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doi:10.1378/chest.06-1997
(Chest. 2007; 131:1006-1012)
© 2007 American College of Chest Physicians
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Influenza and COPD Mortality Protection as Pleiotropic, Dose-Dependent Effects of Statins*

Floyd J. Frost, PhD; Hans Petersen, MS; Kristine Tollestrup, PhD and Betty Skipper, PhD

* From the Health and Environmental Epidemiology Program (Dr. Frost and Mr. Petersen), Lovelace Respiratory Research Institute; and Department of Family and Community Medicine (Drs. Tollestrup and Skipper), University of New Mexico School of Medicine, Albuquerque, NM.

Correspondence to: Floyd J. Frost, PhD, Health and Environmental Epidemiology Program, Lovelace Respiratory Research Institute, 2425 Ridgecrest Dr SE, Albuquerque, NM 87108; e-mail: ffrost{at}LRRI.org

Abstract

Background: Published data on antiinflammatory and immunomodulatory effects of statins suggest they may reduce mortality risks associated with an unchecked immune response to selected infections, including influenza and COPD. We assessed whether statin users had reduced mortality risks from these conditions.

Methods: We conducted a matched cohort study (n = 76,232) and two separate case-control studies (397 influenza and 207 COPD deaths) to evaluate whether statin therapy is associated with increased or decreased mortality risk and survival time using health-care encounter data for members of health maintenance organizations. For the cohort study, baseline illness risks from all causes prior to initiation of statin therapy were used to statistically adjust for the occurrence of outcomes after initiation of treatment.

Results: For moderate-dose (≥ 4 mg/d) statin users, this cohort study found statistically significant reduced odds ratios (ORs) of influenza/pneumonia death (OR, 0.60; 95% confidence interval [CI], 0.44 to 0.81) and COPD death (OR, 0.17; 95% CI, 0.07 to 0.42) and similarly reduced survival hazard ratios. Findings were confirmed with the case-control studies. Confounding factors not considered may explain some of the effects observed.

Conclusions: This study found a dramatically reduced risk of COPD death and a significantly reduced risks of influenza death among moderate-dose statin users.

Key Words: COPD • epidemiology • 3-hydroxy-3-methylglutaryl coenzyme A • influenza • mortality • statins

Statin therapy has demonstrated cardiovascular disease risk reduction that has exceeded expectations based solely on observed reduction of blood lipid levels.123 Evidence suggests that statins, in addition to lipid reduction, may provide other positive pleiotropic effects.456 The disease-risk reduction mechanisms of statins are not completely understood, but prominent among their positive pleiotropic effects are immunomodulatory and antiinflammatory actions. Statins appear to positively affect life-threatening infections associated with cytokine dysregulation, such as bacterial sepsis.7891011 Statins have also been shown to reduce C-reactive protein levels, known markers for increased cardiovascular events.121314

A current global concern is mortality risk from a potential influenza pandemic.1516 The H5N1/97 strain has exhibited potent ability to elevate proinflammatory cytokines.1718 Preparation for the next pandemic in the Unites States has focused on development of vaccines and antiviral drugs. However, progress toward developing an effective, abundantly available vaccine has been disappointing. Estimates for the time from drug discovery to market in the United States range from 5 to 15 years,1920 suggesting new antiviral drugs will arrive too late to protect against a pandemic resulting from the current influenza strains. Alternatively, Dr. David Fedson21 has suggested that existing approved drugs may provide protection from influenza/pneumonia death. One such class of drugs suggested is statins.21 Two studies (Mortenson et al,5 Mancini et al6) suggest that statins may provide protection from community-acquired pneumonia and COPD.

That these diseases can be controlled through attenuation of the immune response is understandable.222324252627 A recent study28 reports that H5N1 influenza deaths have been primarily the result of a rapidly escalating immune response, outpacing the ability of current antiviral drugs to provide sufficient protection. Cellular damage resulting from cytokine dysregulation could be reduced if statins are able to effectively modulate these immune responses. This study compared influenza and COPD mortality risks for low-dose and moderate-dose statin users and nonusers.

