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Accepted Date : 14-Oct-2014 Article type
: Original
Rosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomised controlled trial
Running headline: Statin treatment in COPD Short title: Short-term rosuvastatin treatment in stable COPD
Anke Neukamm1,2, Arne Didrik Høiseth1,2, Gunnar Einvik2,3, Sverre Lehmann4,5, TorArne Hagve2,6, Vidar Søyseth2,3 & Torbjørn Omland1,2 From the 1Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog; 2Center for Heart Failure Research and KG Jebsen Cardiac Research Centre, University of Oslo, Oslo; 3Department of Pulmonology, Division of Medicine, Akershus University Hospital, Lørenskog; 4Department of Thoracic Medicine, Haukeland University Hospital, Bergen; 5Section for Thoracic Medicine, Department of Clinical Science, University of Bergen, Bergen; and 6 Unit of Medical Biochemistry, Division of Diagnostics and Technology, Akershus University Hospital, Lørenskog, Norway
Abbreviations list ANCOVA - Analysis of covariance ATP-III - Adult Treatment Panel III CAD - Coronary artery disease COPD - Chronic obstructive pulmonary disease CRP - C-reactive protein CVD - Cardiovascular disease This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/joim.12337 This article is protected by copyright. All rights reserved.
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FEV1 - Forced expiratory volume in 1 s FVC - Forced vital capacity GCP - Good clinical practice GFR - Glomerular filtration rate IL6 - Interleukin 6 MMRC - Modified medical research council NO- Nitric oxide PAT - Peripheral arterial tonometry SEM - Standard error of mean 6-MWD - 6-min walking distance
ABSTRACT Objectives. The objective of this study was to examine whether statin therapy is associated with enhanced endothelium-dependent vascular function, improved pulmonary function and reduced systemic inflammation in patients with chronic obstructive pulmonary disease (COPD).
Design and setting. This randomised, placebo-controlled, double-blind, parallel trial including patients with COPD was performed at two University hospitals in Norway.
Subjects, intervention and measurements. Patients with stable COPD (n = 99) were assigned randomly to receive rosuvastatin 10 mg (n = 49) or matching placebo (n = 50) once daily for 12 weeks. The primary outcome measure was change in endothelium-dependent vascular function measured using peripheral arterial tonometry and expressed as the reactive hyperaemia index. Secondary endpoints were change in pulmonary function, as assessed by forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC), and change in This article is protected by copyright. All rights reserved.
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abstained from smoking for at least 12 h before biomarker measurements, as mentioned above.
In a recent prospective case–control study, statin use was associated with improved survival among patients with COPD; this association was dependent on the level of systemic inflammation [24]. COPD patients with evidence of chronic low-grade inflammation may therefore represent a subgroup that could potentially benefit from statin treatment. The current results demonstrate that statin therapy attenuates systemic inflammation, and suggest that targeting patients with increased levels of hsCRP may identify those who may benefit most from statin therapy in terms of improvement in vascular function. Because COPD patients are at increased risk of cardiovascular events and measurement of vascular reactivity has been shown previously to provide additional prognostic information to conventional risk markers in patient groups without known CVD, vascular reactivity assessment seems to represent a valid although imperfect surrogate marker of atherosclerotic events. We believe that long-term randomised multicentre trialsincluding at least 3000 patients with a 3-year follow-up will be required to accurately define the beneficial effect of statin therapy in stable COPD patients and to evaluate whether the observed statin effect on endothelial function in patients with evidence of increased systemic inflammation would also translate into reduced incidence of cardiovascular endpoints.
There are several possible explanations for the apparent lack of effect of rosuvastatin on indices of pulmonary function observed in the current study, including insufficient duration of therapy, drug dose or statistical power. However, the effects observed on blood lipids, inflammatory markers and vascular function suggest that the lack of effect on pulmonary This article is protected by copyright. All rights reserved.
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INTRODUCTION During the past few years, it has become increasingly recognised that chronic obstructive pulmonary disease (COPD) is a systemic disorder characterised not only by pulmonary but also by systemic inflammation [1, 2]. The important pathophysiological role of comorbidities in the morbidity and increased mortality associated with COPD has also recently become clear. It has been proposed that the systemic inflammatory component is a link between COPD and its comorbidities, including cardiovascular disease (CVD) [3, 4]. Low-grade inflammation is commonly associated with increased oxidative stress in the vascular wall, the subsequent reduced bioavailability of endothelium-derived nitric oxide (NO) and impaired endothelium-dependent vasodilator function, an initiating event in the atherosclerotic process [5].
Hydroxymethylglutaryl CoA reductase inhibitors, commonly known as statins, have documented effects on mortality and morbidity in patients with established coronary artery disease (CAD), but have also been found to reduce the incidence of cardiovascular events in high-risk individuals in the general population [6-8]. It has been proposed that statins exert important effects on the immune system that are independent of the effect on lipids (i.e. pleiotropic effects) [9]. Anti-inflammatory actions contribute to the beneficial cardiovascular effects, but controversy remains regarding the existence and impact of non-cardiovascular effects of statins. In retrospective observational studies, statin therapy has been associated with improved survival in patients with COPD [10, 11]. Experimental data also suggest that statins may have beneficial effects on airway inflammation, matrix metalloproteinase activity and mucin production [12-14]. Thus, it remains unclear whether statins exert their potential
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beneficial effects in COPD by primarily affecting vascular or respiratory function, and whether or not such beneficial effects are mediated by attenuation of systemic inflammation.
To address these questions, we conducted a randomised, placebo-controlled, double-blind trial to test the hypothesis that treatment with rosuvastatin in patients with stable COPD is associated with (i) enhanced peripheral endothelium-dependent vascular function, (ii) improved pulmonary function and (iii) attenuation of systemic inflammation, as expressed by decreased levels of circulating inflammatory markers. Furthermore, we prospectively hypothesised that the beneficial effect of rosuvastatin may be particularly pronounced in patients with evidence of increased systemic inflammation.
Materials and methods Trial design Effect of ROsuvastatin therapy on peripheral vasoDilator function, inflammatory markers and pulmonary function in patients with stablE chronic Obstructive pulmonary disease (RODEO; clinicaltrials.gov number NCT00929734; EudraCT number 2009-011659-35) was a randomised, placebo-controlled, double-blind, parallel group clinical trial. Participants Consecutive patients referred to the pulmonology outpatient clinics of two university hospitals in Norway with a verified diagnosis of COPD were eligible for participation. Exclusion criteria included history of or active CAD, cerebrovascular or peripheral vascular disease, and diabetes mellitus (see online Supplementary Table S1).
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Intervention After initial investigation, all patients were randomly assigned to either rosuvastatin 10 mg or matching placebo once daily for 12 weeks.
Measurements All patients completed a questionnaire about comorbidities (Charlson comorbidity index), respiratory symptoms according to the Modified Medical Research Council (MMRC) dyspnoea scale [15] and smoking habits. Spirometry was performed with reversibility testing using salbutamol as recommended by Miller et al. [16]. A 6-min walk test was conducted according to the guidelines of the American Thoracic Society [17]. Smoking was expressed as current smoking (yes/no) and number of pack-years. Arterial and venous blood samples were collected after an overnight fast during which patients abstained from smoking. The concentration of high-sensitivity C-reactive protein (hsCRP) was measured with the Cobas c501/502 system (Roche, Mannheim, Germany), and interleukin-6 (IL6) concentration was measured with the Cobas e602 system (Roche).
