Effect of statins on disease-related outcomes in patients with idiopathic pulmonary fibrosis

Michael Kreuter, Francesco Bonella, Toby M Maher, Ulrich Costabel, Paolo Spagnolo, Derek Weycker, Klaus-Uwe Kirchgaessler, Martin Kolb, Michael Kreuter, Francesco Bonella, Toby M Maher, Ulrich Costabel, Paolo Spagnolo, Derek Weycker, Klaus-Uwe Kirchgaessler, Martin Kolb

Abstract

Background: Data are conflicting regarding the possible effects of statins in patients with idiopathic pulmonary fibrosis (IPF). This post hoc analysis assessed the effects of statin therapy on disease-related outcomes in IPF.

Methods: Patients randomised to placebo (n=624) in three controlled trials of pirfenidone in IPF (CAPACITY 004 and 006, ASCEND) were categorised by baseline statin use. Outcomes assessed during the 1-year follow-up included disease progression, mortality, hospitalisation and composite outcomes of death or ≥10% absolute decline in FVC and death or ≥50 m decline in 6-minute walk distance (6MWD).

Results: At baseline, 276 (44%) patients were statin users versus 348 (56%) non-users. Baseline characteristics were similar between groups, except statin users were older and had higher prevalence of cardiovascular disease and risk factors. In multivariate analyses adjusting for differences in baseline characteristics, statin users had lower risks of death or 6MWD decline (HR 0.69; 95% CI 0.48 to 0.99, p=0.0465), all-cause hospitalisation (HR 0.58; 95% CI 0.35 to 0.94, p=0.0289), respiratory-related hospitalisation (HR 0.44; 95% CI 0.25 to 0.80, p=0.0063) and IPF-related mortality (HR 0.36; 95% CI 0.14 to 0.95, p=0.0393) versus non-users. Non-significant treatment effects favouring statin use were observed for disease progression (HR 0.75; 95% CI 0.52 to 1.07, p=0.1135), all-cause mortality (HR 0.54; 95% CI 0.24 to 1.21, p=0.1369) and death or FVC decline (HR 0.71; 95% CI 0.48 to 1.07, p=0.1032).

Conclusions: This post hoc analysis supports the hypothesis that statins may have a beneficial effect on clinical outcomes in IPF. Prospective clinical trials are required to validate these observations.

Trial registration numbers: NCT01366209, NCT00287729 and NCT00287716.

Keywords: Idiopathic pulmonary fibrosis.

Conflict of interest statement

MKr and his institution have received unrestricted grants and personal fees from InterMune International AG which became a wholly owned subsidiary of Roche in 2014, F. Hoffmann-La Roche Ltd and Boehringer Ingelheim. FB has received speaker fees, advisory board honoraria or grants from InterMune International AG which became a wholly owned subsidiary of Roche in 2014, Boehringer Ingelheim, Gilead, Serendex, Centocor and F. Hoffmann-La Roche Ltd. TMM is supported by a National Institute for Health Research Clinician Scientist Fellowship (NIHR Ref: CS:-2013-13-017). He has received research grants from GlaxoSmithKline, UCB and Novartis; and consulting and speaker fees from AstraZeneca, Bayer, Biogen Idec, Boehringer Ingelheim, Cipla, Dosa, GlaxoSmithKline, Lanthio, InterMune International AG which became a wholly owned subsidiary of Roche in 2014, F. Hoffmann-La Roche Ltd, Sanofi-Aventis, Takeda and UCB. UC has received grants, personal fees and non-financial support from Boehringer Ingelheim. He has received grants, personal fees and non-financial support from Intermune International AG which became a wholly owned subsidiary of Roche in 2014, and personal fees from F. Hoffmann-La Roche Ltd, Bayer, Gilead, GlaxoSmithKline, UCB, Biogen and Centocor (all outside the submitted work). PS has received consulting fees from InterMune International AG which became a wholly owned subsidiary of Roche in 2014, F. Hoffmann-La Roche Ltd and Santhera Pharmaceuticals Ltd, and personal fees from Boehringer Ingelheim and Novartis. DW is an employee of Policy Analysis Inc. (PAI), which received funding from F. Hoffmann-La Roche Ltd for this study. K-UK is an employee of F. Hoffmann-La Roche Ltd, Basel, Switzerland. MKo has served as site Principal Investigator in industry-sponsored clinical trials (Centocor, Roche, Sanofi and Boehringer Ingelheim) and is funded by the Canadian Institute for Health Research. He has served and/or serves on the Pulmonary Fibrosis Foundation Medical Advisory Board and on Advisory Boards for Boehringer Ingelheim, Roche Canada, GlaxoSmithKline, AstraZeneca, Vertex, Genoa, Gilead, Janssen and Prometic.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Figures

Figure 1
Figure 1
Adjusted 1-year risk of disease progression*: statin users versus non-users. *≥10% decrease in % predicted FVC, ≥50 m decline in 6MWD or death. 6MWD, 6-minute walk distance.
Figure 2
Figure 2
Adjusted 1-year risk of ≥10% absolute FVC decline or death: statin users versus non-users.

