Effect of statins on preventing infectious complications after surgery: Systematic review and meta-analysis

Abstract

Objective

These authors contributed equally to this work.

A meta-analysis to investigate the association between preoperative statin use and the risk of postoperative infectious complications in patients undergoing surgery.

Methods

PubMed® and Embase® databases were searched for relevant studies. Data were extracted using a standardized data collection form. The primary effect measure was the odds ratio (OR) of postoperative infectious complications. Summary OR were calculated.

Results

The analysis included 10 cohort studies with a total of 147 263 participants. Statin use was associated with a lower incidence of postoperative infectious complications in all studies (summary OR 0.917, 95% conﬁdence intervals [CI] 0.862, 0.975, fixed-effects model; summary OR 0.731, 95% CI 0.584, 0.870, random-effects model); cardiac surgery (summary OR 0.673; 95% CI 0.535, 0.847); treatment in the USA (summary OR 0.678; 95% CI 0.597, 0.770); retrospective cohort studies (summary OR 0.664; 95% CI 0.521, 0.846).

Conclusion

Preoperative statin use is associated with a reduced risk of postoperative infectious complications.

Keywords

Statin postoperative infection surgery

Introduction

Postoperative infections prolong hospital stay and increase mortality rates. Despite prophylactic antibiotic therapy, between 5% and 21% of patients develop postoperative infectious complications.^1–4 Statins (3-hydroxy-3-methylglutaryl coenzyme A [CoA] reductase inhibitors) have antioxidant,^5–7 anti-inﬂammatory^8–10 and antithrombogenic effects,¹¹ as well as lipid-independent effects including direct inhibition of pathogenic micro-organisms.^12,13 The effect of preoperative statin therapy on the incidence of postoperative infectious complications is unclear, with some studies finding a significant reduction in postoperative infections^14,15 and others reporting no effect on infection risk.^16,17 A meta-analysis of six cohort studies of patients undergoing cardiac surgery was performed in 2012, and found no association between statin use and postoperative infectious complications.¹ The aim of the present meta-analysis was to evaluate the association between statin use and postoperative infectious complications by analysing all available cohort studies, including those published since 2012.^14,18–20

Materials and methods

Search strategy

The procedures used for the meta-analysis were consistent with MOOSE guidelines.²¹ Electronic databases, including PubMed® and Embase®, were searched from inception to September 2014, to identify relevant studies, using a combination of keywords related to the type of statin (“hydroxymethylglutaryl coenzyme A reductase inhibitors” or “anticholesteremic agents” or “statin” or “simvastatin” or “rosuvastatin” or “pravastatin” or “atorvastatin” or “fluvastatin” or “cerivastatin” or “pitavastatin” or “lovastatin”) and the type of infection-associated disease (“infection” or “sepsis” or “bacteremia” or “pneumonia”). An English language restriction was imposed. Study selection was based on an initial screening of identiﬁed abstracts or titles and a second screening of full-text articles. The reference lists of relevant review articles and meta-analyses were examined, to identify other potentially eligible studies.

Eligibility criteria

Eligibility criteria were: (i) observational study design, i.e., patients were assigned into statin and control groups; (ii) study investigated the association between statin use for any indication and incidence of postoperative infections; (iii) study quantified outcomes with adjusted odds ratios (ORs), relative risk, or number of events and corresponding 95% confidence intervals (CIs). When studies did not report adjusted OR, authors were contacted to obtain missing information. Exclusion criteria were: (i) experimental group undergoing other therapy; (ii) review articles; (iii) data unavailable for meta-analysis.

Data extraction and quality assessment

Data were extracted using a standardized data collection form. Data extracted included: last name of first author, publication year, country, number of cases, and adjusted OR. Two reviewers (B.-X. M. and H. L.) worked independently and in duplicate; both extracted and recorded data. Disagreements between the two reviewers were resolved by consensus. Unresolved issues were referred to a third author (J.-S. L.).

The methodological quality of included studies was assessed with the Newcastle–Ottawa Scale (NOS), which comprises three quality parameters: selection, comparability, and outcome (cohort studies) or exposure (case–control studies).²² Methodological quality was independently assessed by two reviewers (B.-X. M. and H. L.), and any discrepancies were addressed by a joint revaluation of the original article with the third author (J.-S. L.).

Statistical analyses

The primary effect measure was the OR of postoperative infectious complications. Heterogeneity and publication bias were assessed with I² and Begg’s analysis, respectively.²³ Statistical signiﬁcance was set at P < 0.05 (two-tailed). The fixed-effects model was applied in the case of no significant difference, and the random-effects model was used in the case of significant difference. Statistical analyses were performed with STATA® version 11 (STATA Corp., College Station, TX, USA).

