Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Results of the ADVANCE phase 3 multicenter international trial



Earlier phase 1 and 2 studies have shown that regadenoson has desirable features as a stress agent for myocardial perfusion imaging.

Methods and Results

This multicenter, double-blinded phase 3 trial involved 784 patients at 54 sites. Each patient underwent 2 sets of gated single photon emission computed tomography myocardial perfusion imaging studies: an initial qualifying study with adenosine and a subsequent randomized study with either regadenoson (2/3 of patients) or adenosine. Regadenoson was administered as a rapid bolus (<10 seconds) of 400 μg. The primary endpoint was to demonstrate noninferiority by showing that the difference in the strength of agreement in detecting reversible defects, based on blinded reading, between sequential adenosine-regadenoson images and adenosine-adenosine images, lay above a prespecified noninferiority margin. Other prospectively defined safety and tolerability comparisons and supporting analyses were also performed. The average agreement rate based on the median of 3 independent blinded readers was 0.63±0.03 for regadenoson-adenosine and 0.64±0.04 for adenosine-adenosine—a 1% absolute difference with the lower limit of the 95% confidence interval lying above the prespecified noninferiority margin. Side-by-side interpretation of regadenoson and adenosine images provided comparable results for detecting reversible defects. The peak increase in heart rate was greater with regadenoson than adenosine, but the blood pressure nadir was similar. A summed symptom score of flushing, chest pain, and dyspnea was less with regadenoson than adenosine (P=.013).


This phase 3 trial shows that regadenoson provides diagnostic information comparable to a standard adenosine infusion. There were no serious drug-related side effects, and regadenoson was better tolerated than adenosine.

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  1. 1.

    Shryock JC, Belardinelli L. Adenosine and AdoR in the cardiovascular system: biochemistry, physiology and pharmacology. Am J Cardiol 1997;79:2–10.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Fredholm BB, Ijzerman AP, Jacobson KA, Klotz KN, Linden J. International Union of Pharmacology. XXV. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001;53:527–52.

    PubMed  CAS  Google Scholar 

  3. 3.

    Olsson RA, Pearson JD. Cardiovascular purinoceptors. Physiol Rev 1990;70:761–845.

    PubMed  CAS  Google Scholar 

  4. 4.

    Belardinelli L, Shryock JC, Snowdy S, et al. The A2A adenosine receptor mediates coronary vasodilation. J Pharmacol Exp Ther 1998;284:1066–73.

    PubMed  CAS  Google Scholar 

  5. 5.

    Hein TW, Belardinelli L, Kuo L. Adenosine A2A receptors mediate coronary microvascular dilation to adenosine: role of nitric oxide and ATP-sensitive potassium channels. J Pharmacol Exp Ther 1999;291:655–64.

    PubMed  CAS  Google Scholar 

  6. 6.

    Dhalla AK, Shryock JC, Shreeniwas R, Belardinelli L. Pharmacology and therapeutic applications of A1 adenosine receptor ligands. Curr Top Med Chem 2003;3:369–85.

    PubMed  Article  CAS  Google Scholar 

  7. 7.

    Biaggioni I, Killian TJ, Mosqueda-Garcia R, Robertson RM, Robertson D. Adenosine increases sympathetic nerve traffic in humans. Circulation 1991;83:1668–75.

    PubMed  CAS  Google Scholar 

  8. 8.

    Koos BJ, Chau A. Fetal cardiovascular and breathing responses to an adenosine A2A receptor agonist in sheep. Am J Physiol 1998;274:R152–9.

    PubMed  CAS  Google Scholar 

  9. 9.

    Dhalla AK, Wong MY, Wang WQ, Biaggioni I, Belardinelli L Tachycardia caused by A2A adenosine receptor agonists is mediated by direct sympathoexcitation in awake rats. J Pharmacol Exp Ther 2006;316:695–702.

    PubMed  Article  CAS  Google Scholar 

  10. 10.

    Shryock JC, Snowdy S, Baraldi PG, et al. A2A-adenosine receptor reserve for coronary vasodilation. Circulation 1998;98:711–8.

    PubMed  CAS  Google Scholar 

  11. 11.

    Zhao G, Linke A, Xu X, et al. Comparative profile of vasodilation by CVT-3146, a novel A2A receptor agonist, and adenosine in conscious dogs. J Pharmacol Exp Ther 2003;307:182–9.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Gao Z, Li Z, Baker SP, et al. Novel short-acting A2A adenosine receptor agonists for coronary vasodilation: inverse relationship between affinity and duration of action of A2A agonists. J Pharmacol Exp Ther 2001;298:209–18.

    PubMed  CAS  Google Scholar 

  13. 13.

