Cardiovascular Events after Clarithromycin Use in Lower Respiratory Tract Infections: Analysis of Two Prospective Cohort Studies. S. Schembri, P.A. Williamson, P.M. Short, A. Singanayagam, A. Akram, J. Taylor, A. Singanayagam, A.T. Hill, J.D. Chalmers. BMJ. 2013 Mar 20;346.
OBJECTIVE: To study the association of clarithromycin with cardiovascular events in the setting of acute exacerbations of chronic obstructive pulmonary disease and community acquired pneumonia.
DESIGN: Analysis of two prospectively collected data sets.
SETTING: Chronic obstructive pulmonary disease data set including patients admitted to one of 12 hospitals around the United Kingdom between 2009 and 2011; Edinburgh pneumonia study cohort including patients admitted to NHS Lothian Hospitals between 2005 and 2009.
POPULATION: 1343 patients admitted to hospital with acute exacerbations of chronic obstructive pulmonary disease and 1631 patients admitted with community acquired pneumonia.
MAIN OUTCOME MEASURES: Hazard ratios for cardiovascular events at one year (defined as hospital admissions with acute coronary syndrome, decompensated cardiac failure, serious arrhythmia, or sudden cardiac death) and admissions for acute coronary syndrome (acute ST elevation myocardial infarction, non-ST elevation myocardial infarction, and unstable angina). Secondary outcomes were all cause and cardiovascular mortality at one year.
RESULTS: 268 cardiovascular events occurred in the acute exacerbations of chronic obstructive pulmonary disease cohort and 171 in the community acquired pneumonia cohort over one year. After multivariable adjustment, clarithromycin use in acute exacerbations of chronic obstructive pulmonary disease was associated with an increased risk of cardiovascular events and acute coronary syndrome-hazard ratios 1.50 (95% confidence interval 1.13 to 1.97) and 1.67 (1.04 to 2.68). After multivariable adjustment, clarithromycin use in community acquired pneumonia was associated with increased risk of cardiovascular events (hazard ratio 1.68, 1.18 to 2.38) but not acute coronary syndrome (1.65, 0.97 to 2.80). The association between clarithromycin use and cardiovascular events persisted after matching for the propensity to receive clarithromycin. A significant association was found between clarithromycin use and cardiovascular mortality (adjusted hazard ratio 1.52, 1.02 to 2.26) but not all cause mortality (1.16, 0.90 to 1.51) in acute exacerbations of chronic obstructive pulmonary disease. No association was found between clarithromycin use in community acquired pneumonia and all cause mortality or cardiovascular mortality. Longer durations of clarithromycin use were associated with more cardiovascular events. Use of β lactam antibiotics or doxycycline was not associated with increased cardiovascular events in patients with acute exacerbations of chronic obstructive pulmonary disease, suggesting an effect specific to clarithromycin.
CONCLUSIONS: The use of clarithromycin in the setting of acute exacerbations of chronic obstructive pulmonary disease or community acquired pneumonia may be associated with increased cardiovascular events. These findings require confirmation in other data sets.
Comments: The conclusions from this study are indeed thought provoking considering the recent large NIH funded prospective study with over 1100 subjects that showed Azithromycin versus placebo daily for 1 year significantly reduced COPD exacerbations. In that study there was no difference in the rate of cardiovascular deaths in the macrolide treated group versus placebo. It is important to note that in that study subjects were excluded who had a prolonged QT interval, heart rates over 100, or on medications that prolong the QT interval or are associated with Torsade de pointe. Considering the high rate of cardiovascular co-morbidity in COPD patients, doctors should give pause when deciding if a patient is a good candidate for long term macrolide therapy.
Comparison of Spirometric Thresholds in Diagnosing Smoking-Related Airflow Obstruction. S.P. Bhatt, J.C. Sieren, M.T. Dransfield, G.R. Washko, J.D. Newell Jr, D.A. Stinson, G.K. Zamba, E.A. Hoffman; for the COPDGene Investigators. Thorax. 2013 Mar 23.