Results

A flow chart showing the study selection process is presented in Figure 1. The analysis included 10 studies with 147 263 patients (71 931 of whom received statins).^{14–20,24–26} The characteristics and quality assessment of the included studies are presented in Table 1. According to NOS criteria, two studies were of high quality, ^15,16 six were medium quality,^{14,17,19,20,24,25} and two were low quality.^18,26

Figure 1.

Flow diagram of eligible studies showing the number of citations identiﬁed, retrieved, and included in the final meta-analysis.

Table 1.

Studies included in a meta-analysis to evaluate the relationship between preoperative statin use and the incidence of postoperative infectious complications.

Author	Country	Study type/ dose	n statin/ control	Inclusion criteria	Study design	Adjusted effect estimate (95% CI)	Quality rating NOS
Ali and Buth, 2005²⁴	Canada	NA	3555/1914	CABG with or without valve surgery	Cohort study (retrospective)	0.70 (0.50, 1.10)	8
Coleman et al., 2007¹⁵	USA	NA	1248/686	CABG with or without valve surgery	Cohort study (retrospective)	0.67 (0.46, 0.99)	9
Subramaniam et al., 2008²⁵	USA	NA	1835/662	CABG	Cohort study (prospective)	0.68 (0.31, 1.48)	8
Daneman et al., 2009¹⁶	Canada	Multiple	53565/53565	Cardiac or noncardiac surgery (abdominal, musculoskeletal, etc)	Cohort study (retrospective)	1.03 (0.95, 1.11)	9
Mohammed et al., 2009¹⁷	Canada	NA	2657/5076	Cardiac surgery	Cohort study (prospective)	1.08 (0.89, 1.31)	8
Trezzi et al., 2013¹⁴	USA	NA	3263/3263	Cardiac surgery	Cohort study (retrospective)	0.68 (0.53, 0.88)	8
Kayani et al., 2013¹⁹	USA	Multiple	3869/2384	CABG	Cohort study (retrospective)	0.74 (0.60, 0.90)	8
Tleyjeh et al., 2012²⁶	USA	Multiple	755/669	CABG with or without valve surgery	Cohort study (retrospective)	0.49 (0.32, 0.75)	6
Iannuzzi et al., 2014¹⁸	USA	Multiple	814/6963	Noncardiac surgery	Cohort study (retrospective)	0.65 (0.45, 0.94)	7
Hartholt et al., 2014²⁰	Netherlands	NA	370/150	Cardiac surgery	Cohort study (retrospective)	0.329 (0.189, 0.572)	8

CI, confidence intervals; NOS, Newcastle–Ottawa Scale; NA, not available; CABG, coronary artery bypass graft

Results of meta-analysis including all 10 studies are shown in Figure 2 and Table 2. The use of statins in the preoperative period was associated with a lower incidence of postoperative infections using both a random-effects model (OR 0.731; 95% CI 0.584, 0.870) and a fixed-effects model (OR 0.917; 95% CI 0.862, 0.975).

Figure 2.

Forest plot of a meta-analysis to evaluate the relationship between preoperative statin use and the incidence of postoperative infectious complications. Data are pooled odds ratios (OR) for postoperative infections in statin users versus nonusers, determined using a random-effects model. Error bars indicate 95% confidence intervals.

Table 2.

Total and subgroup meta-analysis of the relationship between preoperative statin use and the incidence of postoperative infectious complications.

Group	Studies, n	Summary OR (95%CI)	P-value for heterogeneity
All included studies	10	0.713 (0.584, 0.870)	<0.001
Cardiac surgery	8	0.673 (0.535, 0.847)	<0.001
Country
USA	6	0.678 (0.597, 0.770)	0.699
Canada	3	1.024 (0.954, 1.099)	0.143
Study design
Cohort study (retrospective)	8	0.664 (0.521, 0.846)	<0.001
Cohort study (prospective)	2	1.052 (0.872, 1.269)	0.260

OR, odds ratio; 95% CI, 95% confidence intervals.

Results of subgroup analyses are shown in Table 2. Statin use was associated with a lower incidence of postoperative infectious complications in cardiac surgery (summary OR 0.673; 95% CI 0.535, 0.847), in the USA (summary OR 0.678; 95% CI 0.597, 0.770) and in retrospective cohort studies (summary OR 0.664; 95% CI 0.521, 0.846). There was significant heterogeneity in cardiac surgery (P < 0.001) and in retrospective cohort studies (P < 0.001). There was no significant heterogeneity in studies conducted in the USA or Canada, or in prospective cohort studies.

