Log in | Register

Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis

Damon P. Eisen
Review
Volume 38, Issue 8 / August , 2012

Pages 1249 - 1257

Abstract

Introduction

Acetyl salicylic acid (ASA) and nonsteroidal anti-inflammatory drugs (NSAIDs) may have potential as adjunctive agents for sepsis.

Materials

This review considers the large body of literature that indicates a basis for sepsis therapy with ASA and suggests an agenda for future intervention studies in sepsis prevention and treatment. ASA and NSAIDs have beneficial effects in numerous experimental models of sepsis. Low doses of ASA of 100 mg/day or less trigger synthesis of lipoxins that are anti-inflammatory and aid in resolution of inflammation. Higher doses of ASA and NSAIDs act to reduce NF-κB stimulation and inhibit numerous septic pathways. While a previous randomised controlled trial of ibuprofen failed to show a reduction in mortality in sepsis, it did reduce clinical manifestations of sepsis. More recent observational studies have shown reduction in sepsis or acute lung injury leading to lower mortality in ICU patients treated with ASA.

Conclusions

Low-dose ASA appears to be beneficial in the prevention and treatment of sepsis and SIRS. If proven, this intervention would have a major, cost-effective impact on sepsis care.

Keywords

References

  1. Sneader W (2000) The discovery of aspirin: a reappraisal. BMJ 321:1591–1594
    • View reference on PubMed
    • View reference on publisher's website
  2. Goodman SG, Menon V, Cannon CP, Steg G, Ohman EM, Harrington RA (2008) Acute ST-segment elevation myocardial infarction: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 133:708S–775S
    • View reference on PubMed
    • View reference on publisher's website
  3. Yalpani N, Raskin I (1993) Salicylic acid: a systemic signal in induced plant disease resistance. Trends Microbiol 1:88–92
    • View reference on PubMed
    • View reference on publisher's website
  4. Claria J, Serhan CN (1995) Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc Natl Acad Sci USA 92:9475–9479
    • View reference on PubMed
    • View reference on publisher's website
  5. Spite M, Serhan CN (2010) Novel lipid mediators promote resolution of acute inflammation: impact of aspirin and statins. Circ Res 107:1170–1184
    • View reference on PubMed
    • View reference on publisher's website
  6. Kopp E, Ghosh S (1994) Inhibition of NF-kappa B by sodium salicylate and aspirin. Science 265:956–959
    • View reference on PubMed
    • View reference on publisher's website
  7. Bernard GR, Wheeler AP, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christman BW, Dupont WD, Higgins SB, Swindell BB (1997) The effects of ibuprofen on the physiology and survival of patients with sepsis. The Ibuprofen in Sepsis Study Group. N Engl J Med 336:912–918
    • View reference on PubMed
    • View reference on publisher's website
  8. Paul-Clark MJ, Van Cao T, Moradi-Bidhendi N, Cooper D, Gilroy DW (2004) 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J Exp Med 200:69–78
    • View reference on PubMed
    • View reference on publisher's website
  9. Morris T, Stables M, Hobbs A, de Souza P, Colville-Nash P, Warner T, Newson J, Bellingan G, Gilroy DW (2009) Effects of low-dose aspirin on acute inflammatory responses in humans. J Immunol 183:2089–2096
    • View reference on PubMed
    • View reference on publisher's website
  10. Watson RW, Rotstein OD, Nathens AB, Parodo J, Marshall JC (1997) Neutrophil apoptosis is modulated by endothelial transmigration and adhesion molecule engagement. J Immunol 158:945–953
    • View reference on PubMed