Endothelial function Endothelium-dependent vascular function was assessed by peripheral arterial tonometry (PAT) using the EndoPAT device (Itamar Medical, Caesarea, Israel). This method has been shown to correlate closely with the vasodilator response of coronary vessels following infusion of the endothelium-dependent vasodilator acetylcholine [18], and to provide prognostic information concerning the future incidence of cardiovascular events in the general population [19, 20].
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Study endpoints The primary endpoint was change from baseline in digital endothelium-dependent vascular function, expressed as reactive hyperaemia index (RHI) measured by PAT. Secondary endpoints were changes from baseline in post-bronchodilator forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) and levels of hsCRP and IL6. Tertiary endpoints included change in MMRC dyspnoea scale and 6-min walking distance (6-MWD). The difference in the changes between treatment groups was used as the effect measure.
Statistical analyses Baseline characteristics of the study population were summarised within each group. The difference in the changes between the rosuvastatin and placebo groups from baseline to 12 weeks for primary and secondary endpoints and feasibility measures was estimated using analysis of covariance (ANCOVA). In accordance with the prespecified analysis plan, we evaluated treatment effects in subgroups with elevated circulating pro-inflammatory markers, defined as levels of hsCRP or IL6 above the median value. We also performed two post hoc sensitivity analyses, first excluding patients with increased CVD risk according to the Adult Treatment Panel III (ATP-III) criteria and secondly excluding those with a history of asthma. All statistical analyses were performed using SPSS Statistics (Version 20; IBM Corporation, NY, USA and SASR (Version 9.2; SAS Institute, Inc., Cary, NC, USA) software.
The study was conducted in compliance with Good Clinical Practice (GCP) regulatory requirements and with approval from independent ethics committees in accordance with the Declaration of Helsinki. Informed written consent was obtained from all participants. Further details of the methods used are available in the online supplement.
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Results Baseline data Complete data were available at the end of the study for 94 of the 99 patients enrolled (Fig. 1). Table 1 presents demographic and baseline characteristics of patients in each group. In the overall population, the mean (±SEM) age was 65 (±0.6) years, 48% were women, the mean body mass index was 24 (±0.4) kg/m2, the mean number of pack-years of smoking was 38 (±1.6), mean FEV1 was 1.4 (±0.06) L and mean FEV1/FVC was 47% (±1.3). Overall, 25% of patients had a history of hypertension, and 23% had a history of bronchial asthma (Table 1). None of the patients had a previous diagnosis of heart failure.
Primary, secondary and tertiary outcome measures In the complete-case analysis (n = 94), there was no significant change in endotheliumdependent vascular function, expressed as the RHI, in either the treatment group or the placebo group. Moreover, there was no significant difference in the primary outcome measure (i.e. the change in RHI) between the groups (Table 2 and Fig. 2).
The relative change in endothelial function, defined as change in RHI, was 6.65% [95% confidence interval (CI) 1.80% to 15.11%] in the rosuvastatin group and –1.27% (95% CI – 8.33% to 5.79%) in the placebo group (P = 0.292). In a secondary, predefined, multivariate regression analysis adjusting for covariates with possible impact on endothelial function (history of hypertension, gender and current smoking status), treatment with rosuvastatin was not significantly associated with change in RHI (P = 0.157). However, in a prespecified subgroup analysis of patients with supra-median hsCRP concentrations (i.e. >1.7 mg/L), rosuvastatin therapy was associated with a significant between-group difference in change in endothelium-dependent vascular function (13% vs. 2%, P = 0.026; Fig. 3), and a similar trend
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was observed in patients with supra-median IL6 concentrations (i.e. >3.7 pg/mL (7% vs. –2%, P = 0.131).
With regard to the secondary outcome measure of change in markers of systemic inflammation, rosuvastatin therapy was associated with a significant reduction in hsCRP level (–20% vs. 11%, P = 0.017) and a significant attenuation of the rise in the level of IL6 (8% vs. 30%, P = 0.028) compared with placebo. By contrast, there were no significant betweengroup differences in change in the spirometry values FEV1 (L), FEV1 (% of predicted) and FEV1/FVC (P = 0.462, P = 0.344 and P = 0.292, respectively; Table 2). Moreover, there was no difference in the changes in the tertiary measures of symptoms of dyspnoea according to the MMRC dyspnoea scale and 6-MWD (data not shown). Both imputation and per-protocol analyses yielded the same results as the complete-case analysis, and sensitivity analyses yielded the same conclusion regarding the effect on endothelial function. Of the 94 patients who completed the RODEO trial, 86 met the criteria for low CVD risk. Among these 86 patients, the effect on endothelial function (expressed as RHI) remained significant (P = 0.032) in the subgroup of patients with signs of elevated baseline inflammation defined as hsCRP >1.7 mg/L (n = 43). 72 patients who completed the study had no previous diagnosis of asthma. In the subgroup of patients without a history of asthma but with elevated baseline inflammation (n = 37), there was a significant effect on endothelial function (P = 0.048) as well as a significant difference in the change in concentration of the inflammatory markers hsCRP and IL6 (P = 0.006 and P = 0.035, respectively).
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Feasibility data Treatment compliance was confirmed by a significant lipid-lowering effect of rosuvastatin. Compared with placebo, rosuvastatin administration caused significant decreases in plasma total and LDL cholesterol levels by 24% and 41%, respectively. HDL cholesterol increased by 7%, and serum triglyceride levels decreased by 11%.
Safety endpoints Rosuvastatin was generally well tolerated by all patients. Possible side effects were reported by a total of 12 (26%) patients in the rosuvastatin group and 21 (43%) in the placebo group. The most frequent adverse events reported were constipation, diarrhoea, nausea and acute exacerbation of COPD. There was a non-significant trend towards more frequent exacerbations during the treatment period in the placebo group (27% vs. 15% in the rosuvastatin group, P = 0.160). There was no significant between-group difference in the change in alanine transaminase and creatine kinase levels (see online Supplementary Table S2. The reported serious adverse events were mainly acute exacerbations requiring hospitalisation during the treatment period [n = 4 (9%) in the rosuvastatin group and n = 3 (6%) in the placebo group]. There were no suspected unexpected serious adverse reactions during the treatment period (see online Supplementary Table S3).
Discussion Main study results The main finding of the present investigator-initiated, randomised, placebo-controlled, double-blind clinical trial is that short-term rosuvastatin treatment does not improve either endothelial function or lung function in patients with stable COPD without a history of CVD
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and diabetes, but significantly attenuates systemic inflammation. Notably, in a prespecified subgroup analysis of patients with hsCRP concentration >1.7 mg/L, rosuvastatin treatment was associated with improved endothelium-dependent vascular function, compared with placebo. Given that systemic inflammation is associated with the frequency of exacerbations [21] and outcome in COPD [22, 23] and that endothelium-dependent vascular function is believed to reflect vascular health and the risk of atherosclerotic disease, these findings are compatible with the theory that long-term treatment with statins may improve COPD outcome in patients with stable disease with elevated hsCRP concentrations. Although no effect of statins on the incidence of COPD exacerbations was observed in a recently reported largescale clinical trial there might nevertheless be an effect on the incidence of cardiovascular events in patients with evidence of elevated baseline inflammation.