The funnel plot (Figure 3) and Begg’s test (P = 0.283) indicated the absence of publication bias.

Figure 3.

Funnel plot of studies included in a meta-analysis to evaluate the relationship between preoperative statin use and the incidence of postoperative infectious complications. Area of each circle represents the contribution of the study to the pooled odds ratio (OR).

Discussion

Findings of our systematic review and meta-analysis show that preoperative statin therapy is associated with reduced numbers of postoperative infections. The large degree of heterogeneity in the present analysis indicates that further investigation is warranted, however.

A systematic review published in 2012 did not find sufficient evidence to support an association between statin use and postoperative infection.¹ Since that time, four additional studies have been published regarding the association between statin use and postoperative infectious complications,^14,18–20 all of which found a reduced risk of postoperative infections with statin therapy. In contrast, however, a retrospective cohort analysis indicated that statin use was associated with an increased incidence of common infections in the general population.²⁷ Our analysis clearly shows that statin use was significantly associated with a reduced risk of infectious complications in patients who underwent surgery.

Statins possess pleiotropic properties,^28,29 including cholesterol lowering, anti-inflammatory, immunomodulatory and antioxidant properties.^{5–13,30–33} High-sensitivity C-reactive protein levels are reduced by statin therapy,³⁰ and statins modulate the function of immune cells by downregulating various cell receptors and cytokines involved in inflammation, activating natural killer cells, and enhancing phagocytosis.^31–35 In addition, studies have demonstrated that statins exert direct antibacterial and antiviral effects on pathogenic micro-organisms.^12,13,36

The present meta-analysis has several limitations. First, observational cohort studies were included in this analysis, and their statistical power may not be as strong as that of randomized controlled trials. Secondly, the high degree of heterogeneity complicated interpretation of our findings. Subgroup analyses were conducted to explore the sources of heterogeneity, and determined that country or study design may have been contributing factors. Thirdly, infectious complications included sternal wound infection, organ space infection, pneumonia, urinary tract infection and sepsis; these have different protocol definitions and therefore may be an additional source of heterogeneity. No attempt was made to recategorize types of infection retrospectively. Finally, statin type and dosage varied between the studies, so we were unable to evaluate the influence of the duration and dosage of preoperative statin therapy on the incidence of postoperative infection.

In conclusion, preoperative statin use is associated with a reduced risk of postoperative infectious complications.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conﬂicts of interest.

Funding

This research received no speciﬁc grant from any funding agency in the public, commercial, or not for-proﬁt sectors.

References

Tleyjeh

Alasmari

Bin Abdulhak

. Association between preoperative statin therapy and postoperative infectious complications in patients undergoing cardiac surgery: a systematic review and meta-analysis. Infect Control Hosp Epidemiol 2012; 33: 1143–1151.

De Santo

Bancone

Santarpino

. Microbiologically documented nosocomial infections after cardiac surgery: an 18-month prospective tertiary care centre report. Eur J Cardiothorac Surg 2008; 33: 666–672.

Michalopoulos

Geroulanos

Rosmarakis

. Frequency, characteristics, and predictors of microbiologically documented nosocomial infections after cardiac surgery. Eur J Cardiothorac Surg 2006; 29: 456–460.

Kollef

Sharpless

Vlasnik

. The impact of nosocomial infections on patient outcomes following cardiac surgery. Chest 1997; 112: 666–675.

Mondo

Yang

Zhang

. Anti-oxidant effects of atorvastatin in dexamethasone-induced hypertension in the rat. Clin Exp Pharmacol Physiol 2006; 33: 1029–1034.

Ajith

Riji

Anu

. In vitro anti-oxidant and DNA protective effects of the novel 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor rosuvastatin. Clin Exp Pharmacol Physiol 2008; 35: 625–629.

Wang

Chen

. Simvastatin combined with antioxidant attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. Biomed Res Int 2014; 2014: 910260–910260.

Araujo

Rocha

Ferreira

. Implant-induced intraperitoneal inflammatory angiogenesis is attenuated by fluvastatin. Clin Exp Pharmacol Physiol 2011; 38: 262–268.

Al-Ghoul

Kim

Fazal

. Evidence for simvastatin anti-inflammatory actions based on quantitative analyses of NETosis and other inflammation/oxidation markers. Results Immunol 2014; 4: 14–22.

10.

Wang

Chen

. Simvastatin attenuates the cerebral vascular endothelial inflammatory response in a rat traumatic brain injury. Ann Clin Lab Sci 2014; 44: 145–150.

