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Vancouver, BC, Canada
Dr. Mancini is Professor of Medicine, Director of Continuing Medical Education, University of British Columbia, Department of Medicine, and Director of Cardiovascular Imaging Research Core Laboratory, Division of Cardiology, Vancouver Hospital.
Correspondence to: G. B. John Mancini, MD, Vancouver Hospital, 10209-2775 Laurel St, Vancouver, BC, Canada V5Z 1M9; e-mail: mancini{at}interchange.ubc.ca
Investigators1 from the University of New Mexico provide in this issue of CHEST (see page 1006) a provocative analysis suggesting novel, lifesaving therapy for patients with COPD and influenza/pneumonia. This work focuses on the potential use of statins in these syndromes, and the conclusions are based on a matched cohort study and two separate case-control studies.
The broadest, mechanistic rationale for this study derives from the fact that the pathogenesis of both diseases involves activation of inflammatory and immune processes that cause progressive lung tissue damage and account for morbidity and mortality. Indeed, diverse forms of pulmonary inflammation lead to systemic inflammatory activation with consequences that are much more widespread than merely in the lungs. For example, animal models of lung inflammation show augmentation of the rate of atherosclerosis accumulation in the coronary vessels and aorta.2 Such observations help to explain the association between pulmonary inflammation and cardiac morbidity and mortality. Thus, medications currently associated with cardiovascular risk reduction might have a substantial impact on the clinical outcome of patients suffering from pulmonary inflammation by at least reducing the cardiovascular component of adverse morbidity and mortality. But in addition, statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, through pleiotropic mechanisms, can directly mitigate lung inflammation and injury, thereby making these agents dual cardiopulmonary protectants.34567 These agents present extremely attractive opportunities to simultaneously improve both lung disease and cardiovascular comorbities.
In spite of feverish work, the feared, imminent influenza pandemic may well occur when antiviral agents and vaccines are unavailable in a timely fashion.8 In addition, there is a real need to identify new therapeutic strategies in COPD because, aside from cessation of cigarette smoking, and use of oxygen therapy in patients with very severe COPD, most therapeutic interventions are of a symptomatic nature, with little or contradictory evidence as to whether outcome or disease progression are affected positively.9
Statins possess pleiotropic effects that can modulate immune and inflammatory responses quite dramatically and which are not due to lipid-lowering properties.67 Frost et al1 sought evidence indicating that such effects might be of clinical benefit in these special patient populations. They provide a compelling analysis with multiple strengths, including the large size of the cohort, the requirement for at least a 90-day follow-up in all strata of the analysis, demonstration of mortality benefits through both a matched cohort approach and a case-control approach, and demonstration of a potential dose-response effect that has not been previously shown. The results add substantially to this emerging area of investigation and confirm prior work in the COPD population10 and in the arena of community-acquired pneumonia.11
Although the article1 demonstrates a dose-dependent gradient in response, the precise dose dependency of effect for any particular outcome or any particular pleiotropic mechanism cannot be fully ascertained from this study. If such therapy was to be implemented, it is unclear how to determine a protective dose in the setting of an influenza pandemic or for more general use in COPD patients. The results suggest, however, that titration to maximally tolerated doses might be a reasonable, initial approach pending further studies, especially randomized trials. The diversity of the databases mandated a focus on in-hospital deaths only. While this pragmatic approach yields a clear-cut and compelling end point, particularly with respect to acute influenza-related deaths that are often in the hospital, the analysis does not provide an assessment of the potential, overall impact of statin therapy in COPD that has a more protracted course, characterized by a high degree of both outpatient and inpatient morbidity and mortality. It is not clear whether this limitation of the study might have resulted in an overestimation or underestimation of putative effects of stains in COPD. Indeed, the beneficial effects on mortality must be viewed as speculative due to inevitably imperfect elimination of all variables that might potentially confound the final results and the potential for ascertainment and treatment biases. Thus, in spite of the novel and interesting results, the evidence provided by this sort of retrospective analysis is valuable mainly for providing a compelling rationale for executing randomized clinical trials that will more clearly define the magnitude of effect and the characteristics of patients that will benefit the most. Even so, the current article is extremely valuable because it suggests that statin therapy may well be efficacious in real-world application to COPD patients and possibly for acute influenza. Moreover, if randomized clinical trials confirm a level of efficacy similar to what was noted in this trial (risk reductions in the 40 to 80% range), then such therapy may also be extremely efficient or cost-effective.
The threat of an influenza pandemic continues to loom, and COPD is increasing in prevalence. While afflicted patients need symptomatic therapy, adjunctive approaches may bear more fruit with respect to improvement of long-term prognosis. In the sphere of COPD, there has been a long-standing recognition of the benefit of ß-blockers for improving long-term outcome in COPD patients, although in practice this benefit is always weighed against an exaggerated perception of risk of deterioration of lung function. This often leads to underutilization of this class of drug in COPD.12 In contrast, drugs such as statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers have potentially beneficial effects directly on lung inflammation while having been proven in both coronary patients and, with respect to the angiotensin drugs, in patients with congestive heart failure, which is commonly associated with COPD.13 It stands to reason that these drugs may lead to very important advances in the therapy of patients with lung disease. The investigators at the University of New Mexico are to be congratulated for adding more evidence supporting execution of randomized clinical trials using these agents that stand an excellent chance of improving the natural history of extremely large populations with diverse forms of inflammatory lung disease, in particular COPD.
Footnotes
Dr. Mancini has received research grants, honoraria, and/or consulting fees from companies marketing statins, angiotensin-converting enzyme inhibitors, and/or angiotensin receptor blockers.
References
Related Article
This article has been cited by other articles:
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  E. Vos, L. Mascitelli, and F. Frost Statins Have No Role in Pulmonary Disease Mortality Chest, October 1, 2007; 132(4): 1408 - 1409. [Full Text] [PDF]
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