Helen Voelker

Simvastatin for the Prevention of Exacerbations in Moderate-to-Severe COPD

BACKGROUND Retrospective studies have shown that statins decrease the rate and severity of exacerbations, the rate of hospitalization, and mortality in chronic obstructive pulmonary disease (COPD). We prospectively studied the efficacy of simvastatin in preventing exacerbations in a large, multicenter, randomized trial. METHODS We designed the Prospective Randomized Placebo-Controlled Trial of Simvastatin in the Prevention of COPD Exacerbations (STATCOPE) as a randomized, controlled trial of simvastatin (at a daily dose of 40 mg) versus placebo, with annual exacerbation rates as the primary outcome. Patients were eligible if they were 40 to 80 years of age, had COPD (defined by a forced expiratory volume in 1 second [FEV1] of less than 80% and a ratio of FEV1 to forced vital capacity of less than 70%), and had a smoking history of 10 or more pack-years, were receiving supplemental oxygen or treatment with glucocorticoids or antibiotic agents, or had had an emergency department visit or hospitalization for COPD within the past year. Patients with diabetes or cardiovascular disease and those who were taking statins or who required statins on the basis of Adult Treatment Panel III criteria were excluded. Participants were treated from 12 to 36 months at 45 centers. RESULTS A total of 885 participants with COPD were enrolled for approximately 641 days; 44% of the patients were women. The patients had a mean (±SD) age of 62.2±8.4 years, an FEV1 that was 41.6±17.7% of the predicted value, and a smoking history of 50.6±27.4 pack-years. At the time of study closeout, the low-density lipoprotein cholesterol levels were lower in the simvastatin-treated patients than in those who received placebo. The mean number of exacerbations per person-year was similar in the simvastatin and placebo groups: 1.36±1.61 exacerbations and 1.39±1.73 exacerbations, respectively (P=0.54). The median number of days to the first exacerbation was also similar: 223 days (95% confidence interval [CI], 195 to 275) and 231 days (95% CI, 193 to 303), respectively (P=0.34). The number of nonfatal serious adverse events per person-year was similar, as well: 0.63 events with simvastatin and 0.62 events with placebo. There were 30 deaths in the placebo group and 28 in the simvastatin group (P=0.89). CONCLUSIONS Simvastatin at a daily dose of 40 mg did not affect exacerbation rates or the time to a first exacerbation in patients with COPD who were at high risk for exacerbations. (Funded by the National Heart, Lung, and Blood Institute and the Canadian Institutes of Health Research; STATCOPE ClinicalTrials.gov number, NCT01061671.).

Weight Gain as a Function of Smoking Cessation and 2-Mg Nicotine Gum Use Among Middle-Aged Smokers With Mild Lung Impairment in the First 2 Years of the Lung Health Study

The extent and predictors of weight change were assessed among sustained nonsmoking special intervention participants in the Lung Health Study. The intervention included a 12-session group program and 2-mg nicotine gum. At 12 months, female sustained quitters (SQs; n = 248) had gained a mean of 8.4% (5.3 kg) of their baseline weight, whereas male SQs (n = 443) had gained 6.7% (5.5 kg). By 24 months, female SQs had gained 9.8% of their baseline weight compared with 6.9% for men. Nicotine gum usage delayed a portion of the weight gain. Multiple regression analysis showed that weight gain at 12 months was associated with a higher baseline salivary cotinine level, a lower baseline body mass index, drinking less alcohol per week, and a lower cotinine level at 12 months (indicating less or no nicotine gum use). We conclude that moderate weight gain is a long-term consequence of smoking cessation--a portion of which can be delayed with 2-mg nicotine gum.

β-Blockers for the prevention of acute exacerbations of chronic obstructive pulmonary disease (βLOCK COPD): a randomised controlled study protocol

Introduction A substantial majority of chronic obstructive pulmonary disease (COPD)-related morbidity, mortality and healthcare costs are due to acute exacerbations, but existing medications have only a modest effect on reducing their frequency, even when used in combination. Observational studies suggest β-blockers may reduce the risk of COPD exacerbations; thus, we will conduct a randomised, placebo-controlled trial to definitively assess the impact of metoprolol succinate on the rate of COPD exacerbations. Methods and analyses This is a multicentre, placebo-controlled, double-blind, prospective randomised trial that will enrol 1028 patients with at least moderately severe COPD over a 3-year period. Participants with at least moderate COPD will be randomised in a 1:1 fashion to receive metoprolol or placebo; the cohort will be enriched for patients at high risk for exacerbations. Patients will be screened and then randomised over a 2-week period and will then undergo a dose titration period for the following 6 weeks. Thereafter, patients will be followed for 42 additional weeks on their target dose of metoprolol or placebo followed by a 4-week washout period. The primary end point is time to first occurrence of an acute exacerbation during the treatment period. Secondary end points include rates and severity of COPD exacerbations; rate of major cardiovascular events; all-cause mortality; lung function (forced expiratory volume in 1 s (FEV1)); dyspnoea; quality of life; exercise capacity; markers of cardiac stretch (pro-NT brain natriuretic peptide) and systemic inflammation (high-sensitivity C reactive protein and fibrinogen). Analyses will be performed on an intent-to-treat basis. Ethics and dissemination The study protocol has been approved by the Department of Defense Human Protection Research Office and will be approved by the institutional review board of all participating centres. Study findings will be disseminated through presentations at national and international conferences and publications in peer-reviewed journals. Trial registration number NCT02587351; Pre-results.