Rationale for randomised trials of statin therapy in COPD Although the results of several retrospective observational trials suggest a beneficial effect of statin therapy on survival in COPD patients [10, 24], the underlying mechanisms remain unclear. To date, the results from three randomised controlled trials on statin treatment among patients with COPD have been published. The first study included 125 patients with stable COPD and reported a beneficial effect of statin treatment on exercise time; the effect was most prominent among patients with decreasing concentrations of inflammatory markers during treatment [25]. The second study, which included 56 patients, failed to demonstrate any significant effect of statins on circulating inflammatory markers [26]. Accordingly, there has been an urgent need for randomised clinical trials to elucidate the potential pathophysiological mechanisms of COPD and to assess the efficacy and safety of statin therapy in patients with stable disease. This was the rationale for conducting the RODEO
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trial. Very recently, the findings of the third study were published (Simvastatin for the prevention of exacerbations in moderate-to-severe COPD (STATCOPE)). In this multicentre trial, no effect of statin treatment on the incidence of COPD exacerbations was observed, but subgroups of COPD patients with different levels of inflammation were not evaluated and the study was not powered to assess the effect on cardiovascular events [27].
Effect of rosuvastatin treatment in stable COPD It has previously been shown that statin treatment exerts anti-inflammatory effects in different patient groups, including patients with CVD, diabetes or rheumatoid arthritis [28-31], and the large-scale Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial extended these findings to individuals with elevated hsCRP levels without hyperlipidaemia [8]. However, two previously reported clinical trials in COPD patients have demonstrated inconsistent results [25, 26]. The beneficial effect of statin therapy appeared to be consistent across a wide range of cardiovascular endpoints and subgroups. However, as JUPITER included a high proportion of obese patients, the characteristics of the participants may not be representative of a population with stable COPD, and therefore the results cannot be extrapolated to this population.
It has previously been shown that hsCRP and IL6 levels are elevated among patients with COPD, and this is associated with unfavourable outcomes [22, 32, 33]. The observed slight increase in the levels of inflammatory markers might reflect disease progression in the placebo group, as we observed a non-significant trend towards increased exacerbations in this group. Inflammation did not correlate with current smoking in our population and correction for smoking status did not change the results in a multivariate model. In addition, patients also
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abstained from smoking for at least 12 h before biomarker measurements, as mentioned above.
In a recent prospective case–control study, statin use was associated with improved survival among patients with COPD; this association was dependent on the level of systemic inflammation [24]. COPD patients with evidence of chronic low-grade inflammation may therefore represent a subgroup that could potentially benefit from statin treatment. The current results demonstrate that statin therapy attenuates systemic inflammation, and suggest that targeting patients with increased levels of hsCRP may identify those who may benefit most from statin therapy in terms of improvement in vascular function. Because COPD patients are at increased risk of cardiovascular events and measurement of vascular reactivity has been shown previously to provide additional prognostic information to conventional risk markers in patient groups without known CVD, vascular reactivity assessment seems to represent a valid although imperfect surrogate marker of atherosclerotic events. We believe that long-term randomised multicentre trialsincluding at least 3000 patients with a 3-year follow-up will be required to accurately define the beneficial effect of statin therapy in stable COPD patients and to evaluate whether the observed statin effect on endothelial function in patients with evidence of increased systemic inflammation would also translate into reduced incidence of cardiovascular endpoints.
There are several possible explanations for the apparent lack of effect of rosuvastatin on indices of pulmonary function observed in the current study, including insufficient duration of therapy, drug dose or statistical power. However, the effects observed on blood lipids, inflammatory markers and vascular function suggest that the lack of effect on pulmonary This article is protected by copyright. All rights reserved.
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function may be real and that the beneficial effects of statins in stable COPD patients may preferentially target the cardiovascular system. This theory is supported by the current finding of a lack of effect on the dyspnoea scale and exercise capacity measures in our study, as well by the recently published results of the STATCOPE trial
Strengths and limitations The strengths of the study include the randomised, placebo-controlled design, the wellcharacterised study population and the use of well-established and reproducible methods to assess changes in vascular function, pulmonary function and inflammatory activity. The low percentage of patients who withdrew from the study and the high acceptability of the study drug represent further strengths.
However, there are several study limitations, including the short duration of treatment and the relatively small sample size. The generalisability of our results depends on the representativeness of the study population. We included an equal number of men and women, and we believe the age range is representative of a typical population with COPD. However, the study population was ethnically homogenous (all Caucasian), and the results may not be generalisable to a non-Caucasian population. Baseline values of RHI in this selected population of COPD patients were generally within the normal range. This may also have contributed to the failure to document a beneficial effect of statin therapy in the overall study population. We limited inclusion to patients without a clear indication for statins based on comorbidities. As the beneficial effect of statin therapy in patients with CAD and diabetes mellitus is well established [34], patients with a history of these diseases were not eligible for the present study. In addition, we showed robust results in the sensitivity analysis excluding This article is protected by copyright. All rights reserved.
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patients at high CVD risk according to the ATP-III criteria. It is considered that patients with COPD without these comorbidities are still at increased CVD risk [35].
Conclusion Short-term treatment with rosuvastatin in patients with stable COPD without known CVD resulted in improved endothelium-dependent vascular function in the subgroup of individuals with supra-median concentrations of hsCRP at baseline and was associated with reduced systemic inflammation. These findings suggest that (i) the beneficial effect of statin therapy in stable COPD patients may be confined to those with evidence of systemic inflammation and (ii) measurement of hsCRP levels might be useful as part of a personalised medicine strategy to identify this patient group.
Acknowledgements We are grateful to Gunn Seim Ekeland and Michael L. Storebø for practical assistance with patient recruitment, Vigdis Bakkelund, Annika Lorentzen, Marit Jørgensen and Eli Nordeide for skilful technical assistance and Morten Fagerland for help with statistical analyses. We are also grateful to Birgitte Lid Adamsen and colleagues at the GCP unit at Oslo University Hospital for help to ensure that the study was conducted in compliance with GCP requirements.
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Conflict of interest statement TO received grants, personal fees and non-financial support from Abbott Laboratories, personal fees from Siemens Healthcare, grants, personal fees and non-financial support from AstraZeneca, and personal fees from Roche DiagnosticsAN has received a speaker fee from AstraZeneca. All other authors have no conflicts of interest to declare.
Funding This study was supported by grants from the Norwegian Extra Foundation for Health and Rehabilitation and The Norwegian Association of Heart and Lung Patients. The study was also conducted with support from the Investigator-Sponsored Study Program of AstraZeneca. Study medication was provided by AstraZeneca. The sponsors, including AstraZeneca, played no role in the study design, the collection, analysis and interpretation of the data, or the writing of or decision to submit the manuscript for publication.
Authors’ contributions AN, study design, data collection and analysis and drafting of the first version of the manuscript; ADH, data collection, data analysis and manuscript preparation; GE, data analysis and manuscript preparation; T-AH, biochemical analyses and manuscript preparation; SL, data collection and manuscript preparation; VS, study conception and design and manuscript preparation; TO, study conception and design, data interpretation and manuscript preparation.
