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Comparative Safety of Interleukin-1 Blockade With Anakinra in Patients With ST-Segment Elevation Acute Myocardial Infarction (from the VCU-ART and VCU-ART2 Pilot Studies)

Published:November 13, 2014DOI:https://doi.org/10.1016/j.amjcard.2014.11.003
      Two pilot studies of interleukin-1 (IL-1) blockade in ST-segment elevation myocardial infarction (STEMI) showed blunted acute inflammatory response and overall favorable outcomes at 3 months follow-up. We hereby present a patient-level pooled analysis with extended follow-up of 40 patients with clinically stable STEMI randomized to anakinra, a recombinant IL-1 receptor antagonist, 100 mg/day for 14 days or placebo in a double-blinded fashion. End points included death, cardiac death, recurrent acute myocardial infarction (AMI), stroke, unstable angina, and symptomatic heart failure. Median follow-up was 28 (interquartile range 3 to 38) months. Sixteen patients (40%) had a total of 22 adverse cardiovascular events: 1 cardiac death, 4 recurrent AMI, 5 episodes of unstable angina pectoris requiring hospitalization and/or urgent revascularization, and 11 new diagnoses of heart failure. Treatment with anakinra was associated with a hazard ratio of 1.08 (95% confidence interval 0.31 to 3.74, p = 0.90) for the combined end point of death, recurrent AMI, unstable angina pectoris, or stroke and a hazard ratio of 0.16 (95% confidence interval 0.03 to 0.76, p = 0.008) for death or heart failure. In conclusion, IL-1 blockade with anakinra for 2 weeks appears, therefore, to have a neutral effect on recurrent ischemic events, whereas it may prevent new-onset heart failure long term after STEMI.
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      References

        • Biasucci L.M.
        • Koenig W.
        • Mair J.
        • Mueller C.
        • Plebani M.
        • Lindahl B.
        • Rifai N.
        • Venge P.
        • Hamm C.
        • Giannitsis E.
        • Huber K.
        • Galvani M.
        • Tubaro M.
        • Collinson P.
        • Alpert J.S.
        • Hasin Y.
        • Katus H.
        • Jaffe A.S.
        • Thygesen K.
        Study Group on Biomarkers in Cardiology of the Acute Cardiovascular Care Association of the European Society of Cardiology. How to use C-reactive protein in acute coronary care.
        Eur Heart J. 2013; 34: 3687-3690
        • Seropian I.M.
        • Seropian I.M.
        • Toldo S.
        • Van Tassell B.W.
        • Abbate A.
        Anti-inflammatory strategies for ventricular remodeling following ST-segment elevation acute myocardial infarction.
        J Am Coll Cardiol. 2014; 63: 1593-1603
        • Dinarello C.A.
        Interleukin-1 in the pathogenesis and treatment of inflammatory diseases.
        Blood. 2011; 117: 3720-3732
        • Van Tassell B.W.
        • Toldo S.
        • Mezzaroma E.
        • Abbate A.
        Targeting interleukin-1 in heart disease.
        Circulation. 2013; 128: 1910-1923
        • Abbate A.
        • Kontos M.C.
        • Grizzard J.D.
        • Biondi-Zoccai G.G.
        • Van Tassell B.W.
        • Robati R.
        • Roach L.M.
        • Arena R.A.
        • Roberts C.S.
        • Varma A.
        • Gelwix C.C.
        • Salloum F.N.
        • Hastillo A.
        • Dinarello C.A.
        • Vetrovec G.W.
        • VCU-ART Investigators
        Interleukin-1 blockade with anakinra to prevent adverse cardiac remodeling after acute myocardial infarction (Virginia Commonwealth University Anakinra Remodeling Trial [VCU-ART] Pilot study).
        Am J Cardiol. 2010; 105: 1371-1377
        • Abbate A.
        • Van Tassell B.W.
        • Biondi-Zoccai G.
        • Kontos M.C.
        • Grizzard J.D.
        • Spillman D.W.
        • Oddi C.
        • Roberts C.S.
        • Melchior R.D.
        • Mueller G.H.
        • Abouzaki N.A.
        • Rengel L.R.
        • Varma A.
        • Gambill M.L.
        • Falcao R.A.
        • Voelkel N.F.
        • Dinarello C.A.
        • Vetrovec G.W.
        Effects of interleukin-1 blockade with anakinra on adverse cardiac remodeling and heart failure after acute myocardial infarction [from the Virginia Commonwealth University-Anakinra Remodeling Trial (2) (VCU-ART2) pilot study].
        Am J Cardiol. 2013; 111: 1394-1400
        • Morton A.C.
        • Rothman A.M.
        • Greenwood J.P.
        • Gunn J.
        • Chase A.
        • Clarke B.
        • Hall A.S.
        • Fox K.
        • Foley C.
        • Banya W.
        • Wang D.
        • Flather M.D.
        • Crossman D.C.
        The effect of Interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study.
        Eur Heart J. 2014, Epub ahead of print;
        • Van Tassell B.W.
        • Arena R.A.
        • Toldo S.
        • Mezzaroma E.
        • Azam T.
        • Seropian I.M.
        • Shah K.
        • Canada J.
        • Voelkel N.F.
        • Dinarello C.A.
        • Abbate A.
        Enhanced Interleukin-1 activity contributes to exercise intolerance in patients with systolic heart failure.
        PLoS One. 2012; 7: e33438
        • Van Tassell B.W.
        • Arena R.
        • Biondi-Zoccai G.
        • McNair Canada J.
        • Oddi C.
        • Abouzaki N.A.
        • Jahangiri A.
        • Falcao R.A.
        • Kontos M.C.
        • Shah K.B.
        • Voelkel N.F.
        • Dinarello C.A.
        • Abbate A.
        Effects of interleukin-1 blockade with anakinra on aerobic exercise capacity in patients with heart failure and preserved ejection fraction (from the D-HART pilot study).
        Am J Cardiol. 2014; 113: 321-327
        • Ridker P.M.
        • Howard C.P.
        • Walter V.
        • Everett B.
        • Libby P.
        • Hensen J.
        • Thuren T.
        CANTOS Pilot Investigative Group. Effects of Interleukin-1β inhibition with canakinumab on hemoglobin A1c, lipids, C-reactive protein, interleukin-6, and fibrinogen: a phase IIb randomized, placebo-controlled trial.
        Circulation. 2012; 126: 2739-2748
        • Cavelti-Weder C.
        • Babians-Brunner A.
        • Keller C.
        • Stahel M.A.
        • Kurz-Levin M.
        • Zayed H.
        • Solinger A.M.
        • Mandrup-Poulsen T.
        • Dinarello C.A.
        • Donath M.Y.
        Effects of gevokizumab on glycemia and inflammatory markers in type 2 diabetes.
        Diabetes Care. 2012; 35: 1654-1662
        • Abbate A.
        • Dinarello C.A.
        Anti-inflammatory therapies in acute coronary syndromes: is IL-1 blockade a solution?.
        Eur Heart J. 2014; (Epub ahead of print)
        • Thygesen K.
        • Alpert J.S.
        • Jaffe A.S.
        • Simoons M.L.
        • Chaitman B.R.
        • White H.D.
        • Thygesen K.
        • Alpert J.S.
        • White H.D.
        • Jaffe A.S.
        • Katus H.A.
        • Apple F.S.
        • Lindahl B.
        • Morrow D.A.
        • Chaitman B.R.
        • Clemmensen P.M.
        • Johanson P.
        • Hod H.
        • Underwood R.
        • Bax J.J.
        • Bonow J.J.
        • Pinto F.
        • Gibbons R.J.
        • Fox K.A.
        • Atar D.
        • Newby L.K.
        • Galvani M.
        • Hamm C.W.
        • Uretsky B.F.
        • Steg P.G.
        • Wijns W.
        • Bassand J.P.
        • Menasche P.
        • Ravkilde J.
        • Ohman E.M.
        • Antman E.M.
        • Wallentin L.C.
        • Armstrong P.W.
        • Simoons M.L.
        • Januzzi J.L.
        • Nieminen M.S.
        • Gheorghiade M.
        • Filippatos G.
        • Luepker R.V.
        • Fortmann S.P.
        • Rosamond W.D.
        • Levy D.
        • Wood D.
        • Smith S.C.
        • Hu D.
        • Lopez-Sendon J.L.
        • Robertson R.M.
        • Weaver D.
        • Tendera M.
        • Bove A.A.
        • Parkhomenko A.N.
        • Vasilieva E.J.
        • Mendis S.
        • Bax J.J.
        • Baumgartner H.
        • Ceconi C.
        • Dean V.
        • Deaton C.
        • Fagard R.
        • Funck-Brentano C.
        • Hasdai D.
        • Hoes A.
        • Kirchhof P.
        • Knuuti J.
        • Kolh P.
        • McDonagh T.
        • Moulin C.
        • Popescu B.A.
        • Reiner Z.
        • Sechtem U.
        • Sirnes P.A.
        • Tendera M.
        • Torbicki A.
        • Vahanian A.
        • Windecker S.
        • Morais J.
        • Aguiar C.
        • Almahmeed W.
        • Arnar D.O.
        • Barili F.
        • Bloch K.D.
