Abstract
Purpose
Elevated levels of serum inflammatory markers such as high-sensitivity C-reactive protein (hs-CRP) represent independent risk factors for further cardiovascular events. In an atherosclerosis model, selective heart rate (HR) reduction with ivabradine has been shown to decrease markers of vascular oxidative stress, to improve endothelial function, and to reduce atherosclerotic plaque formation. We hypothesized that the addition of ivabradine to standard medical therapy has a beneficial effect on markers of inflammatory stress in acute coronary syndromes (ACS) patients.
Methods
RIVIERA is a unicenter, randomized, double-blind, placebo-controlled trial involving 1,270 patients of either gender admitted to hospital with non ST elevation ACS. The primary study aim is to evaluate the effects of ivabradine therapy, initiated at the time of hospital admission, on hs-CRP levels. There is also a combined secondary endpoint i.e. to assess the effects of ivabradine on the occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest at 30-days and 1-year follow up.
Conclusion
We hypothesize that ivabradine therapy, when started immediately after hospital admission for ACS, will result in the reduction of hs-CRP levels and the improvement of cardiovascular outcome.
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References
Ross T. The pathogenesis of atherosclerosis: a perspective for the 1990s. Nature 1993;362:801–9.
Morrow DR, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol. 1998;31:1460–5.
Phillips AN, Neaton JD, Cook DG, et al. Leukocyte count and risk of major coronary heart disease events. Am J Epidemiol. 1992;136:59–70.
Ridker PM, Cushman M, Stampfer MJ, et al. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med. 1997;336:973–9.
Huikuri HV, Malkikallio TH, Airaksinen KEJ, et al. Power-law relationship of heart rate variability as a predictor of mortality in the elderly. Circulation 1998;97:2031–6.
Tsuji H, Larson MG, Venditti FJ, et al. Impact of heart rate variability on risk for cardiac events: the Framingham Heart Study. Circulation 1996;94:2850–5.
Hikuri HV, Jokinen V, Syvanne M, for the Lipid Coronary Angioplasty Trial (LOCAT) study Group, et al. Heart rate variability and progression of coronary atherosclerosis. Arterioscler Thromb Vasc Biol. 1999;19:1979–85.
Kannel WB, Kannel CE, Paffenbarger R. Heart rate and cardiovascular mortality in the Framingham study. Am Heart J. 1987;113:1489–94.
Sajadich A, Nielsen OW, Rasmussen V, et al. Increased heart rate and reduced heart-rate variability are associated with subclinical inflammation in middle-aged and elderly subjects with no apparent heart disease. Eur Heart J. 2004;25:363–70.
Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation 2001;104:1477–82.
Mangoni ME, Nargeot J. Properties of the hyperpolarization-activated current (I f ) in isolated mouse sino-atrial cells. Cardiovasc Res. 2001;52:51–64.
Bois P, Bescond J, Renaudon B, et al. Mode of action of bradycardic agent, S 16257, on ionic currents of rabbit sinoatrial node cells. Br J Pharmacol. 1996;118:1051–7.
Gardiner SM, Kemp PA, March JE, et al. Acute and chronic cardiac and regional haemodynamic effects of the novel bradycardic agent, S16257, in conscious rats. Br J Pharmacol. 1995;115:579–86.
Tardif JC, Ford I, Tendera M, et al. Efficacy of ivabradine, a new selective I(f) inhibitor, compared with atenolol in patients with chronic stable angina. Eur Heart J. 2005;26:2529–36.
Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double blind, multicentered, placebo-controlled trial. Circulation 2003;107:817–23.
Custodis F, Baumhakel M, Schlimmer N, et al. Heart rate reduction by ivabradine reduces oxidative stress, improves endothelial function, and prevents atherosclerosis in apolipoprotein E deficient mice. Circulation 2008;117:2377–87.
Bassand JP, Hamm CW, Ardissino D, et al. Guidelines for the diagnosis and treatment of non-ST-segment elevation acute coronary syndromes: the Task Force for the Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of the European Society of Cardiology. Eur Heart J. 2007;28:1598–660.
Kaski JC, Consuegra-Sanchez L, Fernandez-Berges DJ, et al. SIESTA Investigators. Elevated serum neopterin levels and adverse cardiac events at 6 months follow-up in Mediterranean patients with non-ST-segment elevation acute coronary syndrome. doi:10.1016/j.atherosclerosis.2008.01.009.
O’Brien PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics 1979;35:549–56.
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Dominguez-Rodriguez, A., Fard, S.S., Abreu-Gonzalez, P. et al. Randomised, Double-Blind, Placebo-Controlled Trial of Ivabradine in Patients with Acute Coronary Syndrome: Effects of the I f Current Inhibitor Ivabradine on Reduction of Inflammation Markers in Patients with Acute Coronary Syndrome—RIVIERA Trial Study Design and Rationale. Cardiovasc Drugs Ther 23, 243–247 (2009). https://doi.org/10.1007/s10557-009-6164-9
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DOI: https://doi.org/10.1007/s10557-009-6164-9