Intervention for relapse to smoking : The Lung Health Study restart programs

The Lung Health Study enrolled 3,923 participants in a smoking cessation intervention program, and followed them for 5 years. The study provided intensive group interventions for participants who had relapsed. The purpose of this analysis was to describe and evaluate these Restart programs. Among 1,004 relapsed participants, the percent not smoking at 5th year was higher for men who had used Restart (47) compared to those who had not (28), but not for women (42 vs. 33). Overall, there was equivocal evidence of the impact of the Restart programs due to limitations in the evaluation design. Because relapse is a common feature of efforts to quit smoking, relapse intervention programs need further study and more rigorous evaluation.

Relationship of smoking cessation and nicotine gum use to salivary androstenedione and testosterone in middle-aged men

Cross-sectional studies have associated cigarette smoking in men with elevated androstenedione and little net effect on other sex steroids. However, it is not clear if such findings reflect the impact of nicotine exposure or if sex hormone levels change following smoking cessation. The relationship of the reported number of cigarettes smoked per day and salivary cotinine to salivary testosterone and androstenedione was examined in 221 men aged 35 to 59 years at baseline and 1 year following randomization into a clinical trial including a smoking-cessation intervention. At baseline, salivary cotinine was related to increased salivary androstenedione and testosterone following control for age, body mass, alcohol intake, and time of day of specimen collection (partial r = +.14 and +.30 P < .05 and .01, respectively). The reported number of cigarettes smoked per day was unrelated to either hormone. At the first annual visit, there was a significant decrease in the salivary androstenedione of men who had quite smoking and were currently using nicotine gum (94 v 60 pg/mL, P < .05, n = 34) and of men who had quit smoking and were not exposed to nicotine (86 v 56 pg/mL, P < .05, n = 48), whereas the salivary androstenedione of men who remained smokers at the first annual visit was unchanged (83 v 85 pg/mL, n = 139). Salivary testosterone levels were not significantly affected by a change in smoking status.(ABSTRACT TRUNCATED AT 250 WORDS)

Tumour necrosis factor receptor-75 and risk of COPD exacerbation in the azithromycin trial

To the Editor: We recently found that azithromycin taken daily for 1 year reduced the frequency of acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) in subjects who were selected as having an increased risk of exacerbations [1]. Since azithromycin has potentially adverse effects, identifying patients most likely to benefit might be useful for targeting therapy. Accordingly, we included a substudy in our trial that was prospectively designed to determine whether plasma levels at entry, or a change in levels at 3 months of any of four blood biomarkers, were associated with improved clinical response to azithromycin as compared to placebo. We chose to study biomarkers of inflammatory pathways likely to be relevant to chronic obstructive pulmonary disease (COPD) including C-reactive protein (CRP), interleukin (IL)-6, IL-8 and soluble tumour necrosis factor receptor 75 (sTNFR75). The parent trial comprised 1142 subjects with COPD randomised to receive azithromycin (250 mg orally each day) or placebo (1:1) for 12 months (ClinicalTrials.gov NCT00325897) [1]. To enrich our population for subjects more likely to have an AECOPDs, we required that subjects used either systemic corticosteroids, visited an emergency room or were hospitalised for AECOPD in the preceding 12 months or were using continuous supplemental oxygen [2]. We required subjects to be free of AECOPDs or other acute illness for ≥4 weeks prior to enrolment and excluded subjects with known congestive heart failure (CHF) and those with clinically defined bronchiectasis. The primary outcome was time to first AECOPD defined as “a complex of respiratory symptoms (increased or new onset) of more than one of the following: cough, sputum, wheezing, dyspnoea, or chest tightness with a duration of at least 3 days requiring treatment with antibiotics or systemic steroids” [2]. We monitored participants for AECOPDs at follow-up clinic visits …

Simvastatin in moderate-to-severe COPD.

To the Editor: Criner et al. (June 5 issue)1 found that simvastatin had no effect on the frequency or the severity of exacerbations in patients with moderate-to-severe chronic obstructive pulmonary disease (COPD). These findings must be interpreted with caution because approximately 85% of the patients in the simvastatin group had used systemic glucocorticoids within the previous 12 months. Early evidence suggests that the pleiotropic effects of statins, which include their antiinflammatory effects, may be caused, at least in part, by an increase in sphingosine-1-phosphate (S1P) signaling pathways.2 Other evidence suggests that the concurrent use of systemic glucocorticoid therapy in patients receiving statins may repress or blunt the pleiotropic effects of these drugs by inhibiting S1P signaling.3 These observations are supported by the evidence that atorvastatin may lessen inflammation and promote resolution of the inflammation in the airways, thereby reducing cough in patients with bronchiectasis who have not used systemic glucocorticoids recently.4 The lack of effect of simvastatin on the frequency or severity of exacerbations in patients with moderate-to-severe COPD, as observed in the study by Criner et al., may therefore be due, at least in part, to the concurrent or recent use of systemic glucocorticoid therapy.