        • Bolger A.F.
        • Botker H.E.
        • Bozkurt B.
        • Bugiardini R.
        • Cannon C.
        • de Lemos J.
        • Eberli F.R.
        • Escobar E.
        • Hlatky M.
        • James S.
        • Kern K.B.
        • Moliterno D.J.
        • Mueller C.
        • Neskovic A.N.
        • Pieske B.M.
        • Schulman S.P.
        • Storey R.F.
        • Taubert K.A.
        • Vranckx P.
        • Wagner D.R.
        • Joint ESC/ACCF/AHA/WHF Task Force for Universal Definition of Myocardial Infarction
        • Authors/Task Force Members Chairpersons
        • Biomarker Subcommittee
        • ECG Subcommittee
        • Imaging Subcommittee
        • Classification Subcommittee
        • Intervention Subcommittee
        • Trials & Registries Subcommittee
        • Trials & Registries Subcommittee
        • Trials & Registries Subcommittee
        • Trials & Registries Subcommittee
        • ESC Committee for Practice Guidelines (CPG)
        • Document Reviewers
        Third universal definition of myocardial infarction.
        J Am Coll Cardiol. 2012; 60: 1581-1598
        • Eapen Z.J.
        • Tang W.H.
        • Felker G.M.
        • Hernandez A.F.
        • Mahaffey K.W.
        • Lincoff A.M.
        • Roe M.T.
        Defining heart failure end points in ST-segment elevation myocardial infarction trials: integrating past experiences to chart a path forward.
        Circ Cardiovasc Qual Outcomes. 2012; 5: 594-600
        • Abbate A.
        • Biondi-Zoccai G.G.
        • Brugaletta S.
        • Liuzzo G.
        • Biasucci L.M.
        C-reactive protein and other inflammatory biomarkers as predictors of outcome following acute coronary syndromes.
        Semin Vasc Med. 2003; 3: 375-384
        • Crossman D.C.
        • Morton A.C.
        • Gunn J.P.
        • Greenwood J.P.
        • Hall A.S.
        • Fox K.A.
        • Lucking A.J.
        • Flather M.D.
        • Lees B.
        • Foley C.E.
        Investigation of the effect of Interleukin-1 receptor antagonist (IL-1ra) on markers of inflammation in non-ST elevation acute coronary syndromes (The MRC-ILA-HEART Study).
        Trials. 2008; 9: 8
        • Ridker P.M.
        • Thuren T.
        • Zalewski A.
        • Libby P.
        Interleukin-1β 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
        • Abbate A.
        • Salloum F.
        • Vecile E.
        • Das A.
        • Hoke N.
        • Straino S.
        • Biondi-Zoccai G.G.L.
        • Houser J.
        • Qureshi I.
        • Ownby E.
        • Gustini E.
        • Biasucci L.
        • Severino A.
        • Capogrossi M.
        • Vetrovec G.
        • Crea F.
        • Baldi A.
        • Kukreja R.
        • Dobrina A.
        Anakinra, a recombinant human interleukin-1 receptor antagonist, inhibits apoptosis in experimental acute myocardial infarction.
        Circulation. 2008; 117: 2670-2683
        • Van Tassell B.W.
        • Seropian I.M.
        • Toldo S.
        • Mezzaroma E.
        • Abbate A.
        Interleukin-1β induces a reversible cardiomyopathy in the mouse.
        Inflamm Res. 2013; 62: 637-640
        • Toldo S.
        • Mezzaroma E.
        • Van Tassell B.W.
        • Farkas D.
        • Marchetti C.
        • Voelkel N.F.
        • Abbate A.
        Interleukin-1β blockade improves cardiac remodelling after myocardial infarction without interrupting the inflammasome in the mouse.
        Exp Physiol. 2013; 98: 734-745
        • Toldo S.
        • Mezzaroma E.
        • Bressi E.
        • Marchetti C.
        • Carbone S.
        • Sonnino C.
        • Van Tassell B.W.
        • Abbate A.
        Interleukin-1β blockade improves left ventricular systolic/diastolic function and restores contractility reserve in severe ischemic cardiomyopathy in the mouse.
        J Cardiovasc Pharmacol. 2014; 64: 1-6
      1. VCU-ART3. Available at: www.clinicaltrials.gov/show/NCT01950299. Accessed September 26, 2014.

      2. CANTOS HF, substudy. Available at: www.clinicaltrials.gov/show/NCT01900600. Accessed September 26, 2014.

        • Van Tassell B.W.
        • Raleigh J.M.
        • Abbate A.
        Targeting interleukin-1 in heart failure and inflammatory heart disease.
        Curr Heart Fail Rep. 2014; (Epub ahead of print)