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Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?

  • Statin Drugs (MB Clearfield, Section Editor)
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Abstract

The recent JUPITER trial demonstrated that potent statin therapy reduces by 50 % the risk of heart attack and stroke among men and women with low levels of low-density lipoprotein (LDL)-cholesterol who are at increased vascular risk due to elevated levels of C-reactive protein (CRP), a biomarker of low-grade systemic inflammation. In JUPITER, both absolute risk and the absolute risk reduction with statin therapy were related to the level of CRP, whereas no such relationship was observed for LDL-C. Further, on-treatment levels of CRP and LDL-C were independently associated with residual risk, and the genetic determinants of statin-induced CRP reduction differed from the genetic determinants of statin-induced LDL reduction. Despite these data, it is impossible in any statin trial to establish whether the clinical benefits of treatment are due to LDL-reduction alone, to inflammation inhibition, or to a combination of both processes. To address the hypothesis that lowering inflammation will lower vascular event rates, two large-scale placebo controlled trials using targeted anti-inflammatory agents for the secondary prevention of myocardial infarction have been initiated. The first trial, the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS), is evaluating whether interleukin-1β (IL-1β) inhibition as compared to placebo can reduce rates of recurrent myocardial infarction, stroke, and cardiovascular death among stable coronary artery disease patients who remain at high vascular risk due to persistent elevations of hsCRP (≥ 2 mg/L), despite contemporary secondary prevention strategies. The second trial, the Cardiovascular Inflammation Reduction Trial (CIRT) has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and will evaluate whether low dose methotrexate (target dose 20 mg/week) as compared to placebo will reduce major vascular events among a group of post-myocardial infarction patients with either diabetes or metabolic syndrome, groups known to have high risk on the basis of a persistent pro-inflammatory response. Together, CANTOS and CIRT represent a core test of the inflammation hypothesis of atherothrombosis and the exploration of a potential new phase for cardiovascular therapeutics.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. • Libby P, Ridker PM, Hansson GK. Inflammation in atherosclerosis: from pathophysiology to practice. J Am Coll Cardiol. 2009;54:2129–38. A concise overview of the role of inflammation and atheroslcerosis from both vascular biology and clinical perspectives.

    Article  PubMed  CAS  Google Scholar 

  2. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med. 2000;342:836–43.

    Article  PubMed  CAS  Google Scholar 

  3. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Comparison of C-reactive protein and low-density lipoprotein cholesterol levels in the prediction of first cardiovascular events. N Engl J Med. 2002;347:1557–65.

    Article  PubMed  CAS  Google Scholar 

  4. •• Kaptoge S, Di Angelantonio E, Lowe G, Pepys MB, Thompson SG, Collins R, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant meta-analysis. Lancet. 2010;375:132–40. This meta-analysis of over 54 prospective cohort studies demonstrated that the magnitude of impact inflammation has on future vascular events is at least as large as that of cholesterol or blood pressure, even after adjustment for traditional risk markers.

    Article  PubMed  Google Scholar 

  5. Ridker PM, Buring JE, Rifai N, Cook NR. Development and validation of improved algorithms for the assessment of global cardiovascular risk in women: the Reynolds Risk Score. JAMA. 2007;297:611–9.

    Article  PubMed  CAS  Google Scholar 

  6. • Cook NR, Paynter NP, Eaton CB, Manson JE, Martin LW, Robinson JG, et al. Comparison of the Framingham and Reynolds Risk Scores for global cardiovascular risk prediction in the multiethnic Women’s Health Initiative. Circulation. 2012;125:1748–56. This direct comparison indicates that the Reynolds Risk Score outperforms the more traditional Framingham Risk Score, an important paper since Reynolds includes both CRP and family history.

    Article  PubMed  Google Scholar 

  7. Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, et al. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events (CARE) Investigators. Circulation. 1998;98:839–44.

    Article  PubMed  CAS  Google Scholar 

  8. Ridker PM, Rifai N, Clearfield M, Downs JR, Weis SE, Miles JS, et al. Measurement of C-reactive protein for the targeting of statin therapy in the primary prevention of acute coronary events. N Engl J Med. 2001;344:1959–65.

    Article  PubMed  CAS  Google Scholar 

  9. Morrow DA, de Lemos JA, Sabatine MS, Wiviott SD, Blazing MA, Shui A, et al. Clinical relevance of C-reactive protein during follow-up of patients with acute coronary syndromes in the Aggrastat-to-Zocor Trial. Circulation. 2006;114:281–8.

    Article  PubMed  CAS  Google Scholar 

  10. Nissen SE, Tuzcu EM, Schoenhagen P, Crowe T, Sasiela WJ, Tsai J, et al. Statin therapy, LDL cholesterol, C-reactive protein, and coronary artery disease. N Engl J Med. 2005;352:29–38.

