Usefulness of C-Reactive Protein and Interleukin-6 as Predictors of Outcomes in Patients With Chronic Obstructive Pulmonary Disease Receiving Pravastatin; T. M. Lee, M. S. Lin, N. C. Chang (Am J Cardiol 2008 Feb 15;101(4):530–535. Epub 2007 Dec 26).
Inflammation is increased in chronic obstructive pulmonary disease (COPD) and plays a role in exercise intolerance. We investigated whether pravastatin administration is effective in improving exercise capacity in patients with COPD, and whether baseline or serial changes in high-sensitivity C-reactive protein (hs-CRP) over time are associated with corresponding changes in exercise capacity. In a randomized, double-blinded, and parallel design, 125 patients with clinically stable COPD were randomly assigned to receive placebo or pravastatin (40 mg/day) over a period of 6 months. Plasma hs-CRP levels were measured before randomization and during follow-up. Baseline characteristics were similar in the 2 groups. Exercise time remained stable throughout the study in the placebo group. Exercise time increased by 54% from 599 ± 323 seconds at baseline to 922 ± 328 seconds at the end (p < 0.0001) in pravastatin-treated patients. A decrease in hs-CRP over baseline values was observed in 79% of patients (42 of 53) treated with pravastatin. Pravastatin-treated patients with a greater percent decrease in hs-CRP had a significant improvement in exercise time compared with those without hs-CRP decrease. A significant correlation was found in univariate analysis between decrease of log-transformed hs-CRP and increase of exercise time. Baseline hs-CRP and change of hs-CRP were significantly correlated with exercise time, even after adjustment for lipid profiles and hemodynamics. In conclusion, these data reinforce hs-CRP as a significant surrogate marker in COPD and underscore an important guide to the efficacy of treatment in COPD trials.
Comments: Over the past several years it has been recognized that patients with COPD have elevations in CRP levels which correlate with interleukin 6 levels. It has been proposed that this elevation of CRP may represent a surrogate marker of the inflammatory process that connects the observed association between Chronic Obstructive Pulmonary Disease and Coronary Artery Disease. In the article by Lee and colleagues they examine the effect of administering Pravastatin to patients with COPD and the ability to improve exercise capacity. They also looked to see whether or not baseline levels and improvements in high sensitivity CRP predicted clinical outcomes of patients with stable COPD. COPD was diagnosed with criteria of an FEV1 of less than 80% predicted or an FEV1 /FVC ratio of less than 70%. They could not have acute exacerbations of COPD for at least 3 months prior to entering the study. These patients were all naive to cholesterol lowering agents. To assess their functional capacity they underwent a symptom limited Naughton stress test at baseline and after 6 months. Exercise was discontinued when the imposed workload could not be maintained. There were 95 males and 30 females entered into the study. Mean age was approximately 70 years old. Over 75% of patients in both groups were current smokers and approximately 50% of the patients were steroid dependent. Non responders to Pravastatin were those who showed an increase or no change in their hs-CRP absolute values. It is interesting to note that while the Pravastatin group showed a significant increase in their exercise duration but there was a significant amount of variability within the group and there was no other clear benefit in physiological parameters such as the FEV1 percent, total lung capacity, and expiratory capacity. There was a reduction in the Borg symptom score compared to those on placebo. While the underlying mechanism for this finding remains unclear, previous studies have suggested that use of statins may indeed reduce the exacerbation rate and may be “anti-inflammatory.” It is likely a multifactorial phenomenon. Nonetheless, it clearly gives pause as to whether or not we should be considering the use of pravastatin in our patients who demonstrate elevations in CRP. Particularly highly sensitive CRP and other indicators like inflammation.
Contemporary Management of Acute Exacerbations of COPD: A Systematic Review and Metaanalysis; B. S. Quon, W. Q. Gan, D. D. Sin (Chest 2008 Mar; 133(3):756–766).
Background. Systemic corticosteroids, antibiotics, and noninvasive positive pressure ventilation (NPPV) are recommended for patients with acute exacerbation of COPD. However, their clinical benefits in various settings are uncertain. We undertook a systematic review and metaanalysis to systematically evaluate the effectiveness of these therapies. Methods. MEDLINE and EMBASE were searched to identify relevant randomized controlled clinical trials published from January 1968 to November 2006. We identified additional studies by searching bibliographies of retrieved articles.
Results.Compared with placebo, systemic corticosteroids reduced treatment failure by 46% (95% confidence interval [CI], 0.41 to 0.71), length of hospital stay by 1.4 days (95% CI, 0.7 to 2.2), and improved FEV(1) by 0.13 L after 3 days of therapy (95% CI, 0.04 to 0.21). Meanwhile, the risk of hyperglycemia significantly increased (relative risk, 5.88; 95% CI, 2.40 to 14.41). Compared with placebo, antibiotics reduced treatment failure by 46% (95% CI, 0.32 to 0.92) and in-hospital mortality by 78% (95% CI, 0.08 to 0.62). Compared with standard therapy, NPPV reduced the risk of intubation by 65% (95% CI, 0.26 to 0.47), in-hospital mortality by 55% (95% CI, 0.30 to 0.66), and the length of hospitalization by 1.9 days (95% CI, 0.0 to 3.9).
