Surfactant Protein D and Bronchial Dysplasia in Smokers at High Risk of Lung Cancer; D. D. Sin, S. F. P Man, A. McWilliams, S. Lam (Chest 2008; 134:582–588).
Background. Surfactant dysfunction has been implicated in both lung cancer and chronic obstructive pulmonary disease (COPD). This study evaluated the relationship between surfactant protein D (SP-D) and the progression of bronchial dysplasia in heavy smokers.
Methods. SP-D and oxidized glutathione levels were determined in samples of bronchoalveolar lavage (BAL) fluid from 71 ex-smokers and current heavy smokers who participated in a lung cancer chemoprevention study with inhaled budesonide therapy. Bronchoscopy with biopsy was performed at baseline and was repeated at 6 months. The primary end point was the progression of bronchial dysplasia over 6 months.
Results. Log-normalized SP-D levels in BAL fluid were significantly associated with the progression of bronchial dysplasia. A 1-U decrease in log-normalized SP-D levels at baseline was associated with a 3.2-fold increase (95% confidence interval [CI], 1.24–8.26) in the risk for progression. Reduced forced expiratory volume in 1 second (FEV1) also predicted the progression of bronchial dysplasia (p < 0.05). Additional reductions in BAL fluid SP-D levels over the 6 months further increased the risk of progression (odds ratio [OR] 1.76 for a 1-U decrease in log-normalized SP-D levels in BAL fluid; p_0.023). Thirty-seven percent of the variation in SP-D levels in BAL fluid was related positively to the subjects' FEV1/FVC (forced vital capacity) ratios and inversely to their plasma C-reactive protein levels and number of pack years of smoking.
Conclusion. Reduced SP-D expression in BAL fluid was associated with the progression of bronchial dysplasia. SP-D levels in BAL fluid may serve as a potential biomarker to identify smokers who are at risk of early lung cancer.
Comments: There is a great deal of interest in establishing biomarkers that may help distinguish various phenotypes in COPD. The prognosis for patients diagnosed with lung cancer is generally poor given that they are discovered at advanced stages of disease. There are correlations between low lung function and development of the different types of lung cancer, particularly squamous cell cancers. Subjects had a minimum 30 pack year smoking history with mean history of 48 pack years, and they could not have a comorbid illness. The baseline FEV1 was 84% of predicted and mean FEV1/FVC ratio, which was 71%. Seventy-three percent of the participants were current smokers. It is interesting that a correlation was found between lung function decline and reduced SP-D levels in addition to increased cellular atypia. The biopsies were read by two pathologists. There had to be a worsening of the dysplasia by two or more grades for it to be considered progressive. Regressive disease could be partial or complete. The study length precluded the chance to examine whether these biomarkers help pick up invasive lung cancer. Certainly, finding a biomarker that might identify those at increased risk of lung cancer or for more aggressive disease progression is extremely useful. Finally the data that suggest that budesonide is able to reduce oxidized glutathione levels in BAL supports the concept that inhaled corticosteroids (ICS) can reduce oxidative stress and may in turn have the ability to impact the development of lung cancer. Future studies are needed with longer follow-up and examination of other biomarkers of oxidative stress.
Risk for Death Associated with Medications for Recently Diagnosed Chronic Obstructive Pulmonary Disease; T. A. Lee, A. S. Pickard, D. H. Au, B. Bartle, K. B. Weiss. (Ann Intern Med 2008;149:380–390).
Background. Concerns exist regarding increased risk for mortality associated with some COPD medications.
Objective. To examine the association between various respiratory medications and risk for death in veterans with newly diagnosed COPD.
Design. Nested case-control study in a cohort identified between October 1, 1999, and September 30, 2003, and followed through September 30, 2004, by using National Veterans Affairs inpatient, outpatient, pharmacy, and mortality databases; Centers for Medicare & Medicaid Services databases; and National Death Index Plus data. Cause of death was ascertained for a random sample of 40% of those who died during follow-up. Case patients were categorized on the basis of all-cause, respiratory, or cardiovascular death. Mortality risk associated with medications was assessed by using conditional logistic regression adjusted for comorbid conditions, health care use, and markers of COPD severity.
Setting. US Veterans Health Administration health care system.
Participants. A total of 32,130 case patients and 320,501 control participants in the all-cause mortality analysis. Of the 11,897 patients with cause-of-death data, 2,405 case patients had respiratory deaths, and 3,159 case patients had cardiovascular deaths.
Measurements. All-cause mortality; respiratory and cardiovascular deaths; and exposure to COPD medications, ICS, ipratropium, long-acting beta-agonists, and theophylline in the 6 months preceding death.
