Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study


Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p < 0.001], but hospitalization was comparable between two groups. After stratifying patients based on COPD status, patients with COPD showed a marginally significant survival benefit from statins [HR 0.53 (95% CI 0.26, 1.10), p = 0.09]; and statins significantly reduced 1-year all-cause mortality in patients without COPD [HR 0.36 (95% CI 0.19, 0.67), p = 0.001]. We found no significant difference in the effect of statins on patients with COPD compared to those without (p = 0.16). Statin therapy is associated with reduced mortality risk in patients with severe PH and preserved left ventricular function. This beneficial effect was not found to be dependent on COPD status. These novel findings should be confirmed in large randomized trials.

This is a preview of subscription content, access via your institution.

Fig. 1



Brain-natriuretic peptide


Chronic obstructive pulmonary disease


Left ventricular ejection fraction


Pulmonary artery pressure


Pulmonary artery systolic pressure


Pulmonary hypertension


Right ventricle


Right ventricular systolic pressure


  1. 1.

    Pietra GG, Capron F, Stewart S, Leone O, Humbert M, Robbins IM, Reid LM, Tuder RM (2004) Pathologic assessment of vasculopathies in pulmonary hypertension. J Am Coll Cardiol 43:25S–32S

    Article  PubMed  Google Scholar 

  2. 2.

    Crosswhite P, Sun Z (2010) Nitric oxide, oxidative stress and inflammation in pulmonary arterial hypertension. J Hypertens 28:201–212

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    Soon E, Holmes AM, Treacy CM, Doughty NJ, Southgate L, Machado RD, Trembath RC, Jennings S, Barker L, Nicklin P, Walker C, Budd DC, Pepke-Zaba J, Morrell NW (2010) Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension. Circulation 122:920–927

    CAS  Article  PubMed  Google Scholar 

  4. 4.

    Quarck R, Nawrot T, Meyns B, Delcroix M (2009) C-reactive protein: a new predictor of adverse outcome in pulmonary arterial hypertension. J Am Coll Cardiol 53:1211–1218

    CAS  Article  PubMed  Google Scholar 

  5. 5.

    Price LC, Wort SJ, Perros F, Dorfmuller P, Huertas A, Montani D, Cohen-Kaminsky S, Humbert M (2012) Inflammation in pulmonary arterial hypertension. Chest 141:210–221

    CAS  Article  PubMed  Google Scholar 

  6. 6.

    Bhowmik A, Seemungal TA, Sapsford RJ, Wedzicha JA (2000) Relation of sputum inflammatory markers to symptoms and lung function changes in COPD exacerbations. Thorax 55:114–120

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  7. 7.

    Chaouat A, Savale L, Chouaid C, Tu L, Sztrymf B, Canuet M, Maitre B, Housset B, Brandt C, Le Corvoisier P, Weitzenblum E, Eddahibi S, Adnot S (2009) Role for interleukin-6 in COPD-related pulmonary hypertension. Chest 136:678–687

    CAS  Article  PubMed  Google Scholar 

  8. 8.

    Wierzbicki AS, Poston R, Ferro A (2003) The lipid and non-lipid effects of statins. Pharmacol Ther 99:95–112

    CAS  Article  PubMed  Google Scholar 

  9. 9.

    Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP (2009) Pleiotropic effects of statins—clinical evidence. Curr Pharm Des 15:479–489

    CAS  Article  PubMed  Google Scholar 

  10. 10.

    Katsiki N, Tziomalos K, Chatzizisis Y, Elisaf M, Hatzitolios AI (2010) Effect of HMG-CoA reductase inhibitors on vascular cell apoptosis: beneficial or detrimental? Atherosclerosis 211:9–14

    CAS  Article  PubMed  Google Scholar 

  11. 11.

    Eshtehardi P, McDaniel MC, Dhawan SS, Binongo JN, Krishnan SK, Golub L, Corban MT, Raggi P, Quyyumi AA, Samady H (2012) Effect of intensive atorvastatin therapy on coronary atherosclerosis progression, composition, arterial remodeling, and microvascular function. J Invasive Cardiol 24:522–529

    PubMed  Google Scholar 

  12. 12.

