Sage Journals: Discover world-class research

Abstract

Background:

Evidence suggests statins may improve survival in patients with bloodstream infections. However, there is no consensus on optimal timing and duration of exposure.

Objectives:

To quantify statin therapy duration associated with decreased mortality in bacteremic statin users.

Methods:

We conducted a case-control study using OptumClinformatics™ with matched Premier hospital data (1 October 2009–31 March 2013). Cases who died during the hospitalization were matched 1:1 to survivors on disease risk scores (DRSs). Post-admission statin therapy duration was evaluated in patients with at least 90 days of pre-admission continuous statin use. Classification and regression tree (CART) analysis was conducted to identify the optimal duration of statin continuation which provided the lowest inpatient mortality. Logistic regression was used to calculate the odds of mortality.

Results:

We included 58 DRS matched pairs of cases and controls: 47 patients (41%) continued statin therapy during the hospital admission, 15 (32%) cases and 32 (68%) controls. The CART analysis partitioned the continuation of statin therapy at ⩾2 days, representing lower mortality for patients who continued statins for 2 days or more and higher mortality for patients who did not continue or remained on statins for only 1 day. Inpatient mortality was 76% lower among those with at least 2 days of continued statin use (odds ratio 0.24, 95% confidence interval 0.11–0.55).

Conclusion:

Among matched cases and controls with at least 90 days of baseline statin use prior to the admission, the continuation of statins for at least 2 days after admission demonstrated a survival benefit among bacteremic patients.

Keywords

bacteremia mortality statin treatment duration

Introduction

Inpatient mortality among patients with bloodstream infections remains high (16.3%).¹ Evidence from observational research suggests that statins may improve survival in patients with bacteremia^2–5 and sepsis,^6–8 including 14 day,⁵ 15 day,² 31–180 day,⁹ and all-cause hospital mortality.^3,5,7 While several studies have reported reduced mortality with statins in bacteremic patients, statin duration and measurement of outcomes differ across these studies.^3–5 As a result, rates of survival vary, particularly as statin exposure varies.^3,9 In addition, several of these studies have identified an increase in mortality after cessation of statin therapy.^3,10 Since the length of statin treatment time varies between studies, there is no consensus as to whether statin therapy should be continued among patients presenting to the hospital with bacteremia, and if so, what duration of statin continuation would provide the maximum advantage in terms of clinical outcomes.

While several meta-analyses^11,12 and observational^3–5,9 studies observed protective effects with statins in bacteremia, one meta-analysis¹³ did not observe improvements in clinical outcomes with statin use. However, this meta-analysis was conducted among critically ill patients with severe sepsis, and some of the included studies only had short durations of statin use.^3,4,9 Other studies with shorter statin durations also did not demonstrate a statistically significant association between statin use and mortality.^9,13,14 A recent randomized controlled trial (RCT) evaluating the potential benefits of continued statin therapy on inflammatory parameters and sepsis among patients with pre-existing statin use¹⁵ did not find clinical benefits with continuation. As such, there is a lack of consistent evidence regarding the appropriate exposure duration needed for statins to provide the greatest protective effects in bacteremic patients. The main objective of this study was to identify a duration of statin therapy continuation which minimized inpatient mortality among bacteremic patients.

Methods

A case-control study design was used to estimate a time breakpoint in statin continuation at which the highest clinical benefit would be seen in terms of survival (i.e. lowest inpatient mortality). This study was conducted using de-identified OptumClinformatics™ database (OptumInsight, Eden Prairie, MN, USA) with matched Premier hospital data (1 October 2009 to 31 March 2013) among adult (⩾18 years) patients with a primary diagnosis of bacteremia during a hospital admission.

Adult patients with continuous enrollment for at least 6 months in the commercial health plan prior to hospital admission were included. Patients were included if they were hospitalized between 1 April 2010 and 31 March 2013 with a primary diagnosis of bacteremia or septicemia [International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) codes 003.1, 020.2, 022.3, 036.2, 038.0, 038.1, 038.10–038.12, 038.19, 038.2, 038.3, 038.40–038.44, 038.49, 038.8, 038.9, 054.5, 449, 771.81, 995.91, 995.92, 790.7]¹⁶ by any causative organism. We excluded patients who, on the first 3 days after hospital admission, did not receive a minimum of two successive days of at least one antibiotic therapy that would be used to treat bacteremia.^17–20 The index date was defined as the date of the first hospital admission during the study period, and subsequent hospital admissions were not considered for the analysis. From this cohort, only patients with a minimum of 90 days of continuous statin use in the 90 days prior to admission were selected for inclusion to capture prevalent and adherent statin users (Figure 1). The Charlson comorbidity index and chronic comorbidities were captured from ICD-9-CM codes in the 6 months prior to admission and during the index admission.²¹

Figure 1.