Materials and Methods

We conducted a matched cohort study and two case-control studies to evaluate whether statin use is associated with a reduced risk of death from pneumonia/influenza or COPD. For the case-control studies, two groups of cases and control subjects were selected based on two outcomes: pneumonia/influenza and COPD. This research protocol was reviewed and ruled exempt under the Code of Federal Regulations protection of human subjects.29 The Lovelace Patient Database (LPD), a deidentified, longitudinal, health-care research database comprised of complete health-care encounter data for members of several moderate-sized health maintenance organizations (HMOs), was the data source for these studies. The participating HMOs operate integrated health-care delivery systems. The HMO population considered for this study consisted of approximately 150,000 enrollees per year.

Matched Cohort Study
A file of patients with pharmacy benefits during enrolled periods between January 1, 1992, and December 31, 2003, was compiled using pharmacy dispensing data. Cases were individuals with at least 90 days of cumulative statin exposure prior to death or disenrollment (n = 19,058). All data after December 31, 2003, were censored. Data extracted for analysis included the following: dispensing date, national drug code (uniquely identifying the drug), quantity dispensed, days supply, dosage, and dates of HMO enrollment and disenrollment. Patients using any one or more distinct statin drugs for a minimum of 90 cumulative days were considered to be statin exposed. Based on our data, the usual minimum prescribed statin dose was 10 mg/d. Statin exposure was further classified into low daily dose (< 4 mg/d) and moderate daily dose (≥ 4 mg/d). Daily dose was defined to be the mean milligrams per day for a 3-month to 1-year period following initiation of statin therapy, depending on available enrollment. Ninety-four percent of the moderate-daily-dose group was HMO enrolled at least 1 year after initiation of statin therapy, and 75% of the low-daily-dose group was enrolled for at least 1 year following initiation of statin therapy. Three HMO members without a history of statin therapy (the unexposed group) were matched to each statin-exposed individual based on sex, birth year, and HMO enrollment period. Both cases and comparison group members were required to have at least 90 days of enrollment following initiation of the patient’s statin therapy. Enrollment period matching of statin-exposed and nonexposed individuals permitted observation of health-care events for both groups during closely comparable time periods (ie, 90 days following statin initiation until death or disenrollment). Health-care utilization and hospital discharge data for the statin-exposed and comparison individuals prior to (phase 1) and after (phase 2) initiation of statin therapy were extracted from the LPD. All participants survived phase 1. The Charlson comorbidity index (CCI), an estimate of mortality risk during the subsequent year based on outpatient International Classification of Disease, Ninth Revision Clinical Modification (ICD-9-CM) diagnosis codes, was calculated for both statin-exposed and unexposed patients for matching 12-month periods during phase 1.30

Deaths were based on a patient’s hospital discharge status of deceased. Causes of death were taken from the primary, secondary, and tertiary discharge diagnoses. Grouped causes of death used in the cohort analyses included several broad categories of disease: infectious diseases (ICD-9-CM 001–139), cancer (ICD-9-CM 140–239), nervous system (ICD-9-CM 320–389), circulatory system (ICD-9-CM 340–459), digestive system (ICD-9-CM 520–579), respiratory system (ICD-9-CM 460–519), and external causes (ICD-9-CM 800+). Up to three causes of death were considered for the analyses, with only one cause included in any particular analysis. Respiratory disease deaths were further categorized as follows: (1) pneumonia and influenza deaths (ICD-9-CM 480–487); (2) unspecified pneumonia and influenza deaths (ICD-9-CM 486–487); and (3) COPD deaths (ICD-9-CM 490–496).