BACKGROUND: Diagnosis of chronic obstructive pulmonary disease is based on detection of airflow obstruction on spirometry. There is no consensus regarding using a fixed threshold to define airflow obstruction versus using the lower limit of normal (LLN) adjusted for age. We compared the accuracy and discrimination of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommended fixed ratio of forced expiratory volume in the first second/forced vital capacity < 0.70 with LLN in diagnosing smoking-related airflow obstruction using CT-defined emphysema and gas trapping as the disease gold standard.
METHODS: Data from a large multicentre study (COPDGene), which included current and former smokers (age range 45–80 years) with and without airflow obstruction, were analysed. Concordance between spirometric thresholds was measured. The accuracy of the thresholds in diagnosing emphysema and gas trapping was assessed using quantitative CT as gold standard.
RESULTS: 7743 subjects were included. There was very good agreement between the two spirometric cutoffs (κ = 0.85; 95% CI 0.83 to 0.86, p < 0.001). 7.3% were discordant. Subjects with airflow obstruction by fixed ratio only had a greater degree of emphysema (4.1% versus 1.2%, P < 0.001) and gas trapping (19.8% vs 7.5%, P < 0.001) than those positive by LLN only, and also smoking controls without airflow obstruction (4.1% vs 1.9% and 19.8% vs 10.9%, respectively, P < 0.001). On follow-up, the fixed ratio only group had more exacerbations than smoking controls.
CONCLUSIONS: Compared with the fixed ratio, the use of LLN fails to identify a number of patients with significant pulmonary pathology and respiratory morbidity.
Comments: The findings from this study are instructive. While there has been concern that the absolute cutoff of 70% leads to over-diagnosis of COPD in older smokers the data from COPDGene suggests that there are significant numbers of smokers with clinical evidence of COPD that may not meet criteria using the lower limit of normal. Perhaps there is an age after which the absolute cutoff becomes too sensitive and lower limit of normal may be more useful. This study did not breakdown the data according to age groups. Future studies should address this question.
Use of Tiotropium Respimat(R) SMI vs. Tiotropium Handihaler(R) and Mortality in Patients with COPD. K.M. Verhamme, A. Afonso, S. Romio, B.C. Stricker, G. Brusselle, M. Sturkenboom. Eur Respir J. 2013 Mar 21. [Epub ahead of print]
Tiotropium, a long-acting anticholinergic, is delivered via HandiHaler® or via Respimat®. RCTs suggest that use of Tiotropium Respimat® increases the risk of dying. We compared the risk of mortality between Tiotropium Respimat® vs. HandiHaler®. Within the Integrated Primary Care Information database, we defined a source population of patients, ≥ 40 years, with at least 1 year of follow-up. Based on prescription data, we defined episodes of tiotropium use (Respimat® or Handihaler®). The risk of mortality, within these episodes, was calculated using a Cox proportional hazard regression analysis. From the source population, 11287 patients provided 24522 episodes of tiotropium use; 496 patients died while being exposed to Handihaler® or Respimat®. Use of Respimat® was associated with almost 30% increased risk of dying (HRadj 1.27, 95% CI 1.03–1.57) with the highest risk for cardiovascular/cerebrovascular death (HRadj 1.56, 95% CI 1.08–2.25). The risk was higher in patients with co-existing cardiovascular disease (HRadj 1.36, 95% CI 1.07–1.73) than in patients without (HRadj 1.02, 95% CI 0.61–1.71). Use of Tiotropium Respimat® was associated with an almost 30% increase of mortality compared to Handihaler® and the association was the strongest for cardiovascular/cerebrovascular death. It is unclear whether this association is causal or due to residual confounding by COPD severity.
