2007May22 1

Journal Club for Analysis of Complex Datasets

Frost FJ, Petersen H, Tollestrup K, Skipper B. Influenza and COPD mortality protection as pleiotropic, dose-

dependent effects of statins.Chest 2007; 131: 1006-1012.

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Acknowledgement

• Carlos Grijalva, MD, MPHDepartment of Preventive Medicine

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Background

• Data on antiinflammatory & immunomodulatory effects of statins suggest they may reduce mortality risks from influenza & COPD.

• 2 observational studies suggest statins may protect community-acquired pneumonia & COPD.– Mortenson EM, et al. Respir Res 2005; 6: 82.– Mancini GB, et al. J Am Coll Cardiol 2006; 47: 2554.

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Purpose

• Objective: compare influenza & COPD mortality risks for low-dose & moderate-dose statins users & nonusers.

• Design: matched cohort study & 2 case-control studies.

• Data: Lovelace Patient Database.– Deidentified, longitudinal db of health-care

encounter data comprising several HMO’s.• Time period: 92Jan01 – 03Dec31.

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Matched cohort• E+: 90+ cumulative days statin exposure prior to

death or disenrollment (N=19,058).– Further classified as low daily dose (<4 mg/d) or

moderate dose (4+ mg/d).– Mean mg/d for 3-month – 1-yr period after statin initiation.

• E-: 3 HMO members w/o hx of statin therapy matched to each E+ based on gender, birth yr, & HMO enrollment period (N=57,174).– Enrollment period matching permitted observation of

events for both groups during closely comparable time periods.

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Outcomes• Pneumonia or influenza death.• Unspecified pneumonia & influenza deaths.• COPD deaths.

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Analysis

• Logistic & proportional hazards reg.• Adjusted for:

– Duration of enrollment before initiation of statin therapy (phase 1).

– Phase 1 Charlson comorbidity index.– # of different med’s taken during phase 1.– Receiving 3+ influenza vaccinations after

statin therapy initiation (phase 2).

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Case-control studies• E+ had more CV comorbidities than E-.

– Adjustment for these could have inadvertently affected other outcomes.

• Pneumonia/influenza study:– D+: Hospital discharge of deceased & pneumonia or

influenza.– D-: Surviving patients w/ 1+ in/outpatient visits for

pneumonia or influenza.• COPD study:

– D+: Hospital discharge of deceased & COPD.– D-: Surviving COPD patients w/ 2+ in/outpatient visits.

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Analysis• Logistic reg.• Adjusted for:

– Sex.– Birth year.– Duration of phase 2 enrollment.

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Results: matched cohortlogistic regression

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Results: matched cohortproportional hazards

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Results: case-control study

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Concerns

• Observational study.– Adjusted for few covariates.– Unmeasured confounders?– Confounding by indication.

• “…unlikely explanation since it would affect both low- and moderate-dose statin users.”

– Large cohort (N>75,000).– Propensity scores?– Sensitivity analysis?

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Concerns (2)

• Motivation for case-control studies unclear.– Results similar to cohort study is not a validation of

results.• “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.”

– Cases & controls sampled from same db as matched cohort.

• Case-control studies had 2x’s events as matched cohort.

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Concerns (3)

• Logistic reg analysis of survival data.– Ignores censoring.– Cannot account for time-dependent

covariates.• Immortal-time bias: Ayumi!

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