Logistic regression was used to estimate the odds ratio (OR) of death for statin users (either low or moderate daily dose) compared to nonusers. Similarly, proportional hazards analysis was used to estimate differences in survival times. The comparisons were adjusted for duration of enrollment before (phase 1) initiation of statin therapy of their matched statin-exposed individual, the CCI during phase 1 (≥ 2 vs < 2), the number of different medications taken during phase 1 (0 to ≥ 18), and receiving three or more influenza vaccinations after initiation of statin therapy (phase 2). Analyses for each cause of death were conducted for both low- and moderate-daily-dose statin groups. The large number of strata (n = 19,058) rendered stratified analysis unnecessary.

Case-Control Studies
Statin-exposed individuals in the cohort study exhibited more cardiovascular comorbidities than matched patients not receiving statins due to the intended primary indication for statins. Since adjustment for these comorbidities in the cohort model could have inadvertently affected other outcomes, we conducted two confirmatory case-control studies. Cases and control subjects (n = 64,362) were again drawn from the LPD. We required both cases and control subjects to be HMO enrolled for at least 12 months. Cases for the pneumonia/influenza study consisted of patients with a hospital discharge of deceased and mention of pneumonia or influenza (ICD-9-CM 486–487); cases for the COPD study were patients with a deceased-labeled hospital discharge and mention of COPD (ICD-9-CM 490–496). Control subjects for the pneumonia/influenza study were surviving patients with one or more inpatient or outpatient visits for either specified pneumonia or influenza/pneumonia (ICD-9-CM 480–487). Control subjects for the COPD study were surviving patients with two or more inpatient or outpatient visits with mention of COPD (ICD-9-CM 490–496). Both cases and control subjects were restricted to those born before 1956 to increase the likelihood of including statin users.

ORs were estimated using logistic regression (SAS Proc Logistic; SAS Institute; Cary, NC). Three categories of statin adherence were used: none, low daily dose (< 4 mg/d), and moderate daily dose (≥ 4 mg/d). Adjustments were made for sex, birth year, and duration of phase 2 enrollment in all models.

Results

Matched Cohort Study
Table 1 lists the characteristics of the patients in the matched cohort. Among the 19,058 HMO members with a statin pharmacy fill, 11,583 patients (60.8%) received at least 4 mg/d during phase 2. Statin daily dose was lowest in members born after 1945 (p < 0.001). Statin users had a higher mean number of different medications received in phase 1. A higher fraction of moderate-daily-dose users (≥ 4 mg/d) had three or more influenza vaccinations in phase 2. Significantly more statin users (both moderate- and low-daily-dose groups) had CCI scores ≥ 2 (9.2%) than nonusers (4.4%), suggesting significantly more comorbidities and a higher risk of death during phase 2.


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  		Table 1. Characteristics of Patients in the Matched Cohort Study*

 
ORs for death from the seven broad disease categories for low-daily-dose (< 4 mg/d) and moderate-daily-dose (≥ 4 mg/d) statin users are shown in Table 2 . As expected, deaths due to circulatory diseases (ICD-9-CM 340–459) were significantly elevated for all statin users. Deaths due to nervous system diseases (ICD-9 320–389) were significantly elevated for all statin users. Deaths from these conditions were also elevated (not significantly) for patients with moderate-daily-dose statin use.


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  		Table 2. Inpatient Deaths by Disease and Statin Daily Dose in the Matched Cohort*

 
ORs for deaths from three categories of respiratory diseases—pneumonia/influenza (ICD-9-CM 480–487), unspecified pneumonia and influenza (ICD-9-CM 486–487), and COPD (ICD-9-CM 490–496)—are provided in Table 3 . In each of these categories, patients with a moderate daily dose had significantly reduced ORs of death. For COPD deaths, statin users with a moderate daily dose had a reduced OR of 0.17 (95% confidence interval [CI], 0.07 to 0.42). The ORs of death in the cohort study from COPD and influenza were nearly identical for both male and female subjects (data not shown). There is possibly a greater influenza/pneumonia protective effect for female than male subjects. Adjusting for the co-occurrence of COPD changed the ORs for influenza from 0.49 (95% CI, 0.26 to 0.76) to 0.63 (95% CI, 0.35 to 1.14).