  11. El Kebir D, Jozsef L, Khreiss T, Pan W, Petasis NA, Serhan CN, Filep JG (2007) Aspirin-triggered lipoxins override the apoptosis-delaying action of serum amyloid A in human neutrophils: a novel mechanism for resolution of inflammation. J Immunol 179:616–622
    • View reference on PubMed
  12. El Kebir D, Jozsef L, Pan W, Wang L, Petasis NA, Serhan CN, Filep JG (2009) 15-epi-lipoxin A4 inhibits myeloperoxidase signaling and enhances resolution of acute lung injury. Am J Respir Crit Care Med 180:311–319
    • View reference on PubMed
    • View reference on publisher's website
  13. Negrotto S, Malaver E, Alvarez ME, Pacienza N, D’Atri LP, Pozner RG, Gomez RM, Schattner M (2006) Aspirin and salicylate suppress polymorphonuclear apoptosis delay mediated by proinflammatory stimuli. J Pharmacol Exp Ther 319:972–979
    • View reference on PubMed
    • View reference on publisher's website
  14. Claria J, Planaguma A (2005) Liver: the formation and actions of aspirin-triggered lipoxins. Prostaglandins Leukot Essent Fatty Acids 73:277–282
    • View reference on PubMed
    • View reference on publisher's website
  15. Takada Y, Bhardwaj A, Potdar P, Aggarwal BB (2004) Nonsteroidal anti-inflammatory agents differ in their ability to suppress NF-kappaB activation, inhibition of expression of cyclooxygenase-2 and cyclin D1, and abrogation of tumor cell proliferation. Oncogene 23:9247–9258
    • View reference on PubMed
  16. Oeth P, Mackman N (1995) Salicylates inhibit lipopolysaccharide-induced transcriptional activation of the tissue factor gene in human monocytic cells. Blood 86:4144–4152
    • View reference on PubMed
  17. Weber C, Erl W, Pietsch A, Weber PC (1995) Aspirin inhibits nuclear factor-kappa B mobilization and monocyte adhesion in stimulated human endothelial cells. Circulation 91:1914–1917
    • View reference on PubMed
    • View reference on publisher's website
  18. Yin MJ, Yamamoto Y, Gaynor RB (1998) The anti-inflammatory agents aspirin and salicylate inhibit the activity of I(kappa)B kinase-beta. Nature 396:77–80
    • View reference on PubMed
    • View reference on publisher's website
  19. Zingarelli B, Sheehan M, Wong HR (2003) Nuclear factor-kappaB as a therapeutic target in critical care medicine. Crit Care Med 31:S105–S111
    • View reference on PubMed
    • View reference on publisher's website
  20. Palma M, Bayer A, Kupferwasser LI, Joska T, Yeaman MR, Cheung A (2006) Salicylic acid activates sigma factor B by rsbU-dependent and -independent mechanisms. J Bacteriol 188:5896–5903
    • View reference on PubMed
    • View reference on publisher's website
  21. Kupferwasser LI, Yeaman MR, Nast CC, Kupferwasser D, Xiong YQ, Palma M, Cheung AL, Bayer AS (2003) Salicylic acid attenuates virulence in endovascular infections by targeting global regulatory pathways in Staphylococcus aureus. J Clin Invest 112:222–233
    • View reference on PubMed
  22. Que YA, Haefliger JA, Piroth L, Francois P, Widmer E, Entenza JM, Sinha B, Herrmann M, Francioli P, Vaudaux P, Moreillon P (2005) Fibrinogen and fibronectin binding cooperate for valve infection and invasion in Staphylococcus aureus experimental endocarditis. J Exp Med 201:1627–1635
    • View reference on PubMed
    • View reference on publisher's website
  23. Xiong YQ, Willard J, Yeaman MR, Cheung AL, Bayer AS (2006) Regulation of Staphylococcus aureus alpha-toxin gene (hla) expression by agr, sarA, and sae in vitro and in experimental infective endocarditis. J Infect Dis 194:1267–1275
    • View reference on PubMed
    • View reference on publisher's website