Conclusions. For acute COPD exacerbations, systemic corticosteroids are effective in reducing treatment failures, while antibiotics reduce mortality and treatment failures in those requiring hospitalization and NPPV reduces the risk of intubation and in-hospital mortality, especially in those who demonstrate respiratory acidosis.
Comments: Quon and colleagues conducted a systematic literature review and meta-analysis of the benefits of oral steroids, non-invasive positive pressure ventilation and antibiotics for management of acute exacerbations of COPD. For the purposes of this analysis COPD exacerbations were defined by worsening cough and dyspnea or increased sputum production. Studies were excluded where alternative diagnoses such as asthma, pneumonia or cardiogenic pulmonary edema may have been causes for acute worsening. The review of systemic steroids use included 10 studies, 5 of the studies used IV Solu-Medrol and the other studies used oral prednisone or hydrocortisone. The doses ranged between 30 to 100 mg every 4 to 24 hours. Tapering was generally carried out between 4 to16 days. It is interesting to note that the benefits seemed to be equal whether or not the patients were given oral or IV steroids. The only major complication was hyperglycemia. In the antibiotic analysis the most commonly used antibiotics were beta lactams (43%), or tetracycline derivatives (29%). Antibiotics seemed to be most effective in the hospitalized patient group. With regard to non-invasive positive pressure ventilation most of the studies used bi-level positive airway pressure or BiPAP. The mean duration of non-invasive positive ventilation was 8.5 hours per day with a range between to 6 to 14 hours per day for 4.3 days with the range between 3 to 10 days. While these findings are likely not surprising to most, it is reassuring that this systematic review confirms our current empiric use of antibiotics and systemic steroids in addition to the use of non-invasive positive pressure ventilation as means to have a significant impact on reducing mortality, hospitalization and/or treatment failures.
Survival after Bilateral Versus Single Lung Transplantation for Patients with Chronic Obstructive Pulmonary Disease: A Retrospective Analysis of Registry Data; G. Thabut, J. D. Christie, P. Ravaud, Y. Castier, O. Brugiere, M. Fournier, H. Mal, G. Leseche, R. Porcher (Lancet 2008 Mar 1;371(9614):702–703).
Background. Both single and bilateral lung transplantation are recognised options for patients who have end-stage chronic obstructive pulmonary disease (COPD); however, which procedure leads to longer survival remains unclear. We aimed to compare survival after each procedure by analysing data from the registry of the International Society for Heart and Lung Transplantation.
Methods. We analysed data for 9883 patients with COPD, 3525 (35.7%) of whom underwent bilateral lung transplantation, and 6358 (64.3%) single lung transplantation, between 1987 and 2006. We accounted for possible selection bias with analysis of covariance, propensity-score risk adjustment, and propensity-based matching.
Findings. Median survival after either type of lung transplantation for patients with COPD was 5.0 years (95% CI 4.8–5.2). Survival for patients who had lung transplantation before 1998 was 4.5 years (4.3–4.8), compared with 5.3 years (5.0–5.5) for those who had it after 1998 (p < 0.0001). The proportion of patients who had bilateral lung transplantation increased from 101/467 (21.6%) in 1993 to 345/614 (56.2%) in 2006. Median survival time after bilateral lung transplantation was longer than that after single lung transplantation: 6.41 years (6.02–6.88) versus 4.59 years (4.41–4.76) (p < 0.0001). Pretransplant characteristics of patients who had single and bilateral lung transplantation differed, but whichever method was used to adjust for baseline differences, bilateral lung transplantation was associated with longer survival than was single lung transplantation; the hazard ratio ranged from 0.83 (0.78–0.92) for analysis of covariance to 0.89 (0.80–0.97) for propensity-based matching. However, bilateral lung transplantation had little benefit compared with single lung transplantation for patients who were 60 years and older (HR 0.95; 0.81–1.13).
Interpretation
Bilateral lung transplantation leads to longer survival than single lung transplantation in patients with COPD, especially those who are younger than 60 years.
Comments: The International Society for Heart and Lung Transplantation noted that between 1995 and 2005, 46% of lung transplantations were for people who had Chronic Obstructive Pulmonary Disease. Single lung transplantation had become the most common type of lung transplantation for COPD patients in the past. Drawbacks of single lung transplantation included complications of the native lung such as infection, pneumonias and pneumothorax. In this study the authors reviewed the registry to look at various outcomes particularly with regard to length of survival. While the study did clearly show that double lung transplantation became more common after 1998, and that it was more successful in younger patients, the statistical analysis, particularly with propensity based matching, clearly shows a benefit for bilateral versus single lung transplant. Indeed, the survival benefit of 6.41 years versus 4.59 years is not trivial. It is appropriate to favor the use of bilateral transplantation in patients who have COPD and it is possible that with increased utilization of lung transplantation patients older than 60 years of age may actually see a survival benefit.