Results. Adjusted ORs for all-cause mortality were 0.8 (95% CI 0.78–0.83) for ICS, 1.11 (CI 1.08–1.15) for ipratropium, 0.92 (CI 0.88–0.96) for long-acting beta-agonists, and 1.05 (CI 0.99–1.1) for theophylline. Ipratropium was associated with increased cardiovascular deaths (OR 1.34; CI 1.22–1.47), whereas ICS were associated with reduced risk for cardiovascular death (OR 0.8; CI 0.72–0.88). Results were consistent across sensitivity analyses.
Limitations. Current smoking status and lung function were not measured. Misclassification of cause-specific mortality is unknown.
Conclusion. The possible association between ipratropium and elevated risk for all-cause and cardiovascular death needs further study.
Comments: The Lung Health Study II showed that subjects randomly assigned to ipratropium bromide had more than twice as many cardiovascular deaths as those on placebo, and other studies have raised concern about tiotropium use being associated with increased risk of stroke. This is a large database that reflected standard clinical practice and medication use not within the context of a research study. Unfortunately with databases of this nature there often are missing data, and this study cohort had over 32,000 deaths, but the cause of death was only available in 11,897. Further, smoking status and disease severity were not known which could clearly influence outcomes. It is important that prospective trials be designed to look at these questions more closely. It is also important that studies examine whether this signal is seen in patients on tiotropium and not just on ipratropium.
Inhaled Anticholinergics and Risk of Major Adverse Cardiovascular Events in Patients with Chronic Obstructive Pulmonary Disease: A Systematic Review and Meta-Analysis; S. Singh, Y. K. Loke, C. D. Furberg (JAMA 2008 Sep 24;300(12):1439–1450).
Context. Inhaled anticholinergics (ipratropium bromide or tiotropium bromide) are widely used in patients with COPD, but their effect on the risk of cardiovascular outcomes is unknown.
Objective. To ascertain the cardiovascular risks of inhaled anticholinergics, including cardiovascular death, myocardial infarction (MI), and stroke.
Data Sources. Systematic searches were conducted on March 19, 2008, of relevant articles in MEDLINE, the Cochrane Database of systematic reviews, regulatory authority Web sites in the United States and the United Kingdom, and manufacturers' trial registries with no date restrictions.
Study Selection. Randomized controlled trials of any inhaled anticholinergic for treatment of COPD that had at least 30 days of treatment and reported on cardiovascular events.
Data Extraction. The primary outcome was a composite of cardiovascular death, MI, or stroke. The secondary outcome was all-cause mortality. Relative risks (RRs) were estimated using fixed effects models, and statistical heterogeneity was estimated with the I2 statistic.
Data Synthesis. After a detailed screening of 103 articles, 17 trials enrolling 14,783 patients were analyzed. Follow-up duration ranged from 6 weeks to 5 years. Cardiovascular death, MI, or stroke occurred in 135 of 7,472 patients (1.8%) receiving inhaled anticholinergics and 86 of 7,311 patients (1.2%) receiving control therapy (RR 1.58; 95% CI 1.21–2.06; p < 0.001; I2 = 0%). Among individual components of the primary end point, inhaled anticholinergics significantly increased the risk of MI (RR 1.53; 95% CI 1.05–2.23; p = 0.03; I2 = 0%) and cardiovascular death (RR 1.8; 95% CI 1.17–2.77; p = 0.008; I2 = 0%) without a statistically significant increase in the risk of stroke (RR 1.46; 95% CI 0.81–2.62; p = 0.2; I2 = 0%). All-cause mortality was reported in 149 of the patients treated with inhaled anticholinergics (2%) and 115 of the control patients (1.6%; RR 1.26; 95% CI 0.99–1.61; p = 0.06; I2 = 2%). A sensitivity analysis restricted to 5 long-term trials (more than 6 months' long) confirmed the significantly increased risk of cardiovascular death, MI, or stroke (2.9% of patients treated with anticholinergics versus 1.8% of the control patients; RR 1.73; 95% CI 1.27–2.36; p < 0.001; I2 = 0%).
Conclusion. Inhaled anticholinergics are associated with a significantly increased risk of cardiovascular death, MI, or stroke among patients with COPD. PMID: 18812535 [PubMed – indexed for MEDLINE].
Comments: Meta-analyses are extraordinarily useful studies but do have their limitations when data from numerous studies are grouped together in terms of variable reporting of adverse events, criteria for adverse events, and quality of collection of data. These presumably were all randomized controlled trials that monitored cardiac events prospectively, but we do not know what the criteria were for making various cardiac diagnoses. The analysis did not differentiate between tiotropium use and ipratropium use. Clearly in COPD patients, many of whom have significant comorbid illnesses such as underlying cardiovascular disease, it is important that the potential risks of anticholinergics are established; however, more study is required before physicians jump to discontinuing anticholinergics for COPD patients. It is not unreasonable, however, for individual patients who demonstrate poorly controlled hypertension or angina or are known to be at risk for stroke to have their anticholinergics held for a period of time to assess if cardiovascular problems improve off the medication.