Case-control study design.

Cases included those who died during the admission. Controls were selected from survivors of the same cohort of adult patients who had a primary diagnosis of bacteremia on hospital admission and received antibiotic therapy. Controls were matched to cases on disease risk scores (DRSs).²² DRS is a confounder summary method, which can be used in case-control studies to control for confounding by calculating the predicated probability of an outcome in the absence of exposure.^23,24 The stratified DRS is a retrospective balancing score and therefore, it works in a similar manner in case-control studies as the propensity score works in cohort studies. While propensity score models predict the probability of exposure, DRSs predict the probability of the outcome, which in our study was mortality.²⁴ DRSs were calculated using logistic regression. The c-statistic for the final DRS model was 0.91. The full DRS model equation can be found in the footnote of Figure 2. Using nearest neighbor matching within a caliper of 0.25 distance, a single control without replacement was selected for each case.²⁵ We checked DRS balance between cases and controls using graphical displays (Figure 2).

Figure 2.

Disease risk scores (DRS) distribution among cases and controls.

Among patients with at least 90 days of statin therapy in the 90 days prior to admission (proportion of days covered 100% for all patients), the primary exposure of interest was the number of days of continued statin use during admission. The statins included were atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. A 1 day gap in therapy was allowed, but the gap was not counted in the calculation of the statin use period. To partition statin continuation days associated with the greatest survival benefit, we conducted a classification and regression tree analysis (CART).^26,27 The CART analysis, which includes an optimal tree selection based on pruning and cross-validation, identified subsets of patients at lowest risk of death based on days of statin continuation. CART models are useful because of their non-parametric, non-linear structure.²⁷ The trees were automatically developed to forecast inpatient mortality by considering every possible cut-point on statin continuation duration at every node in the classification tree. Based on the split provided by the CART analysis, conditional logistic regression was conducted to calculate the odds of mortality. Statistical analyses were conducted using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R software version 3.2.0 (The R Foundation for Statistical Computing) with a recursive partitioning technique “rpart” package that was developed for Splus (Insightful Corporation, Seattle, WA, USA).²⁸ This study was reviewed and approved as exempt by the University of Rhode Island’s Institutional Review Board.

Results

Among our study population of prevalent and adherent statin users in the 90 days prior to admission, 61 (6.9%) patients died and 821 (93.1%) survived their hospital stay. Using DRS matching, controls were identified for 58 cases. Due to matching, baseline characteristics were similar between cases and controls, including age (median 68 versus 67 years, p = 0.8520; Table 1), gender (39.7% versus 43.1% females, p = 0.7992), race (20.7% versus 15.5% non-whites, p = 0.7637), and Charlson comorbidity score during the admission (median 4 versus 4, p = 0.8239) and in the 6 months prior to admission (median 4 versus 4, p = 0.4959). The length of hospital stay was significantly longer among controls compared to cases (median = 9 versus 5 days, p = 0.0005). Of the 47 (41%) patients who continued statin use during the hospital admission, 32% (n = 15) were cases and 68% (n = 32) were controls. The average statin therapy duration during admission among cases and controls was 1.5 ± 3.7 versus 4.5 ± 7.5 days, respectively.

Table 1.

Demographic and hospitalization-related characteristics in cases and controls.