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References 1 Sinden NJ, Stockley RA. Systemic inflammation and comorbidity in COPD: a result of 'overspill' of inflammatory mediators from the lungs? Review of the evidence. Thorax 2010; 65: 930-6. 2 Thomsen M, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and comorbidities in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2012; 186: 982-8. 3 MacNee W. Systemic inflammatory biomarkers and co-morbidities of chronic obstructive pulmonary disease. Annals of medicine 2013; 45: 291-300. 4 Sin DD, MacNee W. Chronic obstructive pulmonary disease and cardiovascular diseases: a "vulnerable" relationship. American journal of respiratory and critical care medicine 2013; 187: 2-4. 5 Bonetti PO, Pumper GM, Higano ST, Holmes DR, Jr., Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004; 44: 2137-41. 6 Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383-9. 7 Sacks FM, Pfeffer MA, Moye LA, et al. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial investigators. N Engl J Med 1996; 335: 1001-9. 8 Ridker PM, Danielson E, Fonseca FA, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. NEnglJ Med 2008; 359: 2195-207. 9 Liao JK. Effects of statins on 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibition beyond low-density lipoprotein cholesterol. The American journal of cardiology 2005; 96: 24F-33F. 10 Soyseth V, Brekke PH, Smith P, Omland T. Statin use is associated with reduced mortality in COPD. Eur Respir J 2007; 29: 279-83. 11 Mancini GB, Etminan M, Zhang B, Levesque LE, FitzGerald JM, Brophy JM. Reduction of morbidity and mortality by statins, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers in patients with chronic obstructive pulmonary disease. J Am Coll Cardiol 2006; 47: 2554-60. 12 Chen YJ, Chen P, Wang HX, et al. Simvastatin attenuates acrolein-induced mucin production in rats: involvement of the Ras/extracellular signal-regulated kinase pathway. International immunopharmacology 2010; 10: 685-93. 13 Kim SE, Thanh Thuy TT, Lee JH, et al. Simvastatin inhibits induction of matrix metalloproteinase-9 in rat alveolar macrophages exposed to cigarette smoke extract. Experimental & molecular medicine 2009; 41: 277-87. 14 Zeki AA, Franzi L, Last J, Kenyon NJ. Simvastatin inhibits airway hyperreactivity: implications for the mevalonate pathway and beyond. Am J Respir Crit Care Med 2009; 180: 731-40. 15 Bestall JC, Paul EA, Garrod R, Garnham R, Jones PW, Wedzicha JA. Usefulness of the Medical Research Council (MRC) dyspnoea scale as a measure of disability in patients with chronic obstructive pulmonary disease. Thorax 1999; 54: 581-6. 16 Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26: 319-38. 17 Laboratories ATSCoPSfCPF. ATS statement: guidelines for the six-minute walk test. American journal of respiratory and critical care medicine 2002; 166: 111-7.
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18 Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. Journal of the American College of Cardiology 1995; 26: 1235-41. 19 Hamburg NM, Keyes MJ, Larson MG, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 2008; 117: 2467-74. 20 Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation 2007; 115: 2390-7. 21 Thomsen M, Ingebrigtsen TS, Marott JL, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA : the journal of the American Medical Association 2013; 309: 2353-61. 22 Ferrari R, Tanni SE, Caram LM, Correa C, Correa CR, Godoy I. Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease. Respir Res 2013; 14: 24. 23 Dahl M, Vestbo J, Lange P. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 250 - 5. 24 Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG, Stricker BH. Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 2013; 26: 212-7. 25 Lee TM, Lin MS, Chang NC. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. American Journal of Cardiology 2008; 101: 530-5. 26 Kaczmarek P, Sladek K, Skucha W, Rzeszutko M, Iwaniec T, Dziedzina S, Szczeklik A. The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. PolArchMed Wewn 2010; 120: 11-7. 27 Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014; 370: 2201-10. 28 Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. The New England journal of medicine 2005; 352: 20-8. 29 Albert MA, Danielson E, Rifai N, Ridker PM, Investigators P. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA : the journal of the American Medical Association 2001; 286: 64-70. 30 Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. Journal of immunology 2003; 170: 1524-30. 31 Xu H, Liu P, Liang L, et al. RhoA-mediated, tumor necrosis factor alpha-induced activation of NF-kappaB in rheumatoid synoviocytes: inhibitory effect of simvastatin. Arthritis and rheumatism 2006; 54: 3441-51. 32 Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 2012; 185: 1065-72. 33 Agusti A, Edwards L, Rennard S. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. Plos One 2012; 7: e3y483. 34 Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. 35 Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart 2012; 98: 1055-62. This article is protected by copyright. All rights reserved.
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Correspondence: Professor Torbjørn Omland MD, PhD, MPH Division of Medicine Akershus University Hospital 1478 Lørenskog Norway e-mail: [email protected]
Fig. 1 Patient flow chart. Exclusion details are provided in the online supplement.
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Fig. 2 Reactive hyperaemia index (RHI) and SEM in all patients (n = 94).
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Fig. 3 Reactive hyperaemia index (RHI) and SEM in patients with high-sensitivity C-reactive protein concentration above the median value (n = 47).
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Table 1 Demographic and baseline characteristics
Variable Demographic data Age, years Women BMI, kg/m² Clinical data Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Heart rate, beats/min Prior medical history Hypertension Bronchial asthma Smoking status Pack-years, years Current smoking Laboratory data Haemoglobin, g/dL eGFR, mL/min/1.73 m2 Leucocyte count, x109/L hsCRP, mg/L IL6, pg/mL Glucose, mmol/L Cholesterol, mmol/L LDL-C, mmol/L HDL-C, mmol/L Triglycerides, mmol/L Spirometry FEV1, L FEV1, % of predicted FEV1/FVC, % Medication Antihypertensive treatment ICS (including LABA) LABA (only) LAMA Anti-inflammatory treatment Oestrogen
Rosuvastatin (n = 47)
Placebo (n = 47)
66 (0.8) 21 (45) 23 (0.6)
63 (1.0) 24 (51) 24 (0.6)
131 (2.6) 79 (1.2) 68 (1.6)
135 (2.9) 80 (1.5) 67 (1.6)
12 (26) 9 (19)
11 (23) 13 (28)
39 (2.4) 12 (26)
35 (2.6) 23 (49)
14.1 (0.2) 86.3 (2.6) 6.6 (0.2) 1.4 (0.8, 3.7) 4.1 (2.9, 5.3) 5.0 (0.1) 5.5 (0.1) 3.3 (0.1) 1.8 (0.1) 1.0 (0.1)
14.0 (0.2) 89.6 (3.0) 6.9 (0.3) 1.8 (1.0, 4.4) 3.4 (2.7, 4.7) 5.1 (0.1) 5.7 (0.1) 3.5 (0.1) 1.8 (0.1) 1.1 (0.1)
1.4 (0.1) 48.3 (2.8) 47 (2.0)
1.5 (0.1) 52.1 (2.7) 49 (1.7)
12 (26) 36 (77) 2 (4) 30 (64) 2 (4) 4 (9)
10 (21) 34 (72) 3 (6) 27 (58) 0 (0) 3 (6)
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Continuous data are presented as mean (SEM) and categorical variables as number (percentage). Biomarker data are presented as median (25th,75th percentile). BMI, body mass index; eGFR, estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; hsCRP, high-sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; ICS, inhaled corticosteroids; IL6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist.
Table 2 Change in endpoints between treatment groups
Variable
Rosuvastatin (n = 47)
Placebo (n = 47)
P-valuea
Baseline
Follow-up
Baseline
Follow-up
RHI
2.47 (0.10)
2.54 (0.10)
2.65 (0.10)
2.51 (0.07)
0.292
lnRHI
0.87 (0.04)
0.90 (0.04)
0.94 (0.04)
0.90 (0.03)
0.477
FEV1, L
1.34 (0.09)
1.35 (0.08)
1.47 (0.10)
1.45 (0.94)
0.462
FEV1, %
48.3 (2.77)
49.3 (2.75)
52.1 (2.75)
51.7 (2.76)
0.344
FEV1/FVC, %
46.9 (2.01)
47.3 (1.87)
48.8 (1.72)
47.9 (1.79)
0.292
hsCRP, mg/L
1.4 (0.8, 3.7)
1.2 (0.7, 2.6)
1.8 (1.0, 4.4)
2.2 (1.3, 3.6)c
0.017
IL6, pg/mL
4.1 (2.9, 5.2)
4.1 (3.4, 5.5)
3.4 (2.7, 4.7)
4.4 (3.0, 6.7)b
0.028
Continuous data are presented as mean (SEM). Biomarker data are presented as median (25th, 75th percentile). a
b
c
ANCOVA, P < 0.05 paired t-test, P < 0.05 Student’s t-test.