References

    1. Meltzer EB, Noble PW. Idiopathic pulmonary fibrosis. Orphanet J Rare Dis 2008;3:8 10.1186/1750-1172-3-8
    1. Raghu G, Collard HR, Egan JJ, et al. . An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788–824. 10.1164/rccm.2009-040GL
    1. Raghu G, Rochwerg B, Zhang Y, et al. . An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2015;192:e3–19. 10.1164/rccm.201506-1063ST
    1. Behr J, Kreuter M, Hoeper MM, et al. . Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry. Eur Respir J 2015;46:186–96. 10.1183/09031936.00217614
    1. Durheim MT, Collard HR, Roberts RS, et al. . Association of hospital admission and forced vital capacity endpoints with survival in patients with idiopathic pulmonary fibrosis: analysis of a pooled cohort from three clinical trials. Lancet Respir Med 2015;3:388–96. 10.1016/S2213-2600(15)00093-4
    1. American Cancer Society. Cancer facts and figures 2016. American Cancer Society, 2016.
    1. Nathan SD, Shlobin OA, Weir N, et al. . Long-term course and prognosis of idiopathic pulmonary fibrosis in the new millennium. Chest 2011;140:221–9. 10.1378/chest.10-2572
    1. Kim DS, Collard HR, King TE Jr. Classification and natural history of the idiopathic interstitial pneumonias. Proc Am Thorac Soc 2006;3:285–92. 10.1513/pats.200601-005TK
    1. King TE Jr, Bradford WZ, Castro-Bernardini S, et al. . A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083–92. 10.1056/NEJMoa1402582
    1. Noble PW, Albera C, Bradford WZ, et al. . Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011;377:1760–9. 10.1016/S0140-6736(11)60405-4
    1. Richeldi L, du Bois RM, Raghu G, et al. . Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071–82. 10.1056/NEJMoa1402584
    1. Kreuter M, Ehlers-Tenenbaum S, Palmowski K, et al. . Impact of comorbidities on mortality in patients with idiopathic pulmonary fibrosis. PLoS ONE 2016;11:e0151425 10.1371/journal.pone.0151425
    1. Bansilal S, Castellano JM, Fuster V. Global burden of CVD: focus on secondary prevention of cardiovascular disease. Int J Cardiol 2015;201(Suppl 1):S1–7. 10.1016/S0167-5273(15)31026-3
    1. Briel M, Vale N, Schwartz GG, et al. . Updated evidence on early statin therapy for acute coronary syndromes: meta-analysis of 18 randomized trials involving over 14,000 patients. Int J Cardiol 2012;158:93–100. 10.1016/j.ijcard.2011.01.033
    1. Alexeeff SE, Litonjua AA, Sparrow D, et al. . Statin use reduces decline in lung function: VA Normative Aging Study. Am J Respir Crit Care Med 2007;176:742–7. 10.1164/rccm.200705-656OC
    1. 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. 10.1056/NEJMoa1403086
    1. Fernández AB, Karas RH, Alsheikh-Ali AA, et al. . Statins and interstitial lung disease: a systematic review of the literature and of food and drug administration adverse event reports. Chest 2008;134:824–30. 10.1378/chest.08-0943
    1. Xu JF, Washko GR, Nakahira K, et al. . Statins and pulmonary fibrosis: the potential role of NLRP3 inflammasome activation. Am J Respir Crit Care Med 2012;185:547–56. 10.1164/rccm.201108-1574OC
    1. Saad N, Camus P, Suissa S, et al. . Statins and the risk of interstitial lung disease: a cohort study. Thorax 2013;68:361–4. 10.1136/thoraxjnl-2012-201823
    1. Schroll S, Lange TJ, Arzt M, et al. . Effects of simvastatin on pulmonary fibrosis, pulmonary hypertension and exercise capacity in bleomycin-treated rats. Acta Physiol (Oxf) 2013;208:191–201. 10.1111/apha.12085
    1. Nadrous HF, Ryu JH, Douglas WW, et al. . Impact of angiotensin-converting enzyme inhibitors and statins on survival in idiopathic pulmonary fibrosis. Chest 2004;126:438–46. 10.1378/chest.126.2.438