Characteristics	Cases/died (n = 58)		Controls/DRS matched survivors (n = 58)		p-value
Characteristics	n/median	%/IQR/SD	n/median	%/IQR/SD	p-value
Age (years)	68	61–77	67	60–82	0.8520
Gender
Female	23	39.7	25	43.1	0.7061
Male	35	60.3	33	56.9
Race
Non-White	12	20.7	9	15.5	0.7637
White	46	79.3	49	84.5
Admitting physician specialty
Intensive care/surgery	< 5	3.4	< 5	3.4	0.9190
Medicine	18	31.0	16	27.6
Other	38	65.6	40	69.0
Ventilation status
Non-ventilation	47	81.0	48	82.8	0.8095
Ventilation	11	19.0	10	17.2
Hospital admission year
2010	10	17.3	9	15.5	0.9494
2011	18	31.0	21	36.2
2012	30	51.7	28	48.3
Statin therapy during admission
Average statin therapy duration (days) during admission	1.5	3.7	4.5	7.5	0.0012
Hospital stay
Length of hospital stay (days)	5	4–6	9	7–11	0.0005
Comorbidities (during admission)
Charlson score	4	2–6	4	2–7	0.8239
Elixhauser score	6	4–8	6	5–8	0.2870
Comorbidities (6 months prior to admission)
Charlson score	4	2–8	4	1–7	0.4959
Elixhauser score	5	2–8	5	2–8	0.8413

DRS, disease risk score; IQR, interquartile range; SD, standard deviation.

Data are median, SD, and IQR or number and percent of patients.

The study included an equal number (n = 58) of cases and controls, producing a 50% survival rate at the root node. The CART analysis partitioned the dependent variable of statin therapy duration at ⩾2 days. Those continuing statin therapy for at least 2 days had a survival probability of 71.4%, while those not continuing or only continuing for 1 day had a survival probability of 37.8% (Figure 3). The odds of inpatient mortality was 76% lower among those continuing statin therapy for at least 2 days (odds ratio (OR) 0.24, 95% confidence interval (CI) 0.11–0.55).

Figure 3.

Partitioning from CART analysis.

Discussion

In this DRS matched case-control study, we identified a statin continuation duration threshold providing the maximum survival benefit among bacteremic patients. Our findings are consistent with existing literature^3,4,9 evaluating this association, but we expanded these findings to identify an optimal statin duration of at least 2 days. Although other studies have observed similar protective effects with statin continuation,^3,4,9 as we observed in our study, duration of pre-admission statin therapy, with and without continuation, not only varied between these studies but also within studies. In considering our findings with those from previous studies, the period of statin exposure is directly related to crucial inflammatory periods, including as the infection develops (pre-admission statin exposure) and the time period right after admission when antibiotics are begun (continued statin exposure for at least those first 2 days).^29,30

A retrospective cohort study among bacteremic patients from a 300-bed acute care hospital in Ipswich, Australia found a reduced adjusted hospital mortality rate (OR: 0.39, 95% CI: 0.17–0.91, p = 0.029) in those taking statins prior to admission (n = 66), which decreased even further with the continuation of statins (n = 56) during the admission (OR: 0.06, 95% CI: 0.01–0.44, p = 0.0056) compared to patients not receiving statins (n = 372).³ Pre-admission statin use was based on medication use reported at admission, and therefore, duration of prior statin use was not assessed. Similar effect estimates were observed when restricting the analysis to death attributable to bacteremia (statin use only before admission: OR: 0.29, 95% CI: 0.10–0.86, p = 0.025; continued during admission: OR: 0.09, 95% CI: 0.01–0.64, p = 0.016).³ Another retrospective cohort study⁴ conducted among bacteremic patients taking a statin at the time of admission and continuing throughout the hospitalization (n = 35) at a Veterans Affairs Medical Center in Washington, identified a therapeutic benefit with statin continuation (adjusted OR: 0.13, 95% CI: 0.02–0.99) compared with patients not taking statins (n = 353). Again, duration of pre-admission statin use was not assessed.

These results should be taken into consideration with clinical judgment with regard to safety as they can contribute to liver dysfunction and life-threatening rhabdomyolysis.^31,32 Moreover, elevated statin levels have been observed in critical illness, possibly related to pharmacokinetic and pharmacodynamic changes during sepsis but also due to concomitantly prescribed medications with cytochrome P450 inhibition of statin metabolism.^33,34 Among critically ill patients on continued statins, monitoring of liver function and creatine phosphokinase may be warranted.