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; hsCRP, high-sensitivity C-reactive protein; IL6, interleukin-6; RHI, reactive hyperaemia index.
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Accepted Date : 14-Oct-2014 Article type
: Original
Rosuvastatin treatment in stable chronic obstructive pulmonary disease (RODEO): a randomised controlled trial
Running headline: Statin treatment in COPD Short title: Short-term rosuvastatin treatment in stable COPD
Anke Neukamm1,2, Arne Didrik Høiseth1,2, Gunnar Einvik2,3, Sverre Lehmann4,5, TorArne Hagve2,6, Vidar Søyseth2,3 & Torbjørn Omland1,2 From the 1Department of Cardiology, Division of Medicine, Akershus University Hospital, Lørenskog; 2Center for Heart Failure Research and KG Jebsen Cardiac Research Centre, University of Oslo, Oslo; 3Department of Pulmonology, Division of Medicine, Akershus University Hospital, Lørenskog; 4Department of Thoracic Medicine, Haukeland University Hospital, Bergen; 5Section for Thoracic Medicine, Department of Clinical Science, University of Bergen, Bergen; and 6 Unit of Medical Biochemistry, Division of Diagnostics and Technology, Akershus University Hospital, Lørenskog, Norway
Abbreviations list ANCOVA - Analysis of covariance ATP-III - Adult Treatment Panel III CAD - Coronary artery disease COPD - Chronic obstructive pulmonary disease CRP - C-reactive protein CVD - Cardiovascular disease This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. Please cite this article as doi: 10.1111/joim.12337 This article is protected by copyright. All rights reserved.
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FEV1 - Forced expiratory volume in 1 s FVC - Forced vital capacity GCP - Good clinical practice GFR - Glomerular filtration rate IL6 - Interleukin 6 MMRC - Modified medical research council NO- Nitric oxide PAT - Peripheral arterial tonometry SEM - Standard error of mean 6-MWD - 6-min walking distance
ABSTRACT Objectives. The objective of this study was to examine whether statin therapy is associated with enhanced endothelium-dependent vascular function, improved pulmonary function and reduced systemic inflammation in patients with chronic obstructive pulmonary disease (COPD).
Design and setting. This randomised, placebo-controlled, double-blind, parallel trial including patients with COPD was performed at two University hospitals in Norway.
Subjects, intervention and measurements. Patients with stable COPD (n = 99) were assigned randomly to receive rosuvastatin 10 mg (n = 49) or matching placebo (n = 50) once daily for 12 weeks. The primary outcome measure was change in endothelium-dependent vascular function measured using peripheral arterial tonometry and expressed as the reactive hyperaemia index. Secondary endpoints were change in pulmonary function, as assessed by forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC), and change in This article is protected by copyright. All rights reserved.
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abstained from smoking for at least 12 h before biomarker measurements, as mentioned above.
In a recent prospective case–control study, statin use was associated with improved survival among patients with COPD; this association was dependent on the level of systemic inflammation [24]. COPD patients with evidence of chronic low-grade inflammation may therefore represent a subgroup that could potentially benefit from statin treatment. The current results demonstrate that statin therapy attenuates systemic inflammation, and suggest that targeting patients with increased levels of hsCRP may identify those who may benefit most from statin therapy in terms of improvement in vascular function. Because COPD patients are at increased risk of cardiovascular events and measurement of vascular reactivity has been shown previously to provide additional prognostic information to conventional risk markers in patient groups without known CVD, vascular reactivity assessment seems to represent a valid although imperfect surrogate marker of atherosclerotic events. We believe that long-term randomised multicentre trialsincluding at least 3000 patients with a 3-year follow-up will be required to accurately define the beneficial effect of statin therapy in stable COPD patients and to evaluate whether the observed statin effect on endothelial function in patients with evidence of increased systemic inflammation would also translate into reduced incidence of cardiovascular endpoints.
There are several possible explanations for the apparent lack of effect of rosuvastatin on indices of pulmonary function observed in the current study, including insufficient duration of therapy, drug dose or statistical power. However, the effects observed on blood lipids, inflammatory markers and vascular function suggest that the lack of effect on pulmonary This article is protected by copyright. All rights reserved.
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INTRODUCTION During the past few years, it has become increasingly recognised that chronic obstructive pulmonary disease (COPD) is a systemic disorder characterised not only by pulmonary but also by systemic inflammation [1, 2]. The important pathophysiological role of comorbidities in the morbidity and increased mortality associated with COPD has also recently become clear. It has been proposed that the systemic inflammatory component is a link between COPD and its comorbidities, including cardiovascular disease (CVD) [3, 4]. Low-grade inflammation is commonly associated with increased oxidative stress in the vascular wall, the subsequent reduced bioavailability of endothelium-derived nitric oxide (NO) and impaired endothelium-dependent vasodilator function, an initiating event in the atherosclerotic process [5].
Hydroxymethylglutaryl CoA reductase inhibitors, commonly known as statins, have documented effects on mortality and morbidity in patients with established coronary artery disease (CAD), but have also been found to reduce the incidence of cardiovascular events in high-risk individuals in the general population [6-8]. It has been proposed that statins exert important effects on the immune system that are independent of the effect on lipids (i.e. pleiotropic effects) [9]. Anti-inflammatory actions contribute to the beneficial cardiovascular effects, but controversy remains regarding the existence and impact of non-cardiovascular effects of statins. In retrospective observational studies, statin therapy has been associated with improved survival in patients with COPD [10, 11]. Experimental data also suggest that statins may have beneficial effects on airway inflammation, matrix metalloproteinase activity and mucin production [12-14]. Thus, it remains unclear whether statins exert their potential
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beneficial effects in COPD by primarily affecting vascular or respiratory function, and whether or not such beneficial effects are mediated by attenuation of systemic inflammation.
To address these questions, we conducted a randomised, placebo-controlled, double-blind trial to test the hypothesis that treatment with rosuvastatin in patients with stable COPD is associated with (i) enhanced peripheral endothelium-dependent vascular function, (ii) improved pulmonary function and (iii) attenuation of systemic inflammation, as expressed by decreased levels of circulating inflammatory markers. Furthermore, we prospectively hypothesised that the beneficial effect of rosuvastatin may be particularly pronounced in patients with evidence of increased systemic inflammation.
Materials and methods Trial design Effect of ROsuvastatin therapy on peripheral vasoDilator function, inflammatory markers and pulmonary function in patients with stablE chronic Obstructive pulmonary disease (RODEO; clinicaltrials.gov number NCT00929734; EudraCT number 2009-011659-35) was a randomised, placebo-controlled, double-blind, parallel group clinical trial. Participants Consecutive patients referred to the pulmonology outpatient clinics of two university hospitals in Norway with a verified diagnosis of COPD were eligible for participation. Exclusion criteria included history of or active CAD, cerebrovascular or peripheral vascular disease, and diabetes mellitus (see online Supplementary Table S1).
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Intervention After initial investigation, all patients were randomly assigned to either rosuvastatin 10 mg or matching placebo once daily for 12 weeks.
Measurements All patients completed a questionnaire about comorbidities (Charlson comorbidity index), respiratory symptoms according to the Modified Medical Research Council (MMRC) dyspnoea scale [15] and smoking habits. Spirometry was performed with reversibility testing using salbutamol as recommended by Miller et al. [16]. A 6-min walk test was conducted according to the guidelines of the American Thoracic Society [17]. Smoking was expressed as current smoking (yes/no) and number of pack-years. Arterial and venous blood samples were collected after an overnight fast during which patients abstained from smoking. The concentration of high-sensitivity C-reactive protein (hsCRP) was measured with the Cobas c501/502 system (Roche, Mannheim, Germany), and interleukin-6 (IL6) concentration was measured with the Cobas e602 system (Roche).
