Effects of Interleukin-1β Inhibition on Blood Pressure, Incident Hypertension, and Residual Inflammatory Risk: A Secondary Analysis of CANTOS

Alexander Mk Rothman, Jean MacFadyen, Tom Thuren, Alastair Webb, David G Harrison, Tomasz J Guzik, Peter Libby, Robert J Glynn, Paul M Ridker, Alexander Mk Rothman, Jean MacFadyen, Tom Thuren, Alastair Webb, David G Harrison, Tomasz J Guzik, Peter Libby, Robert J Glynn, Paul M Ridker

Abstract

While hypertension and inflammation are physiologically inter-related, the effect of therapies that specifically target inflammation on blood pressure is uncertain. The recent CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) afforded the opportunity to test whether IL (interleukin)-1β inhibition would reduce blood pressure, prevent incident hypertension, and modify relationships between hypertension and cardiovascular events. CANTOS randomized 10 061 patients with prior myocardial infarction and hsCRP (high sensitivity C-reactive protein) ≥2 mg/L to canakinumab 50 mg, 150 mg, 300 mg, or placebo. A total of 9549 trial participants had blood pressure recordings during follow-up; of these, 80% had a preexisting diagnosis of hypertension. In patients without baseline hypertension, rates of incident hypertension were 23.4, 26.6, and 28.1 per 100-person years for the lowest to highest baseline tertiles of hsCRP (P>0.2). In all participants random allocation to canakinumab did not reduce blood pressure (P>0.2) or incident hypertension during the follow-up period (hazard ratio, 0.96 [0.85-1.08], P>0.2). IL-1β inhibition with canakinumab reduces major adverse cardiovascular event rates. These analyses suggest that the mechanisms underlying this benefit are not related to changes in blood pressure or incident hypertension. Clinical Trial Registration- URL: https://ichgcp.net/clinical-trials-registry/NCT01327846" title="See in ClinicalTrials.gov">NCT01327846.

Keywords: blood pressure; diagnosis; inflammation; interleukins; myocardial infarction.

Figures

Figure 1.
Figure 1.
Incident hypertension by tertile of baseline hsCRP (high sensitivity C-reactive protein; rate per 100-person years ± 95% CI, Cox proportional-hazard compared the time to diagnosis of incidence of hypertension and adjusted for age, sex, and body mass index, P>0.2).
Figure 2.
Figure 2.
Lack of effect of canakinumab compared to placebo on blood pressure. Office blood pressure of patients randomly allocated to canakinumab (50 mg, 150 mg, and canakinumab 300 mg) or placebo at baseline, 3, 6, and 12 months (mean and 95% CI, upper: systolic blood pressure, lower: diastolic blood pressure.
Figure 3.
Figure 3.
The effect of canakinumab on clinical events stratified by baseline systolic blood pressure. Major adverse cardiovascular events (MACE), myocardial infarction, coronary revascularization, stroke, heart failure hospitalization, and mortality adjusted for age, sex, body mass index, LDL (low-density lipoprotein)-Cholesterol, and diabetes mellitus (placebo n=3344, canakinumab n=6717, number of events indicated by box size, hazard ratio indicated by box position with 95% CI, Q1: lowest baseline systolic blood pressure, Q4: highest baseline systolic blood pressure,