11.

Ferrara

Liu

Espinola

. Inhibition of the thrombogenic and inflammatory properties of antiphospholipid antibodies by fluvastatin in an in vivo animal model. Arthritis Rheum 2003; 48: 3272–3279.

12.

del Real

Jiménez-Baranda

Mira

. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 2004; 200: 541–547.

13.

Potena

Frascaroli

Grigioni

. Hydroxymethyl-glutaryl coenzyme a reductase inhibition limits cytomegalovirus infection in human endothelial cells. Circulation 2004; 109: 532–536.

14.

Trezzi

Blackstone

Sun

. Statin therapy is associated with fewer infections after cardiac operations. Ann Thorac Surg 2013; 95: 892–900.

15.

Coleman

Lucek

Hammond

. Preoperative statins and infectious complications following cardiac surgery. Curr Med Res Opin 2007; 23: 1783–1790.

16.

Daneman

Thiruchelvam

Redelmeier

. Statin use and the risk of surgical site infections in elderly patients undergoing elective surgery. Arch Surg 2009; 144: 938–945.

17.

Mohamed

McAlister

Pretorius

. Preoperative statin use and infection after cardiac surgery: a cohort study. Clin Infect Dis 2009; 48: e66–e72.

18.

Iannuzzi

Rickles

Kelly

. Perioperative pleiotropic statin effects in general surgery. Surgery 2014; 155: 398–407.

19.

Kayani

Bandeali

Lee

. Association between statins and infections after coronary artery bypass grafting. Int J Cardiol 2013; 168: 117–120.

20.

Hartholt

Rettig

Schijffelen

. Preoperative statin therapy and infectious complications in cardiac surgery. Neth Heart J 2014; 22: 503–509.

21.

Stroup

Berlin

Morton

. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA 2000; 283: 2008–2012.

22.

Stang

. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol 2010; 25: 603–605.

23.

Begg

Mazumdar

. Operating characteristics of a rank correlation test for publication bias. Biometrics 1994; 50: 1088–1101.

24.

Ali

Buth

. Impact of preoperative statin use on sepsis and deep sternal wound infection. Circulation 2005; 111: e320–e320.

25.

Subramaniam

Koch

Bashour

. Preoperative statin intake and morbid events after isolated coronary artery bypass grafting. J Clin Anesth 2008; 20: 4–11.

26.

Tleyjeh

I AF RM

. A clinical prediction rule of deep sternal wound infections after coronary artery bypass graft surgery: a population-based cohort study, 1993 to 2008. Clin Microbiol Infect 2012; 18(suppl S3): 79–79.

27.

Magulick

Frei

Ali

. The effect of statin therapy on the incidence of infections: a retrospective cohort analysis. Am J Med Sci 2014; 347: 211–216.

28.

Krishna

Issa

Saha

. Pleiotropic effects of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors in pulmonary diseases: a comprehensive review. Pulm Pharmacol Ther 2015; 30: 134–140.

29.

Tziomalos

Karagiannis

Athyros

. Effects of lipid-lowering agents on inflammation, haemostasis and blood pressure. Curr Pharm Des 2014; 20: 6306–6313.

30.

Biasucci

Biasillo

Stefanelli

. Inflammatory markers, cholesterol and statins: pathophysiological role and clinical importance. Clin Chem Lab Med 2010; 48: 1685–1691.

31.

Istvan

Deisenhofer

. Structural mechanism for statin inhibition of HMG-CoA reductase. Science 2001; 292: 1160–1164.

32.

Kwak

Mulhaupt

Myit

. Statins as a newly recognized type of immunomodulator. Nat Med 2000; 6: 1399–1402.

33.

Ulivieri

Baldari

. Statins: from cholesterol-lowering drugs to novel immunomodulators for the treatment of Th17-mediated autoimmune diseases. Pharmacol Res 2014; 88: 41–52.

34.

Gruenbacher

Gander

Nussbaumer

. IL-2 costimulation enables statin-mediated activation of human NK cells, preferentially through a mechanism involving CD56 + dendritic cells. Cancer Res 2010; 70: 9611–9620.

35.

Tanaka

Abe-Dohmae

Iwamoto

. HMG-CoA reductase inhibitors enhance phagocytosis by upregulating ATP-binding cassette transporter A7. Atherosclerosis 2011; 217: 407–414.

36.

Catron

Lange

Borensztajn

. Salmonella enterica serovar Typhimurium requires nonsterol precursors of the cholesterol biosynthetic pathway for intracellular proliferation. Infect Immun 2004; 72: 1036–1042.