    Shimomura M, Oyama J, Takeuchi M, Shibata Y, Yamamoto Y, Kawasaki T, Komoda H, Kodama K, Sakuma M, Toyoda S, Inoue Y, Mine D, Natsuaki M, Komatsu A, Hikichi Y, Yamagishi S, Inoue T, Node K (2016) Acute effects of statin on reduction of angiopoietin-like 2 and glyceraldehyde-derived advanced glycation end-products levels in patients with acute myocardial infarction: a message from SAMIT (Statin for Acute Myocardial Infarction Trial). Heart Vessels 31:1583–1589

    Article  PubMed  Google Scholar 

  13. 13.

    Abramowitz M, Muntner P, Coco M, Southern W, Lotwin I, Hostetter TH, Melamed ML (2010) Serum alkaline phosphatase and phosphate and risk of mortality and hospitalization. Clin J Am Soc Nephrol 5:1064–1071

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Das R, Feuerstadt P, Brandt LJ (2010) Glucocorticoids are associated with increased risk of short-term mortality in hospitalized patients with clostridium difficile-associated disease. Am J Gastroenterol 105:2040–2049

    CAS  Article  PubMed  Google Scholar 

  15. 15.

    Stein EG, Haramati LB, Bellin E, Ashton L, Mitsopoulos G, Schoenfeld A, Amis ES Jr (2010) Radiation exposure from medical imaging in patients with chronic and recurrent conditions. J Am Coll Radiol 7:351–359

    Article  PubMed  Google Scholar 

  16. 16.

    Yoon AJ, Melduni RM, Duncan SA, Ostfeld RJ, Travin MI (2009) The effect of beta-blockers on the diagnostic accuracy of vasodilator pharmacologic SPECT myocardial perfusion imaging. J Nucl Cardiol 16:358–367

    Article  PubMed  Google Scholar 

  17. 17.

    Southern WN, Nahvi S, Arnsten JH (2012) Increased risk of mortality and readmission among patients discharged against medical advice. Am J Med 125:594–602

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Eshtehardi P, Pamerla M, Mojadidi MK, Goodman-Meza D, Hovnanians N, Gupta A, Lupercio F, Mazurek JA, Zolty R (2015) Addition of angiotensin-converting enzyme inhibitors to beta-blockers has a distinct effect on hispanics compared with African Americans and Whites with heart failure and reduced ejection fraction: a propensity score-matching study. J Cardiac Fail 21:448–456

    CAS  Article  Google Scholar 

  19. 19.

    Khan MG (1997) Pulmonary hypertension and cor pulmonale. In: Khan MG, Lynch JPI (eds) Pulmonary disease diagnosis and therapy: a practical approach. Williams & Wilkins, Baltimore, pp 603–616

    Google Scholar 

  20. 20.

    Austin PC (2014) The use of propensity score methods with survival or time-to-event outcomes: reporting measures of effect similar to those used in randomized experiments. Stat Med 33:1242–1258

    Article  PubMed  Google Scholar 

  21. 21.

    Hopkins WE, Ochoa LL, Richardson GW, Trulock EP (1996) Comparison of the hemodynamics and survival of adults with severe primary pulmonary hypertension or Eisenmenger syndrome. J Heart Lung Transplant 15:100–105

    CAS  PubMed  Google Scholar 

  22. 22.

    Hopkins WE (2005) The remarkable right ventricle of patients with Eisenmenger syndrome. Coron Artery Dis 16:19–25

    Article  PubMed  Google Scholar 

  23. 23.

    D’Alonzo GE, Barst RJ, Ayres SM, Bergofsky EH, Brundage BH, Detre KM, Fishman AP, Goldring RM, Groves BM, Kernis JT, Levy PS, Pietra GG, Reid LM, Reeves JT, Rich S, Vreim CE, Williams GW, Wu M (1991) Survival in patients with primary pulmonary hypertension. Results from a national prospective registry. Ann Intern Med 115:343–349

    Article  PubMed  Google Scholar 

  24. 24.