Comments: In 2008 there were several papers including a large meta-analysis that raised concerns about an increased cardiovascular and cerebrovascular morbidity associated with use of Tiotropium Handihaler. Shortly thereafter the results of the Uplift trial, a large multinational randomized control trial with over 6000 subjects, did not demonstrate any increased risk of cardiovascular or cerebrovascular events and the FDA warning of the use of Tiotropium Handihaler was overruled. There remain concerns about the new Respimat device after a recent meta-analysis reported an increased risk of cardiovascular related mortality in patients treated with the Respimat versus the Handihaler device. To date there have been no head to head comparisons and so it is not possible to draw strong conclusions. This is an observational cohort study of registered patients in over 400 practices in the Netherlands on a unified electronic medical record system. It is not a randomized trial. It is important to note that patients that were determined to die from both respiratory failure and cardiovascular or cerebrovascular causes on their death certificates were categorized as cardiovascular/cerebrovascular death. There were significant differences in the number of patients treated with Handihaler versus Respimat. There were also significant differences in the other medications the two groups were on. Of the 496 deaths they reported, 372 (75%) of those that died were using the Handihaler versus (124) were using the Respimat (25%). The fact that there are fewer deaths in the Respimat group, yet a higher hazard ratio reflects that far more subjects were using the Handihaler device than the Respimat device. As this is not a randomized trial and is an observational retrospective study there may have been certain selection bias issues for the group using the Respimat. Hence, while these findings are intriguing more data is necessary before making any final conclusions about the relative safety of the two formulations.
Cardiovascular Disease in COPD: Mechanisms. J.D. Maclay, W. Macnee. Chest. 2013 Mar 1;143(3):798–807.
It is now well established that cardiovascular disease contributes significantly to both morbidity and mortality in COPD. Shared risk factors for cardiovascular disease and COPD, such as smoking, low socioeconomic class, and a sedentary lifestyle contribute to the natural history of each of these conditions. However, it is now apparent that alternative, novel mechanisms are involved in the pathogenesis of cardiovascular disease, and these may play an important role in driving the increased cardiovascular risk associated with COPD. In this article, we discuss the potential mechanisms that link COPD to an increased risk of cardiovascular disease.
Comment: This is an excellent state of the art review of the relationship between COPD and cardiovascular disease. It helps to put in context the reported associations between certain medications used in COPD patients and increased cardiovascular related morbidity and mortality. Conversely it also provides insight as to how medications such as statins and beta blockers used for cardiac patients have been reported for patients with concomitant COPD.
Optimizing the 6-min Walk Test as a Measure of Exercise Capacity in COPD. D. Chandra, R.A. Wise, H.S. Kulkarni, R.P. Benzo, G. Criner, B. Make, W.A. Slivka, A.L. Ries, J.J. Reilly, F.J. Martinez, F.C. Sciurba. Chest. 2012 Dec;142(6):1545–52.
BACKGROUND: It is uncertain whether the effort and expense of performing a second walk for the 6-min walk test improves test performance. Hence, we attempted to quantify the improvement in 6-min walk distance if an additional walk were to be performed.
METHODS: We studied patients consecutively enrolled into the National Emphysema Treatment Trial who prior to randomization and after 6 to 10 weeks of pulmonary rehabilitation performed two 6-min walks on consecutive days (N = 396). Patients also performed two 6-min walks at 6-month follow-up after randomization to lung volume reduction surgery (n = 74) or optimal medical therapy (n = 64). We compared change in the first walk distance to change in the second, average-of-two, and best-of-two walk distances.
RESULTS: Compared with the change in the first walk distance, change in the average-of-two and best-of-two walk distances had better validity and precision. Specifically, 6 months after randomization to lung volume reduction surgery, changes in the average-of-two (r = 0.66 vs r = 0.58, P = .01) and best-of-two walk distances (r = 0.67 vs r = 0.58, P = .04) better correlated with the change in maximal exercise capacity (ie, better validity). Additionally, the variance of change was 14% to 25% less for the average-of-two walk distances and 14% to 33% less for the best-of-two walk distances than the variance of change in the single walk distance, indicating better precision.
CONCLUSIONS: Adding a second walk to the 6-min walk test significantly improves its performance in measuring response to a therapeutic intervention, improves the validity of COPD clinical trials, and would result in a 14% to 33% reduction in sample size requirements. Hence, it should be strongly considered by clinicians and researchers as an outcome measure for therapeutic interventions in patients with COPD.
Comments: The 6-min walk has been suggested as a better assessment of response to therapy than FEV1 in subjects with COPD. It may better reflect improvement in reductions in trapped air in the lungs and dynamic hyperinflation than may be reflected by looking at changes in FEV1. This study was done with subjects returning for testing on consecutive days. Although this may very well provide greater validity and be useful in a research context the logistics, practicality and reimbursement issues may make it difficult to operationalize in a clinical practice. Nonetheless it is helpful in pointing out the day-to-day variability in this test.