    Trochu JN, Zhao G, Post H, et al. Selective A2A adenosine receptor agonist as a coronary vasodilator in conscious dogs: potential for use in myocardial perfusion imaging. J Cardiovasc Pharmacol 2003;41:132–9.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Verani MS, Mahmarian JJ, Hixson JB, Boyce TM, Staudacher RA. Diagnosis of coronary artery disease with adenosine and thallium-201 scintigraphy in patients unable to exercise. Circulation 1990, 82:80–7.

    PubMed  CAS  Google Scholar 

  15. 15.

    Nguyen T, Heo J, Ogilby JD, Iskandrian AS. SPECT with thallium-201 during adenosine-induced coronary hyperemia: correlation with coronary arteriography, exercise thallium and two-dimensional echocardiography. J Am Coll Cardiol 1990; 16:1375–83.

    PubMed  CAS  Google Scholar 

  16. 16.

    Iskandrian AS, Verani MS, Heo J. Pharmacologic stress testing: mechanism of action, hemodynamic responses, and results in detection of coronary artery disease. J Nucl Cardiol 1994;1:94–111.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Udelson JE, Heller GV, Wackers FJT, et al. Randomized controlled dose-ranging study of the selective adenosine A2a-adenosine receptor reserve for coronary vasodilatation. Circulation 2004;109:457–64.

    PubMed  Article  CAS  Google Scholar 

  18. 18.

    Hendel RC, Taillefer R, Crane PD, Widner PJ. Preliminary experience with BMS068645, a selective A2A adenosine agonist, for pharmacologic stress myocardial perfusion imaging [abstract]. Circulation 2005;112(Suppl II):11–474.

    Google Scholar 

  19. 19.

    Lieu HD, Shryock JC, von Mering GO, Gordi T, Blackburn B, Olmsted AW, et al. Regadenoson a selective A2A adenosine receptor agonist causes dose-dependent increases of coronary blood flow velocity in humans. J Nucl Cardiol. In press 2007.

  20. 20.

    Bertolet BD, Belardinelli L, Franco EA, Nichols WW, Kerensky RA, Hill JA. Selective attenuation by N-0861 (N6-endonorboran-2-yl-9-methyladenine) of cardiac A1 adenosine receptor-mediated effects in humans. Circulation 1996;93:1871–6.

    PubMed  CAS  Google Scholar 

  21. 21.

    Hendel RC, Bateman TM, Cerqueira MD, et al. Initial clinical experience with Regadenoson, a novel selective A2A agonist for pharmacologic stress single photon emission computed tomography myocardial perfusion imaging. J Am Coll Cardiol 2005;46:2069–75.

    PubMed  Article  CAS  Google Scholar 

  22. 22.

    American Society of Nuclear Cardiology. Imaging guidelines for nuclear cardiology procedures, part 2. J Nucl Cardiol 1999;6:G47–84.

    Article  Google Scholar 

  23. 23.

    Germano G, Kiat H, Kavanagh PB, et al. Automatic quantification of ejection fraction from gated myocardial perfusion SPECT J Nucl Med 1995;36:2138–47.

    PubMed  CAS  Google Scholar 

  24. 24.

    Cerqueira MD, Weissman NJ, Dilsizian V, et al. Standardized myocardial segmentation and nomenclature for tomographic imaging of the heart: a statement for healthcare professionals from the Cardiac Imaging Committee of the Council of Clinical Cardiology of the American Heart Association. Circulation 2002;105:539–42.

    PubMed  Article  Google Scholar 

  25. 25.

    Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. A prognostic score for prediction of cardiac mortality risk after adenosine stress myocardial perfusion scintigraphy. J Am Coll Cardiol 2005;45:722–9.

    PubMed  Article  Google Scholar 

  26. 26.

    Landis JR, Koch GG. The measurement of observer agreement for categorical data. Biometrics 1977;33:159–74.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Piaggio G, Elbourne DR, Atman DR, Pocock SJ, Evans SJ, for the CONSORT Group. Reporting of noninferiority and equivalence randomized trials: an extension of the CONSORT statement [published erratum appears in JAMA 2006;296:1842]. JAMA 2006;295:1152–60.

    PubMed  Article  CAS  Google Scholar 

  28. 28.

    Henanff AL, Giraudeau B, Baron G, Ravaud P. Quality of reporting of noninferiority and equivalence randomized trials. JAMA 2006;295:1147–51.

    PubMed  Article  Google Scholar 

  29. 29.

    Gotzsche PC. Lessons from and cautions about noninferiority and equivalence randomized trials. JAMA 2006;295:1172–3.

    PubMed  Article  CAS  Google Scholar 

  30. 30.