    Galie N, Hoeper MM, Humbert M, Torbicki A, Vachiery JL, Barbera JA, Beghetti M, Corris P, Gaine S, Gibbs JS, Gomez-Sanchez MA, Jondeau G, Klepetko W, Opitz C, Peacock A, Rubin L, Zellweger M, Simonneau G, Guidelines ESCCfP (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension: the Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J 30:2493–2537

    Article  PubMed  Google Scholar 

  25. 25.

    Forfia PR, Fisher MR, Mathai SC, Housten-Harris T, Hemnes AR, Borlaug BA, Chamera E, Corretti MC, Champion HC, Abraham TP, Girgis RE, Hassoun PM (2006) Tricuspid annular displacement predicts survival in pulmonary hypertension. Am J Respir Crit Care Med 174:1034–1041

    Article  PubMed  Google Scholar 

  26. 26.

    van de Veerdonk MC, Kind T, Marcus JT, Mauritz GJ, Heymans MW, Bogaard HJ, Boonstra A, Marques KM, Westerhof N, Vonk-Noordegraaf A (2011) Progressive right ventricular dysfunction in patients with pulmonary arterial hypertension responding to therapy. J Am Coll Cardiol 58:2511–2519

    Article  PubMed  Google Scholar 

  27. 27.

    Andersen KH, Iversen M, Kjaergaard J, Mortensen J, Nielsen-Kudsk JE, Bendstrup E, Videbaek R, Carlsen J (2012) Prevalence, predictors, and survival in pulmonary hypertension related to end-stage chronic obstructive pulmonary disease. J Heart Lung Transplant 31:373–380

    Article  PubMed  Google Scholar 

  28. 28.

    Girgis RE, Li D, Zhan X, Garcia JG, Tuder RM, Hassoun PM, Johns RA (2003) Attenuation of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Heart Circ Physiol 285:H938–H945

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Taraseviciene-Stewart L, Scerbavicius R, Choe KH, Cool C, Wood K, Tuder RM, Burns N, Kasper M, Voelkel NF (2006) Simvastatin causes endothelial cell apoptosis and attenuates severe pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 291:L668–L676

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Hsu HH, Ruan T, Ko WJ, Hsu JY, Chen JS, Lee YC, Lai IR, Chen CF (2011) Effects of simvastatin on pulmonary C-fiber sensitivity in rats with monocrotaline-induced pulmonary hypertension. J Heart Lung Transplant 30:332–340

    Article  PubMed  Google Scholar 

  31. 31.

    Satoh K, Fukumoto Y, Nakano M, Sugimura K, Nawata J, Demachi J, Karibe A, Kagaya Y, Ishii N, Sugamura K, Shimokawa H (2009) Statin ameliorates hypoxia-induced pulmonary hypertension associated with down-regulated stromal cell-derived factor-1. Cardiovasc Res 81:226–234

    CAS  Article  PubMed  Google Scholar 

  32. 32.

    Laudi S, Trump S, Schmitz V, West J, McMurtry IF, Mutlak H, Christians U, Weimann J, Kaisers U, Steudel W (2007) Serotonin transporter protein in pulmonary hypertensive rats treated with atorvastatin. Am J Physiol Lung Cell Mol Physiol 293:L630–L638

    CAS  Article  PubMed  Google Scholar 

  33. 33.

    Nishimura T, Faul JL, Berry GJ, Vaszar LT, Qiu D, Pearl RG, Kao PN (2002) Simvastatin attenuates smooth muscle neointimal proliferation and pulmonary hypertension in rats. Am J Respir Crit Care Med 166:1403–1408

    Article  PubMed  Google Scholar 

  34. 34.

    Gao YF, Zhu XD, Shi DM, Jing ZC, Li L, Ma D, Fan ZX, Li J, Wang YW, Wu BX (2010) The effects of atorvastatin on pulmonary arterial hypertension and expression of p38, p27, and Jab1 in rats. Int J Mol Med 26:541–547

    CAS  PubMed  Google Scholar 

  35. 35.

