Simvastatin Improves Neutrophil Function and Clinical Outcomes in Pneumonia. A Pilot Randomized Controlled Clinical Trial

Abstract

Rationale: Population studies suggest improved sepsis outcomes with statins, but the results of randomized controlled trials in patients with sepsis and organ dysfunction in critical care settings have broadly been negative. In vitro data suggest that statins modulate age-related neutrophil functions, improving neutrophil responses to infection, but only in older patients and at high doses.Objectives: To determine if high-dose simvastatin improves neutrophil functions and is safe and tolerated in hospitalized older adults with community-acquired pneumonia with sepsis (CAP + S) not admitted to critical care.Methods: We conducted a randomized, double-blind, placebo-controlled pilot study of simvastatin 80 mg or placebo for 7 days for patients with CAP + S aged 55 years or older admitted to a secondary care hospital. The Day 4 primary endpoint was change in neutrophil extracellular trap formation (NETosis). Day 4 secondary endpoints included neutrophil chemotaxis, safety and tolerability, Sequential Organ Failure Assessment score, mortality, readmission, and markers of tissue degradation/inflammation.Measurements and Main Results: Four days of simvastatin adjuvant therapy in patients with CAP + S was associated with improvements in systemic neutrophil function (NETosis and chemotaxis), a reduction in systemic neutrophil elastase burden, and improved Sequential Organ Failure Assessment scores compared with placebo. A post hoc analysis demonstrated that simvastatin therapy was associated with improved hospitalization-free survival compared with placebo. Simvastatin was well tolerated in this elderly and multimorbid patient group with common coprescription of macrolide antibiotics.Conclusions: This pilot study supports high-dose simvastatin as an adjuvant therapy for CAP + S in an older and milder disease cohort than assessed previously. A definitive multicenter study is now warranted in this population to assess the likelihood of benefit and harm.Clinical trial registered with EudraCT (2012-00343-29).

Keywords: elderly care; innate immunity; pneumonia; sepsis; statin.

Figure 1.

The study schedule. Patients with community-acquired pneumonia and sepsis (CAP + S) were identified and recruited within 48 hours of admission. Baseline information (clinical assessment, symptoms, blood samples for neutrophil isolation, clinical studies [including cholesterol, renal function, liver function, a full blood count, clotting status, and creatine kinase], and inflammatory studies) was obtained just before randomization. After randomization, patients were prescribed simvastatin 80 mg or placebo once daily for 7 days. Medications were dispensed by ward nursing staff, and tablet ingestion was noted in an electronic prescribing log. On Day 4 (after the ingestion of the fourth tablet), clinical and safety data were collected alongside blood tests for neutrophil studies, safety information, and inflammatory studies (as described above). These assessments were repeated 7 days after the ingestion of the first tablet (after seven doses of the tablet) if patients remained as inpatients. Patients and their general practitioners were contacted, and electronic health records were analyzed at 12 months after recruitment to gather data on readmission to the hospital and survival. OD = once daily; PO = by mouth.

Figure 2.

Modified Consolidated Standards of Reporting Trials diagram of trial endpoints. A total of 237 patients were screened with community-acquired pneumonia and sepsis (CAP + S), but 28 did not provide consent or assent, 111 did not meet inclusion criteria, and 36 met exclusion criteria. Sixty-two patients were recruited to the study, and all were followed for clinical endpoints at 12 months using an intention-to-treat analysis with consent even if they withdrew from the study. Patients who did not complete simvastatin or placebo therapy to Day 4 endpoints or then to Day 7 endpoints because of study withdrawal or hospital discharge were not included in neutrophil functional studies, because the study compared changes in function from baseline in a paired analysis. D/C = discharged because of clinical recovery; NET = neutrophil extracellular trap.

Figure 3.

Change in neutrophil extracellular trap formation (NETosis) in patients with community-acquired pneumonia and sepsis (Day 4 minus Day 0). Patients with community-acquired pneumonia and sepsis received simvastatin 80 mg or placebo as well as standard medical treatment. Neutrophils were stimulated with formyl-methionyl-leucyl-phenylalanine (100 nM), and after 3 hours, NET formation was measured, both at Day 0 and at Day 4. Each dot represents one patient. NET data are displayed as Day 4 formyl-methionyl-leucyl-phenylalanine–induced reduced NETosis minus Day 0 NETosis (therefore, the change in NETosis), measured in arbitrary units. The lines show the median and interquartile range. Patients receiving simvastatin had a greater reduction in NETosis at Day 4 than patients receiving placebo (P = 0.034 by Mann-Whitney U test).

Figure 4.

Change in chemotaxis in patients with community-acquired pneumonia and sepsis (Day 4 minus Day 0). Patients with community-acquired pneumonia and sepsis received simvastatin 80 mg or placebo as well as standard medical treatment. Neutrophils migrated to CXCL8 (100 nM) isolated both at Day 0 and at Day 4. Each dot represents one patient. Lines are median and interquartile range. Chemotaxis data are measured in μm/min. Compared with placebo, simvastatin treatment was associated with a greater change in the accuracy of neutrophil migration (improvement) from Day 0 to Day 4 (P = 0.03 by Mann-Whitney U test).

Figure 5.

Change in systemic neutrophil elastase activity in patients with community-acquired pneumonia and sepsis (Day 4 minus Day 0). Patients with community-acquired pneumonia and sepsis received simvastatin 80 mg or placebo as well as standard medical treatment. Plasma Aα360^VAL was measured. Each dot represents one patient. The lines are the median and interquartile range. Compared with placebo, simvastatin treatment was associated with a significant reduction in systemic neutrophil elastase activity (Day 4 minus Day 0; P = 0.001 by Mann-Whitney U test).

Figure 6.

Change in Sequential Organ Failure Assessment (SOFA) score in patients with community-acquired pneumonia and sepsis from Day 0 to Day 4. Patients with community-acquired pneumonia and sepsis received simvastatin 80 mg or placebo as well as standard medical treatment. SOFA score was calculated. Each dot represents one patient. The lines are the median and interquartile range. Compared with placebo, simvastatin treatment was associated with a greater change (reduction) in SOFA score (Day 4 minus Day 0; P = 0.026 by Mann-Whitney U test).

Figure 7.

Kaplan-Meier curves for hospitalization-free survival at 365 days in an intention-to-treat analysis. The black line represents the simvastatin group, and the gray line represents patients who received placebo. The 365-day hospitalization-free survival rate demonstrates an odds ratio of 0.45 (95% confidence interval, 0.22–0.90; P = 0.03).