRP increased directly after smoking in the chronic obstructive pulmonary disease patients. Their association with disease risk and/or progression remains to be demonstrated.

Megatrials for Bronchodilators in Chronic Obstructive Pulmonary Disease (COPD) Treatment: Time to Reflect

Introduction: Chronic obstructive pulmonary disease (COPD) is an important cause of morbidity and mortality worldwide. Although (long-acting) bronchodilators are used to relieve symptoms, the impact of bronchodilators on COPD mortality remains an unresolved issue. Our aim was to explore the results and the interpretations of the results of studies of bronchodilator treatment from high-impact COPD trials. Methods: We searched PubMed and Embase for primary publications of randomized controlled trials with more than 1000 participants with COPD and that studied the effectiveness of long-acting bronchodilator treatment. We assessed population characteristics, primary outcomes, focus of outcomes, and possible bias from concomitant pulmonary medication. Results: We retrieved 5 primary publications of large trials. Participants tended to be patients with rather severe COPD who were cared for at a hospital. Only half of the primary outcomes were statistically significant. Reports tended to focus on statically significant outcomes and not necessarily on primary outcomes or outcomes of the whole study population. The relevance of study outcomes was rarely discussed. Discussion: The rather small effects of bronchodilators in a COPD population that is not representative for daily care, together with the tendency of relying on statistical rather than clinical significance, hampers translation to the large number of patients with COPD in the community.

Bronchodilation and smoking interaction in COPD: a cohort pilot study to assess cardiovascular risk.

Background: Smoking and bronchodilator treatment are both extensively studied as key elements in patients with chronic obstructive pulmonary disease. However, little is known about whether or not these elements interact in terms of developing cardiovascular diseases in patients with COPD. Objectives: To explore to what extent the risk of developing ischemic cardiovascular disease in COPD patients is mediated by smoking status, use of bronchodilators and – specifically – their interaction. Methods: We performed an observational pilot study on a relatively healthy Dutch COPD cohort from a primary care diagnostic center database with full information on spirometry tests, smoking status, bronchodilator use and other prescribed medication. We defined first ischemic cardiovascular events as primary outcome, measured by first prescription of antiplatelet drugs and/or nitrates. Unadjusted analyses by Kaplan-Meier were followed by adjusted Cox’ proportional hazards. Results: 845 COPD patients, totaling 2,169 observation years, were included in the analyses. We observed an increased risk for nonfatal ischemic cardiovascular events by smoking (adjusted HR = 3.58, p = 0.001) and a protective effect of bronchodilators (adjusted HR = 0.43, p = 0.01). Although the protective effect of bronchodilators appears to be substantially minimized in patients that persist in smoking, we could not statistically confirm a hazardous interaction between bronchodilators and smoking (HR 2.50, p = 0.21). Conclusion: Our study reveals bronchodilators may protect from ischemic cardiovascular events in a relatively ‘healthy’ COPD population. We did not confirm a hazardous interaction between bronchodilators and smoking, although we observed current smokers benefit substantially less from the protective effect of bronchodilators.

Cigarette smoke retention and bronchodilation in patients with COPD. A controlled randomized trial

INTRODUCTION Bronchodilators are the cornerstone for symptomatic treatment of chronic obstructive pulmonary disease (COPD). Many patients use these agents while persisting in their habit of cigarette smoking. We hypothesized that bronchodilators increase pulmonary retention of cigarette smoke and hence the risk of smoking-related (cardiovascular) disease. Our aim was to investigate if bronchodilation causes increased pulmonary retention of cigarette smoke in patients with COPD. METHODS A double-blinded, placebo-controlled, randomized crossover trial, in which COPD patients smoked cigarettes during undilated conditions at one session and maximal bronchodilated conditions at the other session. Co-primary outcomes were pulmonary tar and nicotine retention. We performed a secondary analysis that excludes errors due to possible contamination. Secondary outcomes included the biomarkers C-reactive protein and fibrinogen, and smoke inhalation patterns. RESULTS Of 39 randomized patients, 35 patients completed the experiment and were included in the final analysis. Bronchodilation did not significantly increase tar retention (-4.5%, p = 0.20) or nicotine retention (-2.6%, p = 0.11). Secondary analysis revealed a potential reduction of retention due to bronchodilation: tar retention (-3.8%, p = 0.13), and nicotine retention (-3.4%, p = 0.01). Bronchodilation did not modify our secondary outcomes. CONCLUSIONS Our results do not support the hypothesis that cigarette tar and nicotine retention in COPD patients is increased by bronchodilation, whereas we observed a possibility towards less retention. TRIAL REGISTRATION www.clinicaltrials.gov: NCT00981851.

Short-acting anticholinergic bronchodilation does not increase cardiovascular events in smokers with mild to moderate pulmonary obstruction

We hypothesized that bronchodilation in patients with chronic obstructive pulmonary disease (COPD) increases the smoke‐related risk to develop cardiovascular disease, and aimed to study the effect of short‐acting anticholinergic bronchodilation and smoking on cardiovascular events.