    Xie L, Lin P, Xie H, Xu C (2010) Effects of atorvastatin and losartan on monocrotaline-induced pulmonary artery remodeling in rats. Clin Exp Hypertens 32:547–554

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Guerard P, Rakotoniaina Z, Goirand F, Rochette L, Dumas M, Lirussi F, Bardou M (2006) The HMG-CoA reductase inhibitor, pravastatin, prevents the development of monocrotaline-induced pulmonary hypertension in the rat through reduction of endothelial cell apoptosis and overexpression of eNOS. Naunyn Schmiedebergs Arch Pharmacol 373:401–414

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Carlin CM, Peacock AJ, Welsh DJ (2007) Fluvastatin inhibits hypoxic proliferation and p38 MAPK activity in pulmonary artery fibroblasts. Am J Respir Cell Mol Biol 37:447–456

    CAS  Article  PubMed  Google Scholar 

  38. 38.

    DeMarco VG, Habibi J, Whaley-Connell AT, Schneider RI, Sowers JR, Andresen BT, Gutweiler AA, Ma L, Johnson MS, Ferrario CM, Dellsperger KC (2009) Rosuvastatin ameliorates the development of pulmonary arterial hypertension in the transgenic (mRen2)27 rat. Am J Physiol Heart Circ Physiol 297:H1128–H1139

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Li J, Li JJ, He JG, Nan JL, Guo YL, Xiong CM (2010) Atorvastatin decreases C-reactive protein-induced inflammatory response in pulmonary artery smooth muscle cells by inhibiting nuclear factor-kappaB pathway. Cardiovasc Ther 28:8–14

    CAS  Article  PubMed  Google Scholar 

  40. 40.

    Girgis RE, Mozammel S, Champion HC, Li D, Peng X, Shimoda L, Tuder RM, Johns RA, Hassoun PM (2007) Regression of chronic hypoxic pulmonary hypertension by simvastatin. Am J Physiol Lung Cell Mol Physiol 292:L1105–L1110

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Zheng X, Hu SJ (2005) Effects of simvastatin on cardiac performance and expression of sarcoplasmic reticular calcium regulatory proteins in rat heart. Acta Pharmacol Sin 26:696–704

    CAS  Article  PubMed  Google Scholar 

  42. 42.

    Saka M, Obata K, Ichihara S, Cheng XW, Kimata H, Nishizawa T, Noda A, Izawa H, Nagata K, Murohara T, Yokota M (2006) Pitavastatin improves cardiac function and survival in association with suppression of the myocardial endothelin system in a rat model of hypertensive heart failure. J Cardiovasc Pharmacol 47:770–779

    CAS  Article  PubMed  Google Scholar 

  43. 43.

    Carlin CM, Celnik DF, Pak O, Wadsworth R, Peacock AJ, Welsh DJ (2012) Low-dose fluvastatin reverses the hypoxic pulmonary adventitial fibroblast phenotype in experimental pulmonary hypertension. Am J Respir Cell Mol Biol 47:140–148

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Tani S, Takahashi A, Nagao K, Hirayama A (2015) Contribution of apolipoprotein A-I to the reduction in high-sensitivity C-reactive protein levels by different statins: comparative study of pitavastatin and atorvastatin. Heart Vessels 30:762–770

    Article  PubMed  Google Scholar 

  45. 45.

    Kao PN (2005) Simvastatin treatment of pulmonary hypertension: an observational case series. Chest 127:1446–1452

    CAS  PubMed  Google Scholar 

  46. 46.

    Wilkins MR, Ali O, Bradlow W, Wharton J, Taegtmeyer A, Rhodes CJ, Ghofrani HA, Howard L, Nihoyannopoulos P, Mohiaddin RH, Gibbs JS, Simvastatin Pulmonary Hypertension Trial Study Group (2010) Simvastatin as a treatment for pulmonary hypertension trial. Am J Respir Crit Care Med 181:1106–1113

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Kawut SM, Bagiella E, Lederer DJ, Shimbo D, Horn EM, Roberts KE, Hill NS, Barr RG, Rosenzweig EB, Post W, Tracy RP, Palevsky HI, Hassoun PM, Girgis RE, Group A-SS (2011) Randomized clinical trial of aspirin and simvastatin for pulmonary arterial hypertension: ASA-STAT. Circulation 123:2985–2993

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Barreto AC, Maeda NY, Soares RP, Cicero C, Lopes AA (2008) Rosuvastatin and vascular dysfunction markers in pulmonary arterial hypertension: a placebo-controlled study. Braz J Med Biol Res 41:657–663

    CAS  Article  PubMed  Google Scholar 

  49. 49.