    1. Vedel-Krogh S, Nielsen SF, Nordestgaard BG. Statin use is associated with reduced mortality in patients with interstitial lung disease. PLoS ONE 2015;10:e0140571 10.1371/journal.pone.0140571
    1. Allison PD. Survival analysis using SAS: a practical guide. 2nd edn. North Carolina: SAS Insitute Inc, 2010.
    1. Pencina MJ, D'Agostino RB Sr, D'Agostino RB Jr, et al. . Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond. Stat Med 2008;27:157–72. 10.1002/sim.2929
    1. Raghu G, Anstrom KJ, King TE Jr, et al. . Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med 2012;366:1968–77. 10.1056/NEJMoa1113354
    1. Ley B, Collard HR, King TE Jr. Clinical course and prediction of survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011;183:431–40. 10.1164/rccm.201006-0894CI
    1. Quanjer PH, Stanojevic S, Cole TJ, et al. . Multi-ethnic reference values for spirometry for the 3–95-yr age range: the global lung function 2012 equations. Eur Respir J 2012;40:1324–43. 10.1183/09031936.00080312
    1. Chambers RC, Mercer PF. Mechanisms of alveolar epithelial injury, repair, and fibrosis. Ann Am Thorac Soc 2015;12(Suppl 1):S16–20. 10.1513/AnnalsATS.201410-448MG
    1. Günther A, Korfei M, Mahavadi P, et al. . Unravelling the progressive pathophysiology of idiopathic pulmonary fibrosis. Eur Respir Rev 2012;21: 152–60. 10.1183/09059180.00001012
    1. Eberlein M, Heusinger-Ribeiro J, Goppelt-Struebe M. Rho-dependent inhibition of the induction of connective tissue growth factor (CTGF) by HMG CoA reductase inhibitors (statins). Br J Pharmacol 2001;133:1172–80. 10.1038/sj.bjp.0704173
    1. Riessen R, Axel DI, Fenchel M, et al. . Effect of HMG-CoA reductase inhibitors on extracellular matrix expression in human vascular smooth muscle cells. Basic Res Cardiol 1999;94:322–32. 10.1007/s003950050158
    1. Watts KL, Sampson EM, Schultz GS, et al. . Simvastatin inhibits growth factor expression and modulates profibrogenic markers in lung fibroblasts. Am J Respir Cell Mol Biol 2005;32:290–300. 10.1165/rcmb.2004-0127OC
    1. Leask A, Abraham DJ. TGF-beta signaling and the fibrotic response. FASEB J 2004;18:816–27. 10.1096/fj.03-1273rev
    1. Lee JH, Lee DS, Kim EK, et al. . Simvastatin inhibits cigarette smoking-induced emphysema and pulmonary hypertension in rat lungs. Am J Respir Crit Care Med 2005;172:987–93. 10.1164/rccm.200501-041OC
    1. Johnson BA, Iacono AT, Zeevi A, et al. . Statin use is associated with improved function and survival of lung allografts. Am J Respir Crit Care Med 2003;167:1271–8. 10.1164/rccm.200205-410OC
    1. Ahn MH, Park BL, Lee SH, et al. . A promoter SNP rs4073T>A in the common allele of the interleukin 8 gene is associated with the development of idiopathic pulmonary fibrosis via the IL-8 protein enhancing mode. Respir Res 2011;12:73 10.1186/1465-9921-12-73
    1. Hayden JM, Swartfiguer J, Szelinger S, et al. . Lysophosphatidylcholine stimulation of alveolar epithelial cell interleukin-8 production and neutrophil chemotaxis is inhibited by statin treatment [abstract]. Proc Am Thorac Soc 2005;2:A72.
    1. Oka H, Ishii H, Iwata A, et al. . Inhibitory effects of pitavastatin on fibrogenic mediator production by human lung fibroblasts. Life Sci 2013;93:968–74. 10.1016/j.lfs.2013.10.026
    1. Coward WR, Marei A, Yang A, et al. . Statin-induced proinflammatory response in mitogen-activated peripheral blood mononuclear cells through the activation of caspase-1 and IL-18 secretion in monocytes. J Immunol 2006;176:5284–92. 10.4049/jimmunol.176.9.5284
    1. Hoshino T, Okamoto M, Sakazaki Y, et al. . Role of proinflammatory cytokines IL-18 and IL-1beta in bleomycin-induced lung injury in humans and mice. Am J Respir Cell Mol Biol 2009;41:661–70. 10.1165/rcmb.2008-0182OC

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir