Affiliations: Sutton, QC, Canada,
Lovelace Respiratory Research Unit, Albuquerque, NM
Correspondence to: Luca Mascitelli, MD, Sanitary Service, Comando Brigata alpina “Julia,” Via S. Agostino, 8, Udine 33100, Italy; e-mail: firstname.lastname@example.org
A clarion call is a risk factor for sunrise as sure as a statin prescription is one for higher-than-minimal cholesterol, dyslipidemia being the on-label prescribing rationale for a statin. It is therefore surprising that neither Frost et al1nor the accompanying “clarion call” editorial2 (April 2007) mentioned the word cholesterol when suggesting that statins may have a role regarding mortality and morbidity in pulmonary diseases. The type of studies,1–2 discussed or referenced cannot prove cause and effect, yet the authors proposed statins as a potential promising agent for influenza, COPD, and even bird flu.
The authors did not discuss baseline cholesterol, previously shown to be inversely associated with pulmonary diseases, where, in men, a statistically significant inverse association was found between serum cholesterol and hospitalizations for pneumonia/influenza.3 A risk reduction of approximately 25% for deaths from miscellaneous respiratory diseases per SD cholesterol increase (1.19 mmol/L) has been shown3; the 16% reduction in women did not reach statistical significance.
The authors1–2 proposed randomized trials, but prescribing information for ezetimibe/simvastatin (Vytorin; Merck/Schering-Plough Pharmaceuticals; North Wales, PA; Table 8)4 already reports such data (ie, a 1.92-times increased incidence of influenza plus upper respiratory tract infections in the simvastatin group, vs placebo [p < 0.05]).
Statin use selects the healthy user or unselects the unhealthy low-cholesterol patient; and while the authors1 attempted to address mortality, total mortality is still the “hard nut” for statins to “crack,” with only simvastatin claiming such short-term benefit, such as in the Heart Protection Study,5 and this in men only. The article by Frost and colleagues1 simply reported a healthy-user effect because we know that “low cholesterol” is no benefit in all-cause mortality6–7 or in the respiratory diseases discussed.3
The authors have no conflicts of interest to disclose.
The author has no conflict of interest to disclose.
We appreciate the concern that our results1contradict a previous study by Iribarren et al2 that found an association between elevated blood lipid levels and reduced hospitalization and mortality from pneumonia/influenza and COPD. However, their study used a cross-sectional design, a weaker design for evaluating causal associations. Also, most of the results were not statistically significant and were inconsistent across strata of gender and age. They concluded that their results might be spurious or even secondary to reverse causality. If high blood lipid levels are protective against morbidity and mortality from COPD and influenza/pneumonia, then the lipid-reducing effect of statins should have resulted in higher rates of hospitalization and mortality in our statin users.
Drs. Vos and Mascitelli also suggest that randomized trials have already been completed. However, the prescribing information for ezetimibe/simvastatin did not demonstrate an association between simvistatin use and the incidence of influenza in a clinical trial.3 Among those receiving simvistatin, 24 of 1,234 patients (1.9%) had influenza diagnosed, compared with 3 of 311 patients (1.0%) who received placebo (p = 0.33, Fisher exact test). Lower respiratory infections were not reported.
We are unable to rule out residual confounding by a “healthy-user” effect due to our limited data. However, we do not believe that it can completely account for the very strong protective effect that we identified, especially in preventing deaths associated with COPD. In our study, like many other observational studies of the effects of statin use, statin users compared to nonusers were somewhat older and had more comorbidities. This is a seemingly paradoxical finding when implicating a healthy-user effect. One of the reasons we recommend randomized clinical trials to study the pleiotropic effects of statins in COPD and influenza is to help prevent confounding by a possible healthy-user effect.
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