Endothelial function Endothelium-dependent vascular function was assessed by peripheral arterial tonometry (PAT) using the EndoPAT device (Itamar Medical, Caesarea, Israel). This method has been shown to correlate closely with the vasodilator response of coronary vessels following infusion of the endothelium-dependent vasodilator acetylcholine [18], and to provide prognostic information concerning the future incidence of cardiovascular events in the general population [19, 20].
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Study endpoints The primary endpoint was change from baseline in digital endothelium-dependent vascular function, expressed as reactive hyperaemia index (RHI) measured by PAT. Secondary endpoints were changes from baseline in post-bronchodilator forced expiratory volume in 1 s (FEV1), FEV1/forced vital capacity (FVC) and levels of hsCRP and IL6. Tertiary endpoints included change in MMRC dyspnoea scale and 6-min walking distance (6-MWD). The difference in the changes between treatment groups was used as the effect measure.
Statistical analyses Baseline characteristics of the study population were summarised within each group. The difference in the changes between the rosuvastatin and placebo groups from baseline to 12 weeks for primary and secondary endpoints and feasibility measures was estimated using analysis of covariance (ANCOVA). In accordance with the prespecified analysis plan, we evaluated treatment effects in subgroups with elevated circulating pro-inflammatory markers, defined as levels of hsCRP or IL6 above the median value. We also performed two post hoc sensitivity analyses, first excluding patients with increased CVD risk according to the Adult Treatment Panel III (ATP-III) criteria and secondly excluding those with a history of asthma. All statistical analyses were performed using SPSS Statistics (Version 20; IBM Corporation, NY, USA and SASR (Version 9.2; SAS Institute, Inc., Cary, NC, USA) software.
The study was conducted in compliance with Good Clinical Practice (GCP) regulatory requirements and with approval from independent ethics committees in accordance with the Declaration of Helsinki. Informed written consent was obtained from all participants. Further details of the methods used are available in the online supplement.
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Results Baseline data Complete data were available at the end of the study for 94 of the 99 patients enrolled (Fig. 1). Table 1 presents demographic and baseline characteristics of patients in each group. In the overall population, the mean (±SEM) age was 65 (±0.6) years, 48% were women, the mean body mass index was 24 (±0.4) kg/m2, the mean number of pack-years of smoking was 38 (±1.6), mean FEV1 was 1.4 (±0.06) L and mean FEV1/FVC was 47% (±1.3). Overall, 25% of patients had a history of hypertension, and 23% had a history of bronchial asthma (Table 1). None of the patients had a previous diagnosis of heart failure.
Primary, secondary and tertiary outcome measures In the complete-case analysis (n = 94), there was no significant change in endotheliumdependent vascular function, expressed as the RHI, in either the treatment group or the placebo group. Moreover, there was no significant difference in the primary outcome measure (i.e. the change in RHI) between the groups (Table 2 and Fig. 2).
The relative change in endothelial function, defined as change in RHI, was 6.65% [95% confidence interval (CI) 1.80% to 15.11%] in the rosuvastatin group and –1.27% (95% CI – 8.33% to 5.79%) in the placebo group (P = 0.292). In a secondary, predefined, multivariate regression analysis adjusting for covariates with possible impact on endothelial function (history of hypertension, gender and current smoking status), treatment with rosuvastatin was not significantly associated with change in RHI (P = 0.157). However, in a prespecified subgroup analysis of patients with supra-median hsCRP concentrations (i.e. >1.7 mg/L), rosuvastatin therapy was associated with a significant between-group difference in change in endothelium-dependent vascular function (13% vs. 2%, P = 0.026; Fig. 3), and a similar trend
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was observed in patients with supra-median IL6 concentrations (i.e. >3.7 pg/mL (7% vs. –2%, P = 0.131).
With regard to the secondary outcome measure of change in markers of systemic inflammation, rosuvastatin therapy was associated with a significant reduction in hsCRP level (–20% vs. 11%, P = 0.017) and a significant attenuation of the rise in the level of IL6 (8% vs. 30%, P = 0.028) compared with placebo. By contrast, there were no significant betweengroup differences in change in the spirometry values FEV1 (L), FEV1 (% of predicted) and FEV1/FVC (P = 0.462, P = 0.344 and P = 0.292, respectively; Table 2). Moreover, there was no difference in the changes in the tertiary measures of symptoms of dyspnoea according to the MMRC dyspnoea scale and 6-MWD (data not shown). Both imputation and per-protocol analyses yielded the same results as the complete-case analysis, and sensitivity analyses yielded the same conclusion regarding the effect on endothelial function. Of the 94 patients who completed the RODEO trial, 86 met the criteria for low CVD risk. Among these 86 patients, the effect on endothelial function (expressed as RHI) remained significant (P = 0.032) in the subgroup of patients with signs of elevated baseline inflammation defined as hsCRP >1.7 mg/L (n = 43). 72 patients who completed the study had no previous diagnosis of asthma. In the subgroup of patients without a history of asthma but with elevated baseline inflammation (n = 37), there was a significant effect on endothelial function (P = 0.048) as well as a significant difference in the change in concentration of the inflammatory markers hsCRP and IL6 (P = 0.006 and P = 0.035, respectively).
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Feasibility data Treatment compliance was confirmed by a significant lipid-lowering effect of rosuvastatin. Compared with placebo, rosuvastatin administration caused significant decreases in plasma total and LDL cholesterol levels by 24% and 41%, respectively. HDL cholesterol increased by 7%, and serum triglyceride levels decreased by 11%.
Safety endpoints Rosuvastatin was generally well tolerated by all patients. Possible side effects were reported by a total of 12 (26%) patients in the rosuvastatin group and 21 (43%) in the placebo group. The most frequent adverse events reported were constipation, diarrhoea, nausea and acute exacerbation of COPD. There was a non-significant trend towards more frequent exacerbations during the treatment period in the placebo group (27% vs. 15% in the rosuvastatin group, P = 0.160). There was no significant between-group difference in the change in alanine transaminase and creatine kinase levels (see online Supplementary Table S2. The reported serious adverse events were mainly acute exacerbations requiring hospitalisation during the treatment period [n = 4 (9%) in the rosuvastatin group and n = 3 (6%) in the placebo group]. There were no suspected unexpected serious adverse reactions during the treatment period (see online Supplementary Table S3).
Discussion Main study results The main finding of the present investigator-initiated, randomised, placebo-controlled, double-blind clinical trial is that short-term rosuvastatin treatment does not improve either endothelial function or lung function in patients with stable COPD without a history of CVD
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and diabetes, but significantly attenuates systemic inflammation. Notably, in a prespecified subgroup analysis of patients with hsCRP concentration >1.7 mg/L, rosuvastatin treatment was associated with improved endothelium-dependent vascular function, compared with placebo. Given that systemic inflammation is associated with the frequency of exacerbations [21] and outcome in COPD [22, 23] and that endothelium-dependent vascular function is believed to reflect vascular health and the risk of atherosclerotic disease, these findings are compatible with the theory that long-term treatment with statins may improve COPD outcome in patients with stable disease with elevated hsCRP concentrations. Although no effect of statins on the incidence of COPD exacerbations was observed in a recently reported largescale clinical trial there might nevertheless be an effect on the incidence of cardiovascular events in patients with evidence of elevated baseline inflammation.