  24. Clifton DR, Rydkina E, Freeman RS, Sahni SK (2005) NF-kappaB activation during Rickettsia rickettsii infection of endothelial cells involves the activation of catalytic IkappaB kinases IKKalpha and IKKbeta and phosphorylation-proteolysis of the inhibitor protein IkappaBalpha. Infect Immun 73:155–165
    • View reference on PubMed
    • View reference on publisher's website
  25. Kupferwasser LI, Yeaman MR, Shapiro SM, Nast CC, Sullam PM, Filler SG, Bayer AS (1999) Acetylsalicylic acid reduces vegetation bacterial density, hematogenous bacterial dissemination, and frequency of embolic events in experimental Staphylococcus aureus endocarditis through antiplatelet and antibacterial effects. Circulation 99:2791–2797
    • View reference on PubMed
    • View reference on publisher's website
  26. Bayer AS, Ramos MD, Menzies BE, Yeaman MR, Shen AJ, Cheung AL (1997) Hyperproduction of alpha-toxin by Staphylococcus aureus results in paradoxically reduced virulence in experimental endocarditis: a host defense role for platelet microbicidal proteins. Infect Immun 65:4652–4660
    • View reference on PubMed
  27. Nicolau DP, Marangos MN, Nightingale CH, Quintiliani R (1995) Influence of aspirin on development and treatment of experimental Staphylococcus aureus endocarditis. Antimicrob Agents Chemother 39:1748–1751
    • View reference on PubMed
    • View reference on publisher's website
  28. Anavekar NS, Tleyjeh IM, Mirzoyev Z, Steckelberg JM, Haddad C, Khandaker MH, Wilson WR, Chandrasekaran K, Baddour LM (2007) Impact of prior antiplatelet therapy on risk of embolism in infective endocarditis. Clin Infect Dis 44:1180–1186
    • View reference on PubMed
    • View reference on publisher's website
  29. Eisen DP, Corey GR, McBryde ES, Fowler VG Jr, Miro JM, Cabell CH, Street AC, Paiva MG, Ionac A, Tan RS, Tribouilloy C, Pachirat O, Jones SB, Chipigina N, Naber C, Pan A, Ravasio V, Gattringer R, Chu VH, Bayer AS (2009) Reduced valve replacement surgery and complication rate in Staphylococcus aureus endocarditis patients receiving acetyl-salicylic acid. J Infect 58:332–338
    • View reference on PubMed
    • View reference on publisher's website
  30. Chan KL, Dumesnil JG, Cujec B, Sanfilippo AJ, Jue J, Turek MA, Robinson TI, Moher D (2003) A randomized trial of aspirin on the risk of embolic events in patients with infective endocarditis. J Am Coll Cardiol 42:775–780
    • View reference on PubMed
    • View reference on publisher's website
  31. Almqvist PM, Kuenzig M, Schwartz SI (1984) Treatment of experimental canine endotoxin shock with ibuprofen, a cyclooxygenase inhibitor. Circ Shock 13:227–232
    • View reference on PubMed
  32. Sigurdsson GH, Youssef HA, Owunnwanne A (1994) Effects of two different inhibitors of the arachidonic acid metabolism on platelet sequestration in endotoxic shock. Res Exp Med (Berl) 194:287–295
    • View reference on publisher's website
  33. Itoh H, Cicala C, Douglas GJ, Page CP (1996) Platelet accumulation induced by bacterial endotoxin in rats. Thromb Res 83:405–419
    • View reference on PubMed
    • View reference on publisher's website
  34. Sigurdsson GH, Christenson JT, el-Rakshy MB, Sadek S (1992) Intestinal platelet trapping after traumatic and septic shock. An early sign of sepsis and multiorgan failure in critically ill patients? Crit Care Med 20:458–467
    • View reference on PubMed
    • View reference on publisher's website
  35. Singer G, Urakami H, Specian RD, Stokes KY, Granger DN (2006) Platelet recruitment in the murine hepatic microvasculature during experimental sepsis: role of neutrophils. Microcirculation 13:89–97
    • View reference on PubMed
    • View reference on publisher's website
  36. Vincent JL, Yagushi A, Pradier O (2002) Platelet function in sepsis. Crit Care Med 30:S313–S317