A 4-Year Trial of Tiotropium in Chronic Obstructive Pulmonary Disease; D. P. Tashkin, B. Celli, S. Senn, D. Burkhart, S. Kesten, S. Menjoge, M. Decramer, the UPLIFT Study Investigators (N Ingl J Med 2008 Oct 5 [E-publication ahead of print])
Background. Previous studies showing that tiotropium improves multiple end points in patients with COPD led to the examination of the long-term effects of tiotropium therapy.
Methods. In this randomized, double-blind trial, we compared 4 years of therapy with either tiotropium or placebo in patients with COPD, who were permitted to use all respiratory medications except inhaled anticholinergic drugs. The patients were at least 40 years of age, with an FEV1 of 70% or less after bronchodilation and an FEV1/FVC ratio of 70% or less. Coprimary end points were the rate of decline in the mean FEV1 before and after bronchodilation beginning on day 30. Secondary end points included measures of FVC, changes in response on St. George's Respiratory Questionnaire (SGRQ), exacerbations of COPD, and mortality.
Results. Of a total of 5,993 patients (mean age 65± 8 years) with a mean FEV1 of 1.32± 0.44 liters after bronchodilation (48% of predicted value), we randomly assigned 2,987 to the tiotropium group and 3,006 to the placebo group. Mean absolute improvements in FEV1 in the tiotropium group were maintained throughout the trial (ranging from 87 to 103 ml before bronchodilation and from 47 to 65 ml after bronchodilation), as compared with the placebo group (p < 0.001). After day 30, the differences between the two groups in the rate of decline in the mean FEV1 before and after bronchodilation were not significant. The mean absolute total score on the SGRQ was improved (lower) in the tiotropium group, as compared with the placebo group, at each time point throughout the 4-year period (ranging from 2.3 to 3.3 units, p < 0.001). At 4 years and 30 days, tiotropium was associated with a reduction in the risks of exacerbations, related hospitalizations, and respiratory failure.
Conclusions. In patients with COPD, therapy with tiotropium was associated with improvements in lung function, quality of life, and exacerbations during a 4-year period but did not significantly reduce the rate of decline in FEV1. (ClinicalTrials.gov number NCT00144339.) Copyright 2008 Massachusetts Medical Society. PMID: 18836213 [PubMed – as supplied by publisher
Comments: This 4-year trial that examined the benefits of tiotropium versus placebo allowed patients to be on ICS, long-acting beta-agonists, and any other medication except another anticholinergic. Thirty percent of participants were current smokers, and approximately 74% of subjects had at least some exposure to ICS during study, 72% to long-acting beta-agonists, and 46% to a fixed combination of the two. The mean bronchodilator response was 23%, but the baseline prebronchodilator FEV1 was quite low at 1.1 L. There were 46% patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage II, 44% patients in GOLD stage III, and 9% in GOLD stage IV. Only 60% of subjects completed the study, and many stopped due to adverse events including cardiac events such as angina, congestive heart failure, and myocardial infarction or lower respiratory events such as bronchitis, pneumonia, respiratory failure, dyspnoea, and COPD exacerbation. In contrast to the studies mentioned above, the consistent trend was for these events to occur more often in the placebo group than the tiotropium group. This study was obviously conceived and conducted before any reports of the potential adverse cardiac events had been reported. This trial was certainly ambitious in designating rate of decline in FEV1 as the primary “comparator” or outcome, in other words attempting to address if tiotropium could be considered a disease-modifying agent, when trials of ipratropium, ICS plus or minus a long-acting beta-agonist, and N-acetylcysteine have not been able to demonstrate such an effect. There would seem limited scientific rationale to suggest that a bronchodilator would somehow modify the rate of decline when patients could be on another, perhaps even more effective, bronchodilator (i.e., beta-agonists for at least some of the patients) not to mention ICS. Further selecting subjects with a baseline FEV1 of 48% predicted likely reduction of their chance of being responsive to any therapy. Of course there is also the acknowledgment that FEV1 is not a particularly sensitive metric for assessing response to therapy in COPD. Perhaps what is instructive is that the addition of tiotropium to a COPD patient's drug regimen did improve quality of life measures and reduce exacerbations. This was the trend, but tiotropium did not reach statistical significance in terms of reducing mortality (p = 0.09). While many may suggest that not much new outcome was learned from this large and fairly expensive trial, it is instructive and indeed reassuring that there was no evidence of any increased risk of adverse cardiovascular events such as myocardial ischemia, myocardial infarction, and other cardiac events for patients treated with tiotropium compared to placebo in this prospective randomized controlled trial. It is worth noting that they did not monitor how many or at least less than 1% of patients developed stroke in either treatment arm. These data will be helpful to counterbalance the concerns about the use of tiotropium in that many patients may now come to the doctor's office with knowledge of the two other studies mentioned above.