Rationale for randomised trials of statin therapy in COPD Although the results of several retrospective observational trials suggest a beneficial effect of statin therapy on survival in COPD patients [10, 24], the underlying mechanisms remain unclear. To date, the results from three randomised controlled trials on statin treatment among patients with COPD have been published. The first study included 125 patients with stable COPD and reported a beneficial effect of statin treatment on exercise time; the effect was most prominent among patients with decreasing concentrations of inflammatory markers during treatment [25]. The second study, which included 56 patients, failed to demonstrate any significant effect of statins on circulating inflammatory markers [26]. Accordingly, there has been an urgent need for randomised clinical trials to elucidate the potential pathophysiological mechanisms of COPD and to assess the efficacy and safety of statin therapy in patients with stable disease. This was the rationale for conducting the RODEO
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trial. Very recently, the findings of the third study were published (Simvastatin for the prevention of exacerbations in moderate-to-severe COPD (STATCOPE)). In this multicentre trial, no effect of statin treatment on the incidence of COPD exacerbations was observed, but subgroups of COPD patients with different levels of inflammation were not evaluated and the study was not powered to assess the effect on cardiovascular events [27].
Effect of rosuvastatin treatment in stable COPD It has previously been shown that statin treatment exerts anti-inflammatory effects in different patient groups, including patients with CVD, diabetes or rheumatoid arthritis [28-31], and the large-scale Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial extended these findings to individuals with elevated hsCRP levels without hyperlipidaemia [8]. However, two previously reported clinical trials in COPD patients have demonstrated inconsistent results [25, 26]. The beneficial effect of statin therapy appeared to be consistent across a wide range of cardiovascular endpoints and subgroups. However, as JUPITER included a high proportion of obese patients, the characteristics of the participants may not be representative of a population with stable COPD, and therefore the results cannot be extrapolated to this population.
It has previously been shown that hsCRP and IL6 levels are elevated among patients with COPD, and this is associated with unfavourable outcomes [22, 32, 33]. The observed slight increase in the levels of inflammatory markers might reflect disease progression in the placebo group, as we observed a non-significant trend towards increased exacerbations in this group. Inflammation did not correlate with current smoking in our population and correction for smoking status did not change the results in a multivariate model. In addition, patients also
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abstained from smoking for at least 12 h before biomarker measurements, as mentioned above.
In a recent prospective case–control study, statin use was associated with improved survival among patients with COPD; this association was dependent on the level of systemic inflammation [24]. COPD patients with evidence of chronic low-grade inflammation may therefore represent a subgroup that could potentially benefit from statin treatment. The current results demonstrate that statin therapy attenuates systemic inflammation, and suggest that targeting patients with increased levels of hsCRP may identify those who may benefit most from statin therapy in terms of improvement in vascular function. Because COPD patients are at increased risk of cardiovascular events and measurement of vascular reactivity has been shown previously to provide additional prognostic information to conventional risk markers in patient groups without known CVD, vascular reactivity assessment seems to represent a valid although imperfect surrogate marker of atherosclerotic events. We believe that long-term randomised multicentre trialsincluding at least 3000 patients with a 3-year follow-up will be required to accurately define the beneficial effect of statin therapy in stable COPD patients and to evaluate whether the observed statin effect on endothelial function in patients with evidence of increased systemic inflammation would also translate into reduced incidence of cardiovascular endpoints.
There are several possible explanations for the apparent lack of effect of rosuvastatin on indices of pulmonary function observed in the current study, including insufficient duration of therapy, drug dose or statistical power. However, the effects observed on blood lipids, inflammatory markers and vascular function suggest that the lack of effect on pulmonary This article is protected by copyright. All rights reserved.
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function may be real and that the beneficial effects of statins in stable COPD patients may preferentially target the cardiovascular system. This theory is supported by the current finding of a lack of effect on the dyspnoea scale and exercise capacity measures in our study, as well by the recently published results of the STATCOPE trial
Strengths and limitations The strengths of the study include the randomised, placebo-controlled design, the wellcharacterised study population and the use of well-established and reproducible methods to assess changes in vascular function, pulmonary function and inflammatory activity. The low percentage of patients who withdrew from the study and the high acceptability of the study drug represent further strengths.
However, there are several study limitations, including the short duration of treatment and the relatively small sample size. The generalisability of our results depends on the representativeness of the study population. We included an equal number of men and women, and we believe the age range is representative of a typical population with COPD. However, the study population was ethnically homogenous (all Caucasian), and the results may not be generalisable to a non-Caucasian population. Baseline values of RHI in this selected population of COPD patients were generally within the normal range. This may also have contributed to the failure to document a beneficial effect of statin therapy in the overall study population. We limited inclusion to patients without a clear indication for statins based on comorbidities. As the beneficial effect of statin therapy in patients with CAD and diabetes mellitus is well established [34], patients with a history of these diseases were not eligible for the present study. In addition, we showed robust results in the sensitivity analysis excluding This article is protected by copyright. All rights reserved.
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patients at high CVD risk according to the ATP-III criteria. It is considered that patients with COPD without these comorbidities are still at increased CVD risk [35].
Conclusion Short-term treatment with rosuvastatin in patients with stable COPD without known CVD resulted in improved endothelium-dependent vascular function in the subgroup of individuals with supra-median concentrations of hsCRP at baseline and was associated with reduced systemic inflammation. These findings suggest that (i) the beneficial effect of statin therapy in stable COPD patients may be confined to those with evidence of systemic inflammation and (ii) measurement of hsCRP levels might be useful as part of a personalised medicine strategy to identify this patient group.
Acknowledgements We are grateful to Gunn Seim Ekeland and Michael L. Storebø for practical assistance with patient recruitment, Vigdis Bakkelund, Annika Lorentzen, Marit Jørgensen and Eli Nordeide for skilful technical assistance and Morten Fagerland for help with statistical analyses. We are also grateful to Birgitte Lid Adamsen and colleagues at the GCP unit at Oslo University Hospital for help to ensure that the study was conducted in compliance with GCP requirements.
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Conflict of interest statement TO received grants, personal fees and non-financial support from Abbott Laboratories, personal fees from Siemens Healthcare, grants, personal fees and non-financial support from AstraZeneca, and personal fees from Roche DiagnosticsAN has received a speaker fee from AstraZeneca. All other authors have no conflicts of interest to declare.
Funding This study was supported by grants from the Norwegian Extra Foundation for Health and Rehabilitation and The Norwegian Association of Heart and Lung Patients. The study was also conducted with support from the Investigator-Sponsored Study Program of AstraZeneca. Study medication was provided by AstraZeneca. The sponsors, including AstraZeneca, played no role in the study design, the collection, analysis and interpretation of the data, or the writing of or decision to submit the manuscript for publication.
Authors’ contributions AN, study design, data collection and analysis and drafting of the first version of the manuscript; ADH, data collection, data analysis and manuscript preparation; GE, data analysis and manuscript preparation; T-AH, biochemical analyses and manuscript preparation; SL, data collection and manuscript preparation; VS, study conception and design and manuscript preparation; TO, study conception and design, data interpretation and manuscript preparation.