    Mansur A, Steinau M, Popov AF, Ghadimi M, Beissbarth T, Bauer M, Hinz J (2015) Impact of statin therapy on mortality in patients with sepsis-associated acute respiratory distress syndrome (ARDS) depends on ARDS severity: a prospective observational cohort study. BMC Med 13:128

    Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    McKenney JM (2003) Pharmacologic characteristics of statins. Clin Cardiol 26:III32–III38

    Article  PubMed  Google Scholar 

  51. 51.

    Corciova FC, Arsenescu-Georgescu C (2012) Prognostic factors in pulmonary hypertension. Maedica (Buchar) 7:30–37

    Google Scholar 

  52. 52.

    Seeger W, Adir Y, Barbera JA, Champion H, Coghlan JG, Cottin V, De Marco T, Galie N, Ghio S, Gibbs S, Martinez FJ, Semigran MJ, Simonneau G, Wells AU, Vachiery JL (2013) Pulmonary hypertension in chronic lung diseases. J Am Coll Cardiol 62:D109–D116

    Article  PubMed  Google Scholar 

  53. 53.

    Young RP, Hopkins RJ (2010) Possible role of statins in COPD-related pulmonary hypertension. Chest 137:1250–1251 (author reply 1251)

    Article  PubMed  Google Scholar 

  54. 54.

    Lee TM, Chen CC, Shen HN, Chang NC (2009) Effects of pravastatin on functional capacity in patients with chronic obstructive pulmonary disease and pulmonary hypertension. Clin Sci (Lond) 116:497–505

    CAS  Article  Google Scholar 

  55. 55.

    Kaczmarek P, Sladek K, Skucha W, Rzeszutko M, Iwaniec T, Dziedzina S, Szczeklik A (2010) The influence of simvastatin on selected inflammatory markers in patients with chronic obstructive pulmonary disease. Pol Arch Med Wewn 120:11–17

    CAS  PubMed  Google Scholar 

  56. 56.

    Lee TM, Lin MS, Chang NC (2008) Usefulness of C-reactive protein and interleukin-6 as predictors of outcomes in patients with chronic obstructive pulmonary disease receiving pravastatin. Am J Cardiol 101:530–535

    CAS  Article  PubMed  Google Scholar 

  57. 57.

    Reed RM, Iacono A, DeFilippis A, Jones S, Eberlein M, Lechtzin N, Girgis RE (2011) Statin therapy is associated with decreased pulmonary vascular pressures in severe COPD. COPD 8:96–102

    Article  PubMed  Google Scholar 

  58. 58.

    Moosavi SA, Raji H, Faghankhani M, Yazdani R, Esmaeili M (2013) Evaluation of the effects of atorvastatin on the treatment of secondary pulmonary hypertension due to chronic obstructive pulmonary diseases: a randomized controlled trial. Iran Red Crescent Med J 15:649–654

    Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Peinado VI, Pizarro S, Barbera JA (2008) Pulmonary vascular involvement in COPD. Chest 134:808–814

    CAS  Article  PubMed  Google Scholar 

  60. 60.

    Greiner S, Jud A, Aurich M, Hess A, Hilbel T, Hardt S, Katus HA, Mereles D (2014) Reliability of noninvasive assessment of systolic pulmonary artery pressure by Doppler echocardiography compared to right heart catheterization: analysis in a large patient population. J Am Heart Assoc 3:4

    Article  Google Scholar 

Download references

Author information



Corresponding author

Correspondence to Ronald Zolty.

Ethics declarations

Conflict of interest


Additional information

L. Holzhauser, N. Hovnanians, and P. Eshtehardi contributed equally to this manuscript.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Holzhauser, L., Hovnanians, N., Eshtehardi, P. et al. Statin therapy improves survival in patients with severe pulmonary hypertension: a propensity score matching study. Heart Vessels 32, 969–976 (2017).

Download citation


  • Statin
  • Pulmonary hypertension
  • Mortality