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  		Table 3. ORs for Inpatient Death Due to Pneumonia/Influenza, Unspecified Pneumonia and Influenza, and COPD in the Matched Cohort*

 
Alternatively, we calculated the proportional hazards regression using SAS Proc PHREG (SAS Institute), adjusted for the same variables used in the logistic regression (Table 4 ). We examined survival times for both low- and moderate-daily-dose statin groups vs unexposed. The moderate-daily-dose hazard ratio was 0.13 (95% CI, 0.05 to 0.32) for COPD, and for influenza/pneumonia it was 0.51 (95% CI, 0.30 to 0.89), similar to the ORs from the logistic regression analysis. For all statin users, the hazard ratio was 0.23 (95% CI, 0.13 to 0.42) for COPD and 0.61 (95% CI, 0.41 to 0.92) for influenza/pneumonia. Moderate-daily-dose statin users without diagnosed COPD had a hazard ratio of 0.54 (95% CI, 0.31 to 0.93) for influenza/pneumonia.


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  		Table 4. Proportional Hazards Survival Analysis

 
Case-Control Studies
Table 5 lists the characteristics of patients in the case-control studies. We identified 397 members who died in the hospital with a discharge diagnosis of unspecified pneumonia/influenza (ICD-9-CM 486–487) and 54,136 surviving members with either an inpatient or outpatient diagnosis with these codes. Similarly, we identified 207 members who died in the hospital with a diagnosis of COPD (ICD-9-CM 490–496) and 9,622 surviving members with either an inpatient or outpatient diagnosis of COPD. We classified patients into three age cohorts: those born in or before 1920, from 1921 to 1945, and from 1946 to 1955.


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  		Table 5. Characteristics of Patients in the Case-Control Studies*

 
Cases compared with surviving control subjects in the pneumonia/influenza study were significantly more likely to have been born prior to 1921 (Table 6 ). Men were at higher risk of influenza/pneumonia death (OR, 1.35; 95% CI, 1.11 to 1.65). For influenza/pneumonia deaths among moderate-daily-dose statin users, the OR of statin exposure was 0.62 (95% CI, 0.43 to 0.91) but was not significantly reduced for lower statin exposure (< 4 mg/d). The OR for statin exposure among COPD deaths was significantly lower for moderate-daily-dose statin users (OR, 0.19; 95% CI, 0.08 to 0.47), whereas the OR of statin exposure for low-daily-dose statin users (< 4 mg/d) was not statistically distinguishable from those with no statin use.


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  		Table 6. Case-Control Study: Influenza/Pneumonia (ICD-9-CM 486–487) Patients (Outpatient or Inpatient) vs Deaths*

 
Due to the limited population size, there was some subject overlap between the cohort and case/control studies. Seventy-seven percent of the statin-exposed patients were included exclusively in the cohort study. Forty-five percent of influenza cases in the influenza case/control study were included exclusively, and 17% of COPD cases in the COPD case/control study were included exclusively.

Discussion

This study found a dramatically reduced risk of death from COPD among statin users and a significantly reduced risk of death from influenza/pneumonia. Since the reductions were observed in both the cohort and case-control studies, it is unlikely they could be due to artifacts of either study design or the analysis.

These findings suggest that moderate-dose statin use reduces the risk of influenza/pneumonia death and strongly suggest that statins reduce the risk of COPD death. Both findings are in general agreement with prior studies.56 A potential concern, confounding by indication, is an unlikely explanation since it would affect both low- and moderate-dose statin users.

Mancini et al6 examined two cohorts of patients ≥ 65 years old with diagnosed COPD. The first cohort included COPD patients who underwent revascularization. The second cohort included people with COPD and no recorded myocardial infarction, and who had a prescription for nonsteroidal antiinflammatory drugs during the first 18 months of a 24-month study period. Exposure to statins was defined as filling at least one statin prescription prior to the index date, with exposure treated as a binary variable and omitting reference to average dose information. Outcomes for both cohorts were analyzed using logistic regression and adjusted for approximately 16 factors. Statin use exhibited an adjusted mortality risk ratio of 0.50 (95% CI, 0.43 to 0.58) for the first cohort and 0.63 (95% CI, 0.54 to 0.74) for the second cohort. The study of Mancini et al6 differed from ours both in its complexity of design and its method for assessing statin exposure. However, despite these differences, the results are in general agreement with our findings.

Our study differs markedly from prior studies of pneumonia and COPD in the methods used to assess statin exposure. Overall, practical statin therapy compliance is thought to be poor,31 suggesting assessment of the daily dose in studies of statin health effects is critical. Studies attempting to quantify the pleiotropic effects of statins for other conditions without adequate consideration of daily dose may risk reaching false-negative conclusions. Our data suggest that consideration of dose is critical in assessing the efficacy of statin therapy.

There are several potential limitations of this study, including the potential for misclassification of disease outcomes. Diagnoses were based on assigned ICD-9-CM codes and are rarely confirmed by identification of a pathogen or antibody response to a pathogen. It is also possible that some drug dispensings were not identified due, for example, to administrative anomalies such as dual insurance coverage. To maximize study power, we considered all drugs in the statin class together. However, different statins could possess different modes of action, with resulting variations in outcomes. Moderate daily dose was defined as an average of ≥ 4 mg/d. In practice, this definition would be considered poor compliance. Finally, deaths occurring outside the hospital were not captured. This potential for underassessment is believed to be minimal for influenza/pneumonia owing to the acute nature and protracted convalescence of the infection. However, this could represent a confounding factor for both the COPD and the influenza studies. These errors might tend to reduce the power of the study either to detect an effect or its ability to estimate the magnitude of an effect.

These studies alone are not proof that the observed associations are causal. We lack specific evidence that statins reduce the risks of influenza mortality. Although statins might be effective in lowering the risks of death from other causes of pneumonia, the current study cannot assess reduced risks during periods when the influenza virus is circulating. Our data suggest that statin-related reduction in influenza/pneumonia mortality is not explained by reduction of COPD-related mortality risks. It remains unclear whether statins will reduce influenza mortality risks for young people who are most likely to be severely affected by an avian influenza pandemic.

The magnitude of the risk reduction for influenza/pneumonia death we observed was less than that reported by Mortenson et al.5 Because statins appear to provide significant protection from COPD-associated death, the prevalence of COPD in a study population could significantly affect the magnitude of the influenza/pneumonia protective effect observed. If a larger proportion of patients in the study by Mortenson et al5 also had COPD, this could have had the effect of inflating the estimated protective effects of statin exposure for influenza/pneumonia death. Another uncertainty is the duration of statin therapy needed to affect risk reduction. A study32 of 107 hypercholesterolemic patients treated with simvastatin for 6 weeks showed a significant decline in cytokine levels; however, greater reductions were observed after 6 months.

Even if statins are not able to significantly reduce the risk of death from avian influenza, their use could significantly extend the time between disease onset and death. This additional survival time could increase the effectiveness of antiinfluenza drugs, providing a longer time to reduce mortality risks. So far, antiinfluenza drugs have not demonstrated an ability to significantly reduce the level of avian influenza human death.28 There remain, unfortunately, many uncertainties about the effectiveness of statins as an approach to preventing or delaying death from avian influenza. However, given the lack of effective alternatives, resolving these uncertainties should be a high priority.

Footnotes

Abbreviations: CCI = Charleson comorbidity index; CI = confidence interval; HMO = health maintenance organization; ICD-9-CM = International Classification of Disease, Ninth Revision, Clinical Modification; LPD = Lovelace Patient Database; OR = odds ratio

This work was performed at Lovelace Respiratory Research Institute.

The authors have no conflicts of interest to disclose.

Received for publication August 10, 2006. Accepted for publication October 10, 2006.

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