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18 Anderson TJ, Uehata A, Gerhard MD, et al. Close relation of endothelial function in the human coronary and peripheral circulations. Journal of the American College of Cardiology 1995; 26: 1235-41. 19 Hamburg NM, Keyes MJ, Larson MG, et al. Cross-sectional relations of digital vascular function to cardiovascular risk factors in the Framingham Heart Study. Circulation 2008; 117: 2467-74. 20 Yeboah J, Crouse JR, Hsu FC, Burke GL, Herrington DM. Brachial flow-mediated dilation predicts incident cardiovascular events in older adults: the Cardiovascular Health Study. Circulation 2007; 115: 2390-7. 21 Thomsen M, Ingebrigtsen TS, Marott JL, Dahl M, Lange P, Vestbo J, Nordestgaard BG. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA : the journal of the American Medical Association 2013; 309: 2353-61. 22 Ferrari R, Tanni SE, Caram LM, Correa C, Correa CR, Godoy I. Three-year follow-up of Interleukin 6 and C-reactive protein in chronic obstructive pulmonary disease. Respir Res 2013; 14: 24. 23 Dahl M, Vestbo J, Lange P. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 2007; 175: 250 - 5. 24 Lahousse L, Loth DW, Joos GF, Hofman A, Leufkens HG, Brusselle GG, Stricker BH. Statins, systemic inflammation and risk of death in COPD: the Rotterdam study. Pulm Pharmacol Ther 2013; 26: 212-7. 25 Lee TM, Lin MS, Chang NC. Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. American Journal of Cardiology 2008; 101: 530-5. 26 Kaczmarek P, Sladek K, Skucha W, Rzeszutko M, Iwaniec T, Dziedzina S, Szczeklik A. The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. PolArchMed Wewn 2010; 120: 11-7. 27 Criner GJ, Connett JE, Aaron SD, et al. Simvastatin for the prevention of exacerbations in moderate-to-severe COPD. N Engl J Med 2014; 370: 2201-10. 28 Ridker PM, Cannon CP, Morrow D, et al. C-reactive protein levels and outcomes after statin therapy. The New England journal of medicine 2005; 352: 20-8. 29 Albert MA, Danielson E, Rifai N, Ridker PM, Investigators P. Effect of statin therapy on C-reactive protein levels: the pravastatin inflammation/CRP evaluation (PRINCE): a randomized trial and cohort study. JAMA : the journal of the American Medical Association 2001; 286: 64-70. 30 Leung BP, Sattar N, Crilly A, et al. A novel anti-inflammatory role for simvastatin in inflammatory arthritis. Journal of immunology 2003; 170: 1524-30. 31 Xu H, Liu P, Liang L, et al. RhoA-mediated, tumor necrosis factor alpha-induced activation of NF-kappaB in rheumatoid synoviocytes: inhibitory effect of simvastatin. Arthritis and rheumatism 2006; 54: 3441-51. 32 Celli BR, Locantore N, Yates J, et al. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease. American journal of respiratory and critical care medicine 2012; 185: 1065-72. 33 Agusti A, Edwards L, Rennard S. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. Plos One 2012; 7: e3y483. 34 Stone NJ, Robinson J, Lichtenstein AH, et al. 2013 ACC/AHA Guideline on the Treatment of Blood Cholesterol to Reduce Atherosclerotic Cardiovascular Risk in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2013. 35 Stone IS, Barnes NC, Petersen SE. Chronic obstructive pulmonary disease: a modifiable risk factor for cardiovascular disease? Heart 2012; 98: 1055-62. This article is protected by copyright. All rights reserved.
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Correspondence: Professor Torbjørn Omland MD, PhD, MPH Division of Medicine Akershus University Hospital 1478 Lørenskog Norway e-mail: [email protected]
Fig. 1 Patient flow chart. Exclusion details are provided in the online supplement.
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Fig. 2 Reactive hyperaemia index (RHI) and SEM in all patients (n = 94).
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Fig. 3 Reactive hyperaemia index (RHI) and SEM in patients with high-sensitivity C-reactive protein concentration above the median value (n = 47).
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Table 1 Demographic and baseline characteristics
Variable Demographic data Age, years Women BMI, kg/m² Clinical data Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Heart rate, beats/min Prior medical history Hypertension Bronchial asthma Smoking status Pack-years, years Current smoking Laboratory data Haemoglobin, g/dL eGFR, mL/min/1.73 m2 Leucocyte count, x109/L hsCRP, mg/L IL6, pg/mL Glucose, mmol/L Cholesterol, mmol/L LDL-C, mmol/L HDL-C, mmol/L Triglycerides, mmol/L Spirometry FEV1, L FEV1, % of predicted FEV1/FVC, % Medication Antihypertensive treatment ICS (including LABA) LABA (only) LAMA Anti-inflammatory treatment Oestrogen
Rosuvastatin (n = 47)
Placebo (n = 47)
66 (0.8) 21 (45) 23 (0.6)
63 (1.0) 24 (51) 24 (0.6)
131 (2.6) 79 (1.2) 68 (1.6)
135 (2.9) 80 (1.5) 67 (1.6)
12 (26) 9 (19)
11 (23) 13 (28)
39 (2.4) 12 (26)
35 (2.6) 23 (49)
14.1 (0.2) 86.3 (2.6) 6.6 (0.2) 1.4 (0.8, 3.7) 4.1 (2.9, 5.3) 5.0 (0.1) 5.5 (0.1) 3.3 (0.1) 1.8 (0.1) 1.0 (0.1)
14.0 (0.2) 89.6 (3.0) 6.9 (0.3) 1.8 (1.0, 4.4) 3.4 (2.7, 4.7) 5.1 (0.1) 5.7 (0.1) 3.5 (0.1) 1.8 (0.1) 1.1 (0.1)
1.4 (0.1) 48.3 (2.8) 47 (2.0)
1.5 (0.1) 52.1 (2.7) 49 (1.7)
12 (26) 36 (77) 2 (4) 30 (64) 2 (4) 4 (9)
10 (21) 34 (72) 3 (6) 27 (58) 0 (0) 3 (6)
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Continuous data are presented as mean (SEM) and categorical variables as number (percentage). Biomarker data are presented as median (25th,75th percentile). BMI, body mass index; eGFR, estimated glomerular filtration rate using the Modification of Diet in Renal Disease formula; FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; hsCRP, high-sensitivity C-reactive protein; HDL-C, high-density lipoprotein cholesterol; ICS, inhaled corticosteroids; IL6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; LABA, long-acting beta-2 agonist; LAMA, long-acting muscarinic antagonist.
Table 2 Change in endpoints between treatment groups
Variable
Rosuvastatin (n = 47)
Placebo (n = 47)
P-valuea
Baseline
Follow-up
Baseline
Follow-up
RHI
2.47 (0.10)
2.54 (0.10)
2.65 (0.10)
2.51 (0.07)
0.292
lnRHI
0.87 (0.04)
0.90 (0.04)
0.94 (0.04)
0.90 (0.03)
0.477
FEV1, L
1.34 (0.09)
1.35 (0.08)
1.47 (0.10)
1.45 (0.94)
0.462
FEV1, %
48.3 (2.77)
49.3 (2.75)
52.1 (2.75)
51.7 (2.76)
0.344
FEV1/FVC, %
46.9 (2.01)
47.3 (1.87)
48.8 (1.72)
47.9 (1.79)
0.292
hsCRP, mg/L
1.4 (0.8, 3.7)
1.2 (0.7, 2.6)
1.8 (1.0, 4.4)
2.2 (1.3, 3.6)c
0.017
IL6, pg/mL
4.1 (2.9, 5.2)
4.1 (3.4, 5.5)
3.4 (2.7, 4.7)
4.4 (3.0, 6.7)b
0.028
Continuous data are presented as mean (SEM). Biomarker data are presented as median (25th, 75th percentile). a
b
c
ANCOVA, P < 0.05 paired t-test, P < 0.05 Student’s t-test.
FEV1, forced expiratory volume in 1 s; FVC, forced vital capacity; hsCRP, high-sensitivity C-reactive protein; IL6, interleukin-6; RHI, reactive hyperaemia index.
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