Our study has a number of limitations. First, we were unable to assess statin drug or dose-dependent effects that might affect bacteremic mortality. Second, our study relied on a claims database, which is subject to misclassification due to coding selected for medical claims processing and reimbursement. Third, we could not study differences in mortality by causative pathogen. A previous study²⁴ observed greater protection with statins in Staphylococcus aureus bacteremia compared to bacteremia caused by Gram-negative bacilli, while also suggesting greater survival in nosocomial versus community-associated bacteremia.²⁴ Our study could not evaluate these differences. We also could not distinguish bacteremic severity or changes in oral intake; however, we incorporated potential causative pathogen proxies (identified using ICD-9 codes) in our DRS model, as well as sepsis and ventilation status proxies from diagnosis-related group codes. Moreover, the sample size of our study was small. While we included antibiotic treatment in the DRS mode, we could not evaluate the appropriateness of antibiotic therapy. The intensity of statin therapy was also not assessed. In addition, the limitations of CART analysis include an inability to fully describe the observed data due to uncertainty that remains in the prediction of the model and potential existence of multiple threshold values despite a single “optimal” split.³⁵ Finally, since statin use prior to admission was captured from pharmacy dispensing, misclassification due to non-adherence may have impacted our findings.

In conclusion, we found that continuation of statins for at least 2 days in prevalent, adherent statin users, significantly reduced hospital mortality in our DRS matched case-control study conducted in a real-world clinical population. To further understand the relationship between statin use and improved clinical outcomes among those with serious infections, future research should assess drug/dose-response, while accounting for duration-response. Although our findings indicate benefits with continuation of statins during admission, greater information is needed regarding the risks of continuation, in terms of adverse events, to enable a clear benefit–risk assessment.

Footnotes

Author’s Note

The views expressed in this article are those of the authors and do not necessarily reflect the position or policy of the U.S. Department of Veterans Affairs.

Conflict of interest statement

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Ajinkya M. Pawar has no conflicts to disclose. Tristan T. Timbrook, has received honoraria for speaking and/or consulting from BioFire Diagnostics, GenMark Diagnostics, and Roche Diagnostics. Kerry L. LaPlante, has received research funding or acted as a scientific advisor for Allergan, Bard, Merck (Cubist), Pfizer, and The Medicines Company. Aisling R. Caffrey, has received research funding from Pfizer Inc, Merck (Cubist), and The Medicines Company.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Elixhauser

Friedman

Stranges

. Septicemia in U.S. hospitals, 2009: Statistical brief #122. Healthcare Cost and Utilization Project (HCUP) statistical briefs. Rockville, MD: Agency for Healthcare Research and Quality (US), 2006.

Hsu

Andes

Knasinski

et al . Statins are associated with improved outcomes of bloodstream infection in solid-organ transplant recipients. Eur J Clin Microbiol Infect Dis 2009; 28: 1343–1351.

Kruger

Fitzsimmons

Cook

et al . Statin therapy is associated with fewer deaths in patients with bacteraemia. Intensive Care Med 2006; 32:75–79.

Liappis

Kan

Rochester

et al . The effect of statins on mortality in patients with bacteremia. Clin Infect Dis 2001; 33:1352–1357.

Lopez-Cortes

Galvez-Acebal

Del Toro

et al . Effect of statin therapy in the outcome of bloodstream infections due to Staphylococcus aureus: a prospective cohort study.PLoS ONE 2013; 8: e82958.

Tseng

Hutchinson

Czosnyka

et al . Effects of acute pravastatin treatment on intensity of rescue therapy, length of inpatient stay, and 6-month outcome in patients after aneurysmal subarachnoid hemorrhage. Stroke 2007; 38:1545–1550.

Dobesh

Klepser

McGuire

et al . Reduction in mortality associated with statin therapy in patients with severe sepsis.Pharmacotherapy 2009; 29: 621–630.

Mortensen

Restrepo

Copeland

et al . Impact of previous statin and angiotensin II receptor blocker use on mortality in patients hospitalized with sepsis. Pharmacotherapy 2007; 27: 1619–1626.

Thomsen

Hundborg

Johnsen

et al . Statin use and mortality within 180 days after bacteremia: a population-based cohort study. Crit Care Med 2006; 34: 1080–1086.

10.

Weant

Cook

. Potential roles for statins in critically ill patients. Pharmacotherapy 2007; 27: 1279–1296.

11.

Wen

Peng

et al . Systematic review and meta-analysis on the association between outpatient statins use and infectious disease-related mortality. PLoS ONE 2012; 7: e51548.

12.

Janda

Young

Fitzgerald

et al . The effect of statins on mortality from severe infections and sepsis: a systematic review and meta-analysis. J Crit Care 2010; 25: 656.e7–656.e22.

13.

Thomas

Hraiech

Loundou

et al . Statin therapy in critically-ill patients with severe sepsis: a review and meta-analysis of randomized clinical trials. Minerva Anestesiol 2015; 81: 921–930.