    • View reference on PubMed
    • View reference on publisher's website
  37. Keane C, Tilley D, Cunningham A, Smolenski A, Kadioglu A, Cox D, Jenkinson HF, Kerrigan SW (2010) Invasive Streptococcus pneumoniae trigger platelet activation via Toll-like receptor 2. J Thromb Haemost 8:2757–2765
    • View reference on PubMed
    • View reference on publisher's website
  38. Hagiwara S, Iwasaka H, Hasegawa A, Oyama M, Imatomi R, Uchida T, Noguchi T (2011) Adenosine diphosphate receptor antagonist clopidogrel sulfate attenuates LPS-induced systemic inflammation in a rat model. Shock 35:289–292
    • View reference on PubMed
    • View reference on publisher's website
  39. Seidel M, Winning J, Claus RA, Bauer M, Losche W (2009) Beneficial effect of clopidogrel in a mouse model of polymicrobial sepsis. J Thromb Haemost 7:1030–1032
    • View reference on PubMed
    • View reference on publisher's website
  40. Sibelius U, Grandel U, Buerke M, Mueller D, Kiss L, Kraemer HJ, Braun-Dullaeus R, Haberbosch W, Seeger W, Grimminger F (2000) Staphylococcal alpha-toxin provokes coronary vasoconstriction and loss in myocardial contractility in perfused rat hearts: role of thromboxane generation. Circulation 101:78–85
    • View reference on PubMed
    • View reference on publisher's website
  41. Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer HJ, Mayer K, Bohle RM, Seeger W, Grimminger F, Sibelius U (2000) Endotoxin-induced myocardial tumor necrosis factor-alpha synthesis depresses contractility of isolated rat hearts: evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production. Circulation 102:2758–2764
    • View reference on PubMed
    • View reference on publisher's website
  42. Jarrar D, Kuebler JF, Rue LW 3rd, Matalon S, Wang P, Bland KI, Chaudry IH (2002) Alveolar macrophage activation after trauma-hemorrhage and sepsis is dependent on NF-kappaB and MAPK/ERK mechanisms. Am J Physiol Lung Cell Mol Physiol 283:L799–L805
    • View reference on PubMed
  43. Chen ZT, Li SL, Cai EQ, Wu WL, Jin JS, Zhu B (2003) LPS induces pulmonary intravascular macrophages producing inflammatory mediators via activating NF-kappaB. J Cell Biochem 89:1206–1214
    • View reference on PubMed
    • View reference on publisher's website
  44. Walmrath D, Scharmann M, Konig R, Pilch J, Grimminger F, Seeger W (1993) Staphylococcal alpha-toxin induced ventilation-perfusion mismatch in isolated blood-free perfused rabbit lungs. J Appl Physiol 74:1972–1980
    • View reference on PubMed
    • View reference on publisher's website
  45. Walmrath D, Griebner M, Kolb B, Grimminger F, Galanos C, Schade U, Seeger W (1993) Endotoxin primes perfused rabbit lungs for enhanced vasoconstrictor response to staphylococcal alpha-toxin. Am Rev Respir Dis 148:1179–1186
    • View reference on PubMed
  46. Steudel W, Kramer HJ, Degner D, Rosseau S, Schutte H, Walmrath D, Seeger W (1997) Endotoxin priming of thromboxane-related vasoconstrictor responses in perfused rabbit lungs. J Appl Physiol 83:18–24
    • View reference on PubMed
  47. Jin SW, Zhang L, Lian QQ, Liu D, Wu P, Yao SL, Ye DY (2007) Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1. Anesth Analg 104:369–377
    • View reference on PubMed
    • View reference on publisher's website
  48. Fukunaga K, Kohli P, Bonnans C, Fredenburgh LE, Levy BD (2005) Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J Immunol 174:5033–5039
    • View reference on PubMed
  49. Northover BJ, Subramanian G (1962) Analgesic-antipyretic drugs as antagonists of endotoxin shock in dogs. J Pathol Bacteriol 83:463–468
    • View reference on PubMed
    • View reference on publisher's website