    Article  PubMed  CAS  Google Scholar 

  11. McMurray JJ, Kjekshus J, Gullestad L, Dunselman P, Hjalmarson A, Wedel H, et al. Effects of statin therapy according to plasma high-sensitivity C-reactive protein concentration in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA): a retrospective analysis. Circulation. 2009;120:2188–96.

    Article  PubMed  CAS  Google Scholar 

  12. Ridker PM, Cannon CP, Morrow D, Rifai N, Rose LM, McCabe CH, et al. C-reactive protein levels and outcomes after statin therapy. N Engl J Med. 2005;352:20–8.

    Article  PubMed  CAS  Google Scholar 

  13. •• Braunwald E. Creating controversy where none exists: the important role of C-reactive protein in the CARE, AFCAPS/TexCAPS, PROVE IT, REVERSAL, A to Z, JUPITER, HEART PROTECTION, and ASCOT trials. Eur Heart J. 2012;33:430–2. An excellent overview describing common misunderstadings and controversies with regard to the inflammation hypothesis of atherosclerosis.

    Article  PubMed  Google Scholar 

  14. Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med. 2008;359:2195–207.

    Article  PubMed  CAS  Google Scholar 

  15. Mora S, Glynn RJ, Hsia J, Macfadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia. Results from the Justification for the Use of Statins in Prevention: An intervention trial evaluating rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation. 2010;121:1069–77.

    Article  PubMed  CAS  Google Scholar 

  16. Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker PM. Rosuvastatin for primary prevention in older persons with elevated C-reactive protein and low to average low-density lipoprotein cholesterol levels: exploratory analysis of a randomized trial. Ann Intern Med. 2010;152:488–96.

    PubMed  Google Scholar 

  17. Ridker PM, MacFadyen JG, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al. Number needed to treat with rosuvastatin to prevent first cardiovascular events and death among men and women with low low-density lipoprotein cholesterol and elevated high-sensitivity C-reactive protein: justification for the use of statins in prevention: an intervention trial evaluating rosuvastatin (JUPITER). Circ Cardiovasc Qual Outcomes. 2009;2:616–23.

    Article  PubMed  Google Scholar 

  18. Genest J, McPherson R, Frohlich J, et al. 2009 Canadian Cardiovascular Society/Canadian guidelines for the diagnosis and treatment of dyslipidemia and prevention of cardiovascular disease in the adult—2009 recommendations. Can J Cardiol. 2009;25:567–79.

    Article  PubMed  CAS  Google Scholar 

  19. Glynn RJ, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. A randomized trial of rosuvastatin in the prevention of venous thromboembolism. N Engl J Med. 2009;360:1851–61.

    Article  PubMed  CAS  Google Scholar 

  20. • Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto Jr AM, Kastelein JJ, et al. Reduction in C-reactive protein and LDL cholesterol and cardiovascular event rates after initiation of rosuvastatin: a prospective study of the JUPITER trial. Lancet. 2009;373:1175–82. This paper from the JUPITER trial demonstrates that lowering CRP was as important as lowering LDL-C in terms of preventing first ever vascular events.

    Article  PubMed  CAS  Google Scholar 

  21. Ridker PM, MacFadyen J, Libby P, Glynn RJ. Relation of baseline high-sensitivity C-reactive protein level to cardiovascular outcomes with rosuvastatin in the Justification for Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER). Am J Cardiol. 2010;106:204–9.

    Article  PubMed  CAS  Google Scholar 

  22. Chu AY, Guilianini F, Barratt BJ, Nyberg F, Chasman DI, Ridker PM. Pharmacogenetic determinants of statin-induced reduction in C-reactive protein. Circ Cardiovasc Genet. 2012;5:58–65.

    Article  PubMed  CAS  Google Scholar 

  23. Chasman DI, Guilianini F, MacFadyen J, Barratt BJ, Nyberg F, Ridker PM. Genetic determinants of statini-induced low-density lipoprotein cholesterol reduction. The Justificaton for the Use of statins in Prevention: an Intervention Trial Evalauting Rosuvastatin (JUPITER) Trial. Circ Cardiovasc Genet. 2012;5:257–64.

    Article  PubMed  CAS  Google Scholar 

  24. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost. 2009;7 Suppl 1:332–9.

    Article  PubMed  CAS  Google Scholar 

  25. • Ridker PM, Thuren T, Zalewski A, Libby P. Interleukin-1beta inhibition and the prevention of recurrent cardiovascular events: rationale and design of the Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS). Am Heart J. 2011;162:597–605. This is the formal rationale and design paper for the CANTOS trial and contains full details of the protocol.

    Article  PubMed  CAS  Google Scholar 

  26. •• Duewell P, Kono H, Rayner KJ, Sirois CM, Vladimer G, Bauernfeind FG, et al. NLRP3 inflammasomes are required for atherogenesis and activated by cholesterol crystals. Nature. 2010;464:1357–61. An important biologic paper describing the role played by cholesterol crystals in activating the inflammasome and thus leading to increased interleukin-1 production.