14.

Leung

Pokharel

Gong

. Statins and outcomes in patients with bloodstream infection: a propensity-matched analysis. Crit Care Med 2012; 40: 1064–1071.

15.

Kruger

Harward

Jones

et al . Continuation of statin therapy in patients with presumed infection: a randomized controlled trial. Am J Respir Crit Care Med 2011; 183: 774–781.

16.

Clinical Classifications Software (CCS). Healthcare Cost and Utilization Project (HCUP). Rockville, MD: Agency for Healthcare Research and Quality, 2009, http://www.hcup-us.ahrq.gov/toolssoftware/ccs/AppendixASingleDX.txt (accessed November 2015).

17.

Hooton

Bradley

Cardenas

et al . Diagnosis, prevention, and treatment of catheter-associated urinary tract infection in adults: 2009 international clinical practice guidelines from the Infectious Diseases Society of America. Clin Infect Dis 2010; 50: 625–663.

18.

Solomkin

Mazuski

Bradley

et al . Diagnosis and management of complicated intra-abdominal infection in adults and children: guidelines by the Surgical Infection Society and the Infectious Diseases Society of America. Surg Infect (Larchmt) 2010; 11:79–109.

19.

Stevens

Bisno

Chambers

et al .Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update by the Infectious Diseases Society of America. Clin Infect Dis 2014; 59: e10–e52.

20.

Timsit

Laupland

. Update on bloodstream infections in icus. Curr Opin Crit Care 2012; 18: 479–486.

21.

Quan

Sundararajan

Halfon

et al . Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data. Med Care 2005; 43: 1130–1139.

22.

Tadrous

Gagne

Sturmer

et al . Disease risk score as a confounder summary method: systematic review and recommendations. Pharmacoepidemiol Drug Saf 2013; 22: 122–129.

23.

Arbogast

Ray

. Use of disease risk scores in pharmacoepidemiologic studies. Stat Methods Med Res 2009; 18: 67–80.

24.

Allen

Satten

. Control for confounding in case-control studies using the stratification score, a retrospective balancing score. Am J Epidemiol 2011; 173: 752–760.

25.

Stuart

. Matching methods for causal inference: a review and a look forward. Stat Sci 2010; 25: 1–21.

26.

Breiman

. Classification and regression trees. Pacific Grove, CA: The Wadsworth & Brooks/Cole, 1984.

27.

Breiman

Olshen

Stone

et al . Classification and regression trees (Wadsworth statistics/probability). Boca Raton, FL: Chapman & Hall, 1984.

28.

Therneau

Atkinson

. An introduction to recursive partitioning using the RPART routines (Technical report series no. 61.). Rochester, MN: Department of Health, Mayo Clinic, 1997.

29.

Falagas

Makris

Matthaiou

et al . Statins for infection and sepsis: a systematic review of the clinical evidence. J Antimicrob Chemother 2008; 61: 774–785.

30.

Almog

Novack

Eisinger

et al . The effect of statin therapy on infection-related mortality in patients with atherosclerotic diseases.Crit Care Med 2007; 35: 372–378.

31.

Thapar

Russo

Bonkovsky

. Statins and liver injury. Gastroenterol Hepatol (NY) 2013; 9: 605–606.

32.

Mendes

Robles

Mathur

. Statin-induced rhabdomyolysis: a comprehensive review of case reports. Physiother Can 2014; 66:124–132.

33.

Kruger

Freir

Venkatesh

et al . A preliminary study of atorvastatin plasma concentrations in critically ill patients with sepsis. Intensive Care Med 2009; 35: 717–721.

34.

Dessap

Ouanes

Rana

et al . Effects of discontinuing or continuing ongoing statin therapy in severe sepsis and septic shock: a retrospective cohort study. Crit Care 2011; 15: R171.

35.

Rhodes

O’Donnell

Lizza

et al . Tree-based models for predicting mortality in gram-negative bacteremia: avoid putting the cart before the horse. Antimicrob Agents Chemother 2016; 60: 838–844.

Optimal duration for continuation of statin therapy in bacteremic patients

Abstract

Background:

Objectives:

Methods:

Results:

Conclusion:

Keywords

Introduction

Methods

Results

Discussion

Footnotes

Author’s Note

Conflict of interest statement

Funding

References