The EXERRT trial: "EXErcise to Regadenoson in Recovery Trial": A phase 3b, open-label, parallel group, randomized, multicenter study to assess regadenoson administration following an inadequate exercise stress test as compared to regadenoson without exercise for myocardial perfusion imaging using a SPECT protocol

Gregory S Thomas, S James Cullom, Therese M Kitt, Kathleen M Feaheny, Karthikeyan Ananthasubramaniam, Robert J Gropler, Diwakar Jain, Randall C Thompson, Gregory S Thomas, S James Cullom, Therese M Kitt, Kathleen M Feaheny, Karthikeyan Ananthasubramaniam, Robert J Gropler, Diwakar Jain, Randall C Thompson

Abstract

Background: This study assessed the non-inferiority and safety of regadenoson administration during recovery from inadequate exercise compared with administration without exercise.

Methods: Patients unable to achieve adequate exercise stress were randomized to regadenoson 0.4 mg either during recovery (Ex-Reg) or 1 hour after inadequate exercise (Regadenoson) (MPI1). All patients also underwent non-exercise regadenoson MPI 1-14 days later (MPI2). The number of segments with reversible perfusion defects (RPDs) detected using single photon emission computerized tomography imaging was categorized. The primary analysis evaluated the majority agreement rate between Ex-Reg and Regadenoson groups.

Results: 1,147 patients were randomized. The lower bound of the 95% confidence interval of the difference in agreement rates (-6%) was above the -7.5% non-inferiority margin, demonstrating non-inferiority of Ex-Reg to Regadenoson. Adverse events were numerically less with Ex-Reg (MPI1). In the Ex-Reg group, one patient developed an acute coronary syndrome and another had a myocardial infarction following regadenoson after exercise. Upon review, both had electrocardiographic changes consistent with ischemia prior to regadenoson.

Conclusions: Administering regadenoson during recovery from inadequate exercise results in comparable categorization of segments with RPDs and with careful monitoring appears to be well tolerated in patients without signs/symptoms of ischemia during exercise and recovery.

Trial registration: ClinicalTrials.gov NCT01618669.

Keywords: Exercise; myocardial perfusion imaging; pharmacologic stress; regadenoson; vasodilator stress.

Figures

Figure 1
Figure 1
Illustration of the flow of patients through all stages of the study. *As described in the Methods section, patients experiencing signs or symptoms of ischemia prior to receiving regadenoson were not to be randomized. †Administered intravenously over 10 seconds. MPI, Myocardial perfusion imaging; SPECT, single photon emission computed tomography
Figure 2
Figure 2
Diagram outlining the flow of patients in the study, including events that precluded patients from analysis. Reasons for exclusion from efficacy analysis set were factors that prevented completion of all MPI assessments. MET, Metabolic equivalent; MPHR, maximum predicted heart rate
Figure 3
Figure 3
Primary endpoint: Majority agreement rate difference (results of the primary endpoint). MPI, Myocardial perfusion imaging; SE, standard error
Figure 4
Figure 4
Responses for heart rate (A) and systolic blood pressure (B). Illustration of the mean and SD changes in heart rates (A) and systolic blood pressure (B) over 60 minutes in Ex-Reg and Regadenoson during the first and second stress MPI procedures. MPI, Myocardial perfusion imaging; SD, standard deviation