  50. Hinshaw LB, Solomon LA, Erdos EG, Reins DA, Gunter BJ (1967) Effects of acetylsalicylic acid on the canine response to endotoxin. J Pharmacol Exp Ther 157:665–671
    • View reference on PubMed
  51. Halushka PV, Wise WC, Cook JA (1981) Protective effects of aspirin in endotoxic shock. J Pharmacol Exp Ther 218:464–469
    • View reference on PubMed
  52. Jacobs ER, Soulsby ME, Bone RC, Wilson FJ Jr, Hiller FC (1982) Ibuprofen in canine endotoxin shock. J Clin Invest 70:536–541
    • View reference on PubMed
    • View reference on publisher's website
  53. Adams T Jr, Traber DL (1982) The effects of a prostaglandin synthetase inhibitor, ibuprofen, on the cardiopulmonary response to endotoxin in sheep. Circ Shock 9:481–489
    • View reference on PubMed
  54. Peevy KJ, Ronnlund RD, Chartrand SA, Boerth RC, Longenecker GL (1988) Ibuprofen in experimental group B streptococcal shock. Circ Shock 24:35–41
    • View reference on PubMed
  55. Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ (2001) Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol 281:L537–L543
    • View reference on PubMed
  56. Remick DG, Newcomb DE, Bolgos GL, Call DR (2000) Comparison of the mortality and inflammatory response of two models of sepsis: lipopolysaccharide vs. cecal ligation and puncture. Shock 13:110–116
    • View reference on PubMed
    • View reference on publisher's website
  57. Chiang N, Bermudez EA, Ridker PM, Hurwitz S, Serhan CN (2004) Aspirin triggers antiinflammatory 15-epi-lipoxin A4 and inhibits thromboxane in a randomized human trial. Proc Natl Acad Sci USA 101:15178–15183
    • View reference on PubMed
    • View reference on publisher's website
  58. Hennekens CH, Schneider WR, Pokov A, Hetzel S, Demets D, Serebruany V, Schroder H (2010) A randomized trial of aspirin at clinically relevant doses and nitric oxide formation in humans. J Cardiovasc Pharmacol Ther 15:344–348
    • View reference on PubMed
    • View reference on publisher's website
  59. Cerletti C, Dell’Elba G, Manarini S, Pecce R, Di Castelnuovo A, Scorpiglione N, Feliziani V, de Gaetano G (2003) Pharmacokinetic and pharmacodynamic differences between two low dosages of aspirin may affect therapeutic outcomes. Clin Pharmacokinet 42:1059–1070
    • View reference on PubMed
    • View reference on publisher's website
  60. Cerletti C, Marchi S, Lauri D, Domanin M, Lorenzi G, Urso R, Dejana E, Latini R, de Gaetano G (1987) Pharmacokinetics of enteric-coated aspirin and inhibition of platelet thromboxane A2 and vascular prostacyclin generation in humans. Clin Pharmacol Ther 42:175–180
    • View reference on PubMed
    • View reference on publisher's website
  61. Needs CJ, Brooks PM (1985) Clinical pharmacokinetics of the salicylates. Clin Pharmacokinet 10:164–177
    • View reference on PubMed
    • View reference on publisher's website
  62. Muir N, Nichols JD, Stillings MR, Sykes J (1997) Comparative bioavailability of aspirin and paracetamol following single dose administration of soluble and plain tablets. Curr Med Res Opin 13:491–500
    • View reference on PubMed
    • View reference on publisher's website
  63. Derhaschnig U, Schweeger-Exeli I, Marsik C, Cardona F, Minuz P, Jilma B (2010) Effects of aspirin and NO-aspirin (NCX 4016) on platelet function and coagulation in human endotoxemia. Platelets 21:320–328
    • View reference on PubMed
    • View reference on publisher's website
  64. Pernerstorfer T, Stohlawetz P, Hollenstein U, Dzirlo L, Eichler HG, Kapiotis S, Jilma B, Speiser W (1999) Endotoxin-induced activation of the coagulation cascade in humans: effect of acetylsalicylic acid and acetaminophen. Arterioscler Thromb Vasc Biol 19:2517–2523
    • View reference on PubMed