    Article  PubMed  CAS  Google Scholar 

  27. Rajama K, Lappalainen J, Oorni K, Valimaki E, Matikainen S, Kovanen PT, et al. Cholesterol crystals activate the NLRP3 inflammasome in human macrophages: a novel link between cholesterol metabolism and inflammation. PLoS One. 2010;5:e11765.

    Article  Google Scholar 

  28. Razani B, Feng C, Coleman T, et al. Autophagy links inflammasomes to atherosclerotic progression. Cell Metab. 2012;15:534–44.

    Article  PubMed  CAS  Google Scholar 

  29. Dinarello CA. The role of the interleukin-1-receptor antagonist in blocking inflammation mediated by interleukin-1. N Engl J Med. 2000;343:732–4.

    Article  PubMed  CAS  Google Scholar 

  30. Fearon WF, Fearon DT. Inflammation and cardiovascular disease: role of the interleukin-1 receptor antagonist. Circulation. 2008;117:2577–9.

    Article  PubMed  Google Scholar 

  31. Kirii H, Niwa T, Yamada Y, Wada H, Saito K, Iwakura Y, et al. Lack of interleukin-1beta decreases the severity of atherosclerosis in ApoE-deficient mice. Arterioscler Thromb Vasc Biol. 2003;23:656–60.

    Article  PubMed  CAS  Google Scholar 

  32. Isoda K, Shiigai M, Ishigami N, Matsuki T, Horai R, Nishikawa K, et al. Deficiency of interleukin-1 receptor antagonist promotes neointimal formation after injury. Circulation. 2003;108:516–8.

    Article  PubMed  CAS  Google Scholar 

  33. Saag KG, Teng GG, Patkar NM, et al. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis. Arthritis Rheum. 2008;59(6):762–84.

    Article  PubMed  CAS  Google Scholar 

  34. Choi HK, Hernan MA, Seeger JD, Robins JM, Wolfe F. Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study. Lancet. 2002;359(9313):1173–7.

    Article  PubMed  CAS  Google Scholar 

  35. • Micha R, Imamura F, Wyler von Ballmoos M, et al. Systematic review and meta-analysis of methotrexate use and risk of cardiovascular disease. Am J Cardiol. 2011;108:1362–70. A meta-analysis of non-randomized data indicating the reduced rate of vascular events in arthritis patients being treated with low dose methotrexate.

    Article  PubMed  CAS  Google Scholar 

  36. Bernatsky S, Hudson M, Suissa S. Anti-rheumatic drug use and risk of hospitalization for congestive heart failure in rheumatoid arthritis. Rheumatology (Oxford). 2005;44(5):677–80.

    Article  CAS  Google Scholar 

  37. Krishnan E, Lingala VB, Singh G. Declines in mortality from acute myocardial infarction in successive incidence and birth cohorts of patients with rheumatoid arthritis. Circulation. 2004;110:1774–9.

    Article  PubMed  Google Scholar 

  38. Reiss AB, Carsons SE, Anwar K, et al. Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP-1 monocyte/macrophages. Arthritis Rheum. 2008;58(12):3675–83.

    Article  PubMed  CAS  Google Scholar 

  39. Coomes E, Chan ES, Reiss AB. Methotrexate in atherogenesis and cholesterol metabolism. Cholesterol 2011;503028.

  40. Bulgarelli A, Dias AAM, Caramelli B, Maranhao RC. Treatment with methotrexate inhibits atherogenesis in cholesterol-fed rabbits. J Cardiovasc Pharmacol. 2012;59:308–14.

    Article  PubMed  CAS  Google Scholar 

  41. •• Donath MY, Schoelson SE. Type 2 diabetes as an inflammatory disease. Nat Rev Immunol. 2011;11:98–107. An excellent overview of the role played by innate and acquired immunity in the development of diabetes.

    Article  PubMed  CAS  Google Scholar 

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Disclosure

P.M. Ridker: Listed as a co-inventor on patents held by the Brigham and Women’s Hospital (BWH) that relate to the use of inflammatory biomarkers in cardiovascular disease and diabetes that have been licensed to Siemens and AstraZeneca. Dr. Ridker is the Principle Investigator of the Cardiovascular Inflammation Reduction Trial (CIRT) (funded by the National Heart Lung and Blood Institute) and the Principle Investigator of the Canakinumab Anti-inflammaatory Throbosis Outcomes Study (CANTOS) (funded by Novartis). Neither Dr. Ridker nor the BWH will receive any royalties related to the use of the CRP test in either of these trials.

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  1. Center for Cardiovascular Disease Prevention and the Cardiovascular Division, Brigham and Women’s Hospital, Harvard Medical School, 900 Commonwealth Avenue East, Boston, MA, 02215, USA

    Paul M Ridker

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Ridker, P.M. Moving Beyond JUPITER: Will Inhibiting Inflammation Reduce Vascular Event Rates?. Curr Atheroscler Rep 15, 295 (2013). https://doi.org/10.1007/s11883-012-0295-3

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