References

    1. Henzlova MJ, Cerqueira MD, Hansen CL, Taillefer R, Yao S-S. ASNC imaging guidelines for nuclear cardiology procedures: Stress protocols and tracers. J Nucl Cardiol. 2009
    1. Ahlberg AW, Baghdasarian SB, Athar H, Thompsen JP, Katten DM, Noble GL, et al. Symptom-limited exercise combined with dipyridamole stress: Prognostic value in assessment of known or suspected coronary artery disease by use of gated SPECT imaging. J Nucl Cardiol. 2008;15:42–56. doi: 10.1016/j.nuclcard.2007.09.025.
    1. AlJaroudi WA, Alraies MC, Cerquiera MD, Jaber WA. Safety and tolerability of regadenoson in 514 SPECT MPI patients with and without coronary artery disease and submaximal exercise heart rate response. Eur J Nucl Med Mol Imaging. 2013;40:341–348. doi: 10.1007/s00259-012-2296-4.
    1. Casale PN, Guiney TE, Strauss HW, Boucher CA. Simultaneous low level treadmill exercise and intravenous dipyridamole stress thallium imaging. Am J Cardiol. 1988;62:799–802. doi: 10.1016/0002-9149(88)91225-8.
    1. Holly TA, Satran A, Bromet DS, Mieres JH, Frey MJ, Elliott MD, et al. The impact of adjunctive adenosine infusion during exercise myocardial perfusion imaging: Results of the Both Exercise and Adenosine Stress Test (BEAST) trial. J Nucl Cardiol. 2003;10:291–296. doi: 10.1016/S1071-3581(02)43236-9.
    1. Kwon DH, Cerqueira MD, Young R, Houghtaling P, Lieber E, Menon V, et al. Lessons from regadenoson and low-level treadmill/regadenoson myocardial perfusion imaging: Initial clinical experience in 1263 patients. J Nucl Cardiol. 2010;17:853–857. doi: 10.1007/s12350-010-9229-z.
    1. Parker MW, Morales DC, Slim HB, Ahlberg AW, Katten DM, Cyr G, et al. A strategy of symptom-limited exercise with regadenoson-as-needed for stress myocardial perfusion imaging: A randomized controlled trial. J Nucl Cardiol. 2013;20:185–196. doi: 10.1007/s12350-012-9641-7.
    1. Partington SL, Lanka V, Hainer J, Blankstein R, Skali H, Forman DE, et al. Safety and feasibility of regadenoson use for suboptimal heart rate response during symptom-limited standard Bruce exercise stress test. J Nucl Cardiol. 2012;19:970–978. doi: 10.1007/s12350-012-9562-5.
    1. Ross MI, Wu E, Wilkins JT, Gupta D, Shen S, Aulwes D, et al. Safety and feasibility of adjunctive regadenoson injection at peak exercise during exercise myocardial perfusion imaging: The Both Exercise and Regadenoson Stress Test (BERST) trial. J Nucl Cardiol. 2013;20:197–204. doi: 10.1007/s12350-013-9679-1.
    1. Samady H, Wackers FJ, Joska TM, Zaret BL, Jain D. Pharmacologic stress perfusion imaging with adenosine: Role of simultaneous low-level treadmill exercise. J Nucl Cardiol. 2002;9:188–196. doi: 10.1067/mnc.2002.119973.
    1. Thomas GS, Prill NV, Majmundar H, Fabrizi RR, Thomas JJ, Hayashida C, et al. Treadmill exercise during adenosine infusion is safe, results in fewer adverse reactions, and improves myocardial perfusion image quality. J Nucl Cardiol. 2000;7:439–446. doi: 10.1067/mnc.2000.108030.
    1. Thomas GS, Thompson RC, Miyamoto MI, Ip TK, Rice DL, Milikien D, et al. The RegEx trial: A randomized, double-blind, placebo- and active-controlled pilot study combining regadenoson, a selective A(2A) adenosine agonist, with low-level exercise, in patients undergoing myocardial perfusion imaging. J Nucl Cardiol. 2009;16:63–72. doi: 10.1007/s12350-008-9001-9.
    1. Thompson RC, Patil H, Thompson EC, Thomas GS, Al-Amoodi M, Kennedy KF, et al. Regadenoson pharmacologic stress for myocardial perfusion imaging: A three-way comparison between regadenoson administered at peak exercise, during walk recovery, or no-exercise. J Nucl Cardiol. 2013;20:214–221. doi: 10.1007/s12350-012-9660-4.