    • View reference on publisher's website
  65. Jilma B, Blann A, Pernerstorfer T, Stohlawetz P, Eichler HG, Vondrovec B, Amiral J, Richter V, Wagner OF (1999) Regulation of adhesion molecules during human endotoxemia. No acute effects of aspirin. Am J Respir Crit Care Med 159:857–863
    • View reference on PubMed
  66. Martich GD, Danner RL, Ceska M, Suffredini AF (1991) Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med 173:1021–1024
    • View reference on PubMed
    • View reference on publisher's website
  67. Arons MM, Wheeler AP, Bernard GR, Christman BW, Russell JA, Schein R, Summer WR, Steinberg KP, Fulkerson W, Wright P, Dupont WD, Swindell BB (1999) Effects of ibuprofen on the physiology and survival of hypothermic sepsis. Ibuprofen in Sepsis Study Group. Crit Care Med 27:699–707
    • View reference on PubMed
    • View reference on publisher's website
  68. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr (2001) Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med 344:699–709
    • View reference on PubMed
    • View reference on publisher's website
  69. Winning J, Neumann J, Kohl M, Claus RA, Reinhart K, Bauer M, Losche W (2010) Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med 38:32–37
    • View reference on PubMed
    • View reference on publisher's website
  70. Winning J, Reichel J, Eisenhut Y, Hamacher J, Kohl M, Deigner HP, Claus RA, Bauer M, Losche W (2009) Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms. Platelets 20:50–57
    • View reference on PubMed
    • View reference on publisher's website
  71. Legras A, Giraudeau B, Jonville-Bera AP, Camus C, Francois B, Runge I, Kouatchet A, Veinstein A, Tayoro J, Villers D, Autret-Leca E (2009) A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock. Crit Care 13:R43
    • View reference on PubMed
    • View reference on publisher's website
  72. Eisen DP, Reid D, McBryde ES (2012) Acetyl salicylic acid usage and mortality in critically-ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med. doi:10.1097/CCM.0b013e318246b9df
  73. Erlich JM, Talmor DS, Cartin-Ceba R, Gajic O, Kor DJ (2011) Prehospitalization antiplatelet therapy is associated with a reduced incidence of acute lung injury: a population-based cohort study. Chest 139:289–295
    • View reference on PubMed
    • View reference on publisher's website
  74. Kor DJ, Erlich J, Gong MN, Malinchoc M, Carter RE, Gajic O, Talmor DS (2011) Association of prehospitalization aspirin therapy and acute lung injury: results of a multicenter international observational study of at-risk patients. Crit Care Med 39:2393–2400
    • View reference on PubMed
    • View reference on publisher's website
  75. O’Neal HR Jr, Koyama T, Koehler EA, Siew E, Curtis BR, Fremont RD, May AK, Bernard GR, Ware LB (2011) Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome. Crit Care Med 39:1343–1350
    • View reference on PubMed
    • View reference on publisher's website
  76. Clive DM, Stoff JS (1984) Renal syndromes associated with nonsteroidal antiinflammatory drugs. N Engl J Med 310:563–572
    • View reference on PubMed
    • View reference on publisher's website
  77. Huang ES, Strate LL, Ho WW, Lee SS, Chan AT (2011) Long-term use of aspirin and the risk of gastrointestinal bleeding. Am J Med 124:426–433
    • View reference on PubMed
    • View reference on publisher's website
  78. Nelson MR, Reid CM, Ames DA, Beilin LJ, Donnan GA, Gibbs P, Johnston CI, Krum H, Storey E, Tonkin A, Wolfe R, Woods R, McNeil JJ (2008) Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study. Med J Aust 189:105–109
    • View reference on PubMed

Sign In

Connect with ICM

Top 5 Articles Editors Picks Supplement