    Iskandrian AE. Pharmacologic stress testing and other alternative techniques in the diagnosis of coronary artery disease. In: Iskandrian AE, Verani MS, editors. Nuclear cardiac imaging: principles and applications. 3rd ed. New York: Oxford University Press. 2003. p. 164–89.

    Google Scholar 

  31. 31.

    Cerqueira MD, Verani MS, Schwaiger M, Heo J, Iskandrian AS. Safety profile of adenosine stress perfusion imaging: results from the Adenoscan Multicenter Trial Registry. J Am Coll Cardiol 1994;23:384–9.

    PubMed  CAS  Article  Google Scholar 

  32. 32.

    Spaan JAE, Piek JJ, Hoffman JIE, Siebes M. Physiological basis of clinically used coronary hemodynamic Indices. Circulation 2006; 113:446–55.

    PubMed  Article  Google Scholar 

  33. 33.

    Rimoldi OE, Camici PG. Positron emission tomography for quantitation of myocardial perfusion. J Nucl Cardiol 2004;11:482–90.

    PubMed  Article  Google Scholar 

  34. 34.

    Doucette JW, Corl PD, Payne HM, et al. Validation of a Doppler guide wire for intravascular measurement of coronary artery flow velocity. Circulation 1992;85:1899–911.

    PubMed  CAS  Google Scholar 

  35. 35.

    Kern MJ. Coronary physiology revisited: practical insights from the cardiac catheterization laboratory. Circulation 2000;101:1344–51.

    PubMed  CAS  Google Scholar 

  36. 36.

    DeBruyne B, Baudhuin T, Melin JA, et al. Coronary flow reserve calculated from pressure measurements in humans: validation with positron emission tomography. Circulation 1994;89:1013–22.

    CAS  Google Scholar 

  37. 37.

    Ghods M, Mangal R, Iskandrian AS, et al. Importance of intraluminal pressure on hemodynamics and vasoconstriction responses of stenotic arteries. Circulation 1992;85:708–16.

    PubMed  CAS  Google Scholar 

  38. 38.

    Serruys PW, Di Marion C, Meneveau N, et al. Intracoronary pressure and flow velocity with sensor-tip guide wires: a new methodological comprehensive approach for the assessment of coronary hemodynamics before and after coronary interventions. Am J Cardiol 1993;71:41D-53D.

    PubMed  Article  CAS  Google Scholar 

  39. 39.

    Pijls NHJ, Van Gelder B, Van der Voon P, et al. Fractional flow reserve: a useful index to evaluate the influence of an epicardial coronary stenosis on myocardial blood flow. Circulation 1995;92:318–9.

    Google Scholar 

  40. 40.

    Iskandrian AS, Chae SC, Heo J, Stanberry CD, Wasserleben V, Cave V. Independent and incremental prognostic value of exercise single-photon emission computed tomographic (SPECT) thallium imaging in coronary disease. J Am Coll Cardiol 1993;22:665–70.

    PubMed  CAS  Google Scholar 

  41. 41.

    Iskander S, Iskandrian AE. Risk assessment using SPECT technetium-99m sestamibi imaging. J Am Coll Cardiol 1998;32:57–62.

    PubMed  Article  CAS  Google Scholar 

  42. 42.

    Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol 2004;11:171–85.

    PubMed  Article  Google Scholar 

  43. 43.

    Navare SM, Mather JF, Shaw LJ, Fowler MS, Heller GV. Comparison of risk stratification with pharmacologic and exercise stress myocardial perfusion imaging: a meta-analysis. J Nucl Cardiol 2004;11:551–61.

    PubMed  Article  Google Scholar 

  44. 44.

    Verani MS, Jeroudi MO, Mahmarian JJ, et al. Quantification of myocardial infarction during coronary occlusion and myocardial salvage after reperfusion using cardiac imaging with technetium-99m hexakis 2-methoxyisobutyl isonitrile. J Am Coll Cardiol 1988;12:1573–81.

    PubMed  CAS  Google Scholar 

  45. 45.

    Mahmarian JJ, Moye LA, Verani MS, Bloom MF, Pratt CM. High reproducibility of myocardial perfusion defects in patients undergoing serial exercise thallium-201 tomography. Am J Cardiol 1995;75:1116–9.

    PubMed  Article  CAS  Google Scholar 

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Correspondence to Ami E. Iskandrian.

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Iskandrian, A.E., Bateman, T.M., Belardinelli, L. et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol 14, 645–658 (2007).

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Key Words

  • Adenosine
  • regadenoson
  • single photon emission computed tomography
  • stress imaging
  • coronary artery disease
  • ischemia
  • perfusion imaging