    1. Vitola JV, Brambatti JC, Caligaris F, Lesse CR, Nogueira PR, Joaquim AI, et al. Exercise supplementation to dipyridamole prevents hypotension, improves electrocardiogram sensitivity, and increases heart-to-liver activity ratio on Tc-99m sestamibi imaging. J Nucl Cardiol. 2001;8:652–659. doi: 10.1067/mnc.2001.117204.
    1. Astellas Pharma US Inc. LEXISCAN® (regadenoson) injection for intravenous use [package insert]. . Accessed August 15, 2015.
    1. Hendel RC, Bateman TM, Cerqueira MD, Iskandrian AE, Leppo JA, Blackburn B, 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;46:2069–2075. doi: 10.1016/j.jacc.2005.05.097.
    1. Iskandrian AE, Bateman TM, Belardinelli L, Blackburn B, Cerqueira MD, Hendel RC, et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: Results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol. 2007;14:645–658. doi: 10.1016/j.nuclcard.2007.06.114.
    1. 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 in coronary blood flow velocity in humans. J Nucl Cardiol. 2007;14:514–520. doi: 10.1016/j.nuclcard.2007.02.016.
    1. Fletcher GF, Balady GJ, Amsterdam EA, Chaitman B, Eckel R, Fleg J, et al. Exercise standards for testing and training: A statement for healthcare professionals from the American Heart Association. Circulation. 2001;104:1694–1740. doi: 10.1161/hc3901.095960.
    1. Gibbons RJ, Balady GJ, Bricker JT, Chaitman BR, Fletcher GF, Froelicher VF, et al. ACC/AHA 2002 guideline update for exercise testing: Summary article. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Update the 1997 Exercise Testing Guidelines) J Am Coll Cardiol. 2002;40:1531–1540. doi: 10.1016/S0735-1097(02)02164-2.
    1. Cerqueira MD, Weissman NJ, Dilsizian V, Jacobs AK, Kaul S, Laskey WK, 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 on Clinical Cardiology of the American Heart Association. Circulation. 2002;105:539–542. doi: 10.1161/hc0402.102975.
    1. Rehm PK, Atkins FB, Ziessman HA, Green SE, Akin EA, Fox LM, et al. Frequency of extra-cardiac activity and its effect on 99Tcm-MIBI cardiac SPET interpretation. Nucl Med Commun. 1996;17:851–856. doi: 10.1097/00006231-199610000-00005.
    1. Newcombe RG. Two-sided confidence intervals for the single proportion: Comparison of seven methods. Stat Med. 1998;17:857–872. doi: 10.1002/(SICI)1097-0258(19980430)17:8<857::AID-SIM777>;2-E.
    1. Klocke FJ, Baird MG, Lorell BH, Bateman TM, Messer JV, Berman DS, et al. ACC/AHA/ASNC guidelines for the clinical use of cardiac radionuclide imaging—executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (ACC/AHA/ASNC Committee to Revise the 1995 Guidelines for the Clinical Use of Cardiac Radionuclide Imaging) J Am Coll Cardiol. 2003;42:1318–1333. doi: 10.1016/j.jacc.2003.08.011.
    1. Matsumoto N, Sato Y, Suzuki Y, Yoda S, Kunimasa T, Kato M, et al. Usefulness of rapid low-dose/high-dose 1-day 99mTc-sestamibi ECG-gated myocardial perfusion single-photon emission computed tomography. Circ J. 2006;70:1585–1589. doi: 10.1253/circj.70.1585.
    1. Henzlova MJ, Duvall WL, Einstein AJ, Travin MI, Verberne HJ. ASNC imaging guidelines for SPECT nuclear cardiology procedures: Stress, protocols, and tracers. J Nucl Cardiol. 2016;23:606–639. doi: 10.1007/s12350-015-0387-x.
    1. Duvall WL, Rai M, Ahlberg AW, O’Sullivan DM, Henzlova MJ. A multi-center assessment of the temporal trends in myocardial perfusion imaging. J Nucl Cardiol. 2015;22:539–551. doi: 10.1007/s12350-014-0051-x.
    1. Thompson RC, Allam AH. More risk factors, less ischemia, and the relevance of MPI testing. J Nucl Cardiol. 2015;22:552–554. doi: 10.1007/s12350-015-0072-0.

Source: PubMed

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