References

    1. Harrison DG, Guzik TJ, Lob HE, Madhur MS, Marvar PJ, Thabet SR, Vinh A, Weyand CM. Inflammation, immunity, and hypertension. Hypertension. 2011;57:132–140. doi: 10.1161/HYPERTENSIONAHA.110.163576.
    1. Blake GJ, Rifai N, Buring JE, Ridker PM. Blood pressure, C-reactive protein, and risk of future cardiovascular events. Circulation. 2003;108:2993–2999. doi: 10.1161/.
    1. Bautista LE, Shab-Bidar S, Nazarzadeh M, Jayedi A, Rahimi K, Zargar MS. Inflammation markers and risk of developing hypertension: a meta-analysis of cohort studies. Heart. 2019;105:686–692. doi: 10.1136/heartjnl-2018-314216.
    1. Kunutsor SK, Laukkanen JA. Should inflammatory pathways be targeted for the prevention and treatment of hypertension? Heart. 2019;105:665–667. doi: 10.1136/heartjnl-2018-314625.
    1. Testa M, Yeh M, Lee P, Fanelli R, Loperfido F, Berman JW, LeJemtel TH. Circulating levels of cytokines and their endogenous modulators in patients with mild to severe congestive heart failure due to coronary artery disease or hypertension. J Am Coll Cardiol. 1996;28:964–971. doi: 10.1016/s0735-1097(96)00268-9.
    1. Sesso HD, Buring JE, Rifai N, Blake GJ, Gaziano JM, Ridker PM. C-reactive protein and the risk of developing hypertension. JAMA. 2003;290:2945–2951. doi: 10.1001/jama.290.22.2945.
    1. Crowley SD, Song YS, Sprung G, Griffiths R, Sparks M, Yan M, Burchette JL, Howell DN, Lin EE, Okeiyi B, et al. A role for angiotensin II type 1 receptors on bone marrow-derived cells in the pathogenesis of angiotensin II-dependent hypertension. Hypertension. 2010;55:99–108. doi: 10.1161/HYPERTENSIONAHA.109.144964.
    1. Zhang J, Rudemiller NP, Patel MB, Karlovich NS, Wu M, McDonough AA, Griffiths R, Sparks MA, Jeffs AD, Crowley SD. Interleukin-1 receptor activation potentiates salt reabsorption in angiotensin II-induced hypertension via the NKCC2 co-transporter in the nephron. Cell Metab. 2016;23:360–368. doi: 10.1016/j.cmet.2015.11.013.
    1. Chamberlain J, Francis S, Brookes Z, Shaw G, Graham D, Alp NJ, Dower S, Crossman DC. Interleukin-1 regulates multiple atherogenic mechanisms in response to fat feeding. PLoS One. 2009;4:e5073. doi: 10.1371/journal.pone.0005073.
    1. Ling YH, Krishnan SM, Chan CT, Diep H, Ferens D, Chin-Dusting J, Kemp-Harper BK, Samuel CS, Hewitson TD, Latz E, et al. Anakinra reduces blood pressure and renal fibrosis in one kidney/DOCA/salt-induced hypertension. Pharmacol Res. 2017;116:77–86. doi: 10.1016/j.phrs.2016.12.015.
    1. Bhaskar V, Yin J, Mirza AM, Phan D, Vanegas S, Issafras H, Michelson K, Hunter JJ, Kantak SS. Monoclonal antibodies targeting IL-1 beta reduce biomarkers of atherosclerosis in vitro and inhibit atherosclerotic plaque formation in apolipoprotein e-deficient mice. Atherosclerosis. 2011;216:313–320. doi: 10.1016/j.atherosclerosis.2011.02.026.
    1. Vongpatanasin W, Thomas GD, Schwartz R, Cassis LA, Osborne-Lawrence S, Hahner L, Gibson LL, Black S, Samols D, Shaul PW. C-reactive protein causes downregulation of vascular angiotensin subtype 2 receptors and systolic hypertension in mice. Circulation. 2007;115:1020–1028. doi: 10.1161/CIRCULATIONAHA.106.664854.
    1. Madhur MS, Lob HE, McCann LA, Iwakura Y, Blinder Y, Guzik TJ, Harrison DG. Interleukin 17 promotes angiotensin II-induced hypertension and vascular dysfunction. Hypertension. 2010;55:500–507. doi: 10.1161/HYPERTENSIONAHA.109.145094.
    1. Kranzhöfer R, Schmidt J, Pfeiffer CA, Hagl S, Libby P, Kübler W. Angiotensin induces inflammatory activation of human vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 1999;19:1623–1629. doi: 10.1161/01.atv.19.7.1623.
    1. Marvar PJ, Thabet SR, Guzik TJ, Lob HE, McCann LA, Weyand C, Gordon FJ, Harrison DG. Central and peripheral mechanisms of T-lymphocyte activation and vascular inflammation produced by angiotensin II-induced hypertension. Circ Res. 2010;107:263–270. doi: 10.1161/CIRCRESAHA.110.217299.
    1. Muller DN, Shagdarsuren E, Park JK, Dechend R, Mervaala E, Hampich F, Fiebeler A, Ju X, Finckenberg P, Theuer J, et al. Immunosuppressive treatment protects against angiotensin II-induced renal damage. Am J Pathol. 2002;161:1679–1693. doi: 10.1016/S0002-9440(10)64445-8.
    1. Ridker PM, Everett BM, Thuren T, MacFadyen JG, Chang WH, Ballantyne C, Fonseca F, Nicolau J, Koenig W, Anker SD, et al. CANTOS Trial Group. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–1131. doi: 10.1056/NEJMoa1707914.
    1. Everett BM, Cornel JH, Lainscak M, Anker SD, Abbate A, Thuren T, Libby P, Glynn RJ, Ridker PM. Anti-inflammatory therapy with canakinumab for the prevention of hospitalization for heart failure. Circulation. 2019;139:1289–1299. doi: 10.1161/CIRCULATIONAHA.118.038010.
    1. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ CANTOS Trial Group. Relationship of C-reactive protein reduction to cardiovascular event reduction following treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled trial. Lancet. 2018;391:319–328. doi: 10.1016/S0140-6736(17)32814-3.
    1. Ridker PM, Libby P, MacFadyen JG, Thuren T, Ballantyne C, Fonseca F, Koenig W, Shimokawa H, Everett BM, Glynn RJ. Modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the Canakinumab Anti-Inflammatory Thrombosis Outcomes Study (CANTOS). Eur Heart J. 2018;39:3499–3507. doi: 10.1093/eurheartj/ehy310.
    1. Ridker PM, 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. doi: 10.1016/j.ahj.2011.06.012.
    1. Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ CANTOS Trial Group. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390:1833–1842. doi: 10.1016/S0140-6736(17)32247-X.
    1. Morton AC, Rothman AM, Greenwood JP, Gunn J, Chase A, Clarke B, Hall AS, Fox K, Foley C, Banya W, et al. 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. 2015;36:377–384. doi: 10.1093/eurheartj/ehu272.
    1. Rothman AM, Morton AC, Crossman DC MRC-ILA Heart Investigators. Canakinumab for atherosclerotic disease. N Engl J Med. 2018;378:197–198. doi: 10.1056/NEJMc1714635.
    1. Alfaidi MA, Chamberlain J, Rothman A, Crossman D, Villa-Uriol MC, Hadoke P, Wu J, Schenkel T, Evans PC, Francis SE. Dietary docosahexaenoic acid reduces oscillatory wall shear stress, atherosclerosis, and hypertension, most likely mediated via an Il-1-mediated mechanism. J Am Heart Assoc. 2018;7:e008757. doi: 10.1161/JAHA.118.008757.
    1. Markó L, Kvakan H, Park JK, Qadri F, Spallek B, Binger KJ, Bowman EP, Kleinewietfeld M, Fokuhl V, Dechend R, et al. Interferon-γ signaling inhibition ameliorates angiotensin II-induced cardiac damage. Hypertension. 2012;60:1430–1436. doi: 10.1161/HYPERTENSIONAHA.112.199265.

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