Heart and Vessels

, Volume 33, Issue 12, pp 1570–1575 | Cite as

Intravenous nicorandil versus adenosine for fractional flow reserve measurement: a crossover, randomized study

  • Takeshi Nishi
  • Hideki Kitahara
  • Yoshihide Fujimoto
  • Takashi Nakayama
  • Kengo Nagashima
  • Hideki Hanaoka
  • Yoshio Kobayashi
Short Communication


Nicorandil has vasodilatory effects on both the epicardial coronary arteries and the coronary microvasculature, thereby increasing coronary blood flow. The objective of the present study was to investigate the effectiveness of intravenous (IV) nicorandil infusion for fractional flow reserve (FFR) measurement. In this crossover randomized study, 49 patients underwent FFR measurement with a consecutive randomized order of patient-blind infusions of continuous IV adenosine administration and a single bolus IV administration of nicorandil. The primary endpoint was the difference between the FFR by nicorandil and the FFR by adenosine, as assessed by the Bland–Altman method. The mean FFR value measured by nicorandil was not significantly different from that measured by adenosine [0.8125 ± 0.1349 vs. 0.7978 ± 0.124; mean difference, 0.0147 (95% confidence interval − 0.0373, 0.0667); P = 0.58]. There was no clinically significant diagnostic discordance, with the FFR by nicorandil > 0.80 and that by adenosine < 0.75. Hyperemia was achieved earlier using nicorandil than adenosine (34 ± 13 vs. 58 ± 15, P < 0.001). The duration of hyperemia after IV nicorandil was variable (6–570 s, mean 89 ± 98 s). IV nicorandil decreased systolic blood pressure by 32 ± 16 mm Hg (24 ± 10%) from baseline. Linear regression analysis showed that the average FFR value and the difference in systolic blood pressure were significantly associated with the bias in the FFR value between the two drugs. In conclusions, the results of the present study suggest that IV nicorandil can achieve maximal hyperemia easily and rapidly, providing an acceptable diagnostic performance for FFR assessment. However, a wide range of variation in hyperemic plateau and a decrease in blood pressure are the major limitations of this method.


Nicorandil Fractional flow reserve Hyperemia 



The authors thank Akito Ito and Megumi Hata for their meticulous work in managing this study.

Compliance with ethical standards

Conflict of interest

The authors report no relationships that could be construed as a conflict of interest.


  1. 1.
    Tonino PA, De Bruyne B, Pijls NH, Siebert U, Ikeno F, van’t Veer M, Klauss V, Manoharan G, Engstrøm T, Oldroyd KG, Ver Lee PN, MacCarthy PA, Fearon WF, FAME Study Investigators (2009) Fractional flow reserve versus angiography for guiding percutaneous coronary intervention. N Engl J Med 360(3):213–224CrossRefGoogle Scholar
  2. 2.
    De Bruyne B, Pijls NH, Kalesan B, Barbato E, Tonino PA, Piroth Z, Jagic N, Möbius-Winkler S, Rioufol G, Witt N, Kala P, MacCarthy P, Engström T, Oldroyd KG, Mavromatis K, Manoharan G, Verlee P, Frobert O, Curzen N, Johnson JB, Jüni P, Fearon WF, FAME 2 Trial Investigators (2012) Fractional flow reserve-guided PCI versus medical therapy in stable coronary disease. N Engl J Med 367(11):991–1001CrossRefGoogle Scholar
  3. 3.
    Fearon WF, Nishi T, De Bruyne B, Boothroyd DB, Barbato E, Tonino P, Jüni P, Pijls NHJ, Hlatky MA, FAME 2 Trial Investigators (2018) Clinical outcomes and cost-effectiveness of fractional flow reserve-guided percutaneous coronary intervention in patients with stable coronary artery disease: three-year follow-up of the FAME 2 trial (fractional flow reserve versus angiography for multivessel evaluation). Circulation 137(5):480–487CrossRefGoogle Scholar
  4. 4.
    Layland J, Carrick D, Lee M, Oldroyd K, Berry C (2014) Adenosine: physiology, pharmacology, and clinical applications. JACC Cardiovasc Interv 7(6):581–591CrossRefGoogle Scholar
  5. 5.
    Koo BK (2014) The present and future of fractional flow reserve. Circ J 78:1048–1054CrossRefGoogle Scholar
  6. 6.
    Akai K, Wang Y, Sato K, Sekiguchi N, Sugimura A, Kumagai T, Komaru T, Kanatsuka H, Shirato K (1995) Vasodilatory effect of nicorandil on coronary arterial microvessels: its dependency on vessel size and the involvement of the ATP-sensitive potassium channels. J Cardiovasc Pharmacol 26(4):541–547CrossRefGoogle Scholar
  7. 7.
    Okamura A, Rakugi H, Ohishi M, Yanagitani Y, Shimizu M, Nishii T, Taniyama Y, Asai T, Takiuchi S, Moriguchi K, Ohkuro M, Komai N, Yamada K, Inamoto N, Otsuka A, Higaki J, Ogihara T (2001) Additive effects of nicorandil on coronary blood flow during continuous administration of nitroglycerin. J Am Coll Cardiol 37(3):719–725CrossRefGoogle Scholar
  8. 8.
    Taira N (1989) Nicorandil as a hybrid between nitrates and potassium channel activators. Am J Cardiol 63:18J–24JCrossRefGoogle Scholar
  9. 9.
    Frampton J, Buckley MM, Fitton A (1992) Nicorandil. A review of its pharmacology and therapeutic efficacy in angina pectoris. Drugs 44:625–655CrossRefGoogle Scholar
  10. 10.
    Nishi T, Kitahara H, Fujimoto Y, Nakayama T, Sugimoto K, Nagashima K, Hanaoka H, Kobayashi Y (2016) Efficacy of intravenous nicorandil for fractional flow reserve assessment: study protocol for a crossover randomised trial. BMJ Open 6(11):e012737CrossRefGoogle Scholar
  11. 11.
    van Nunen LX, Lenders GD, Schampaert S, van ‘t Veer M, Wijnbergen I, Brueren GR, Tonino PA, Pijls NH (2015) Single bolus intravenous regadenoson injection versus central venous infusion of adenosine for maximum coronary hyperaemia in fractional flow reserve measurement. EuroIntervention 11(8):905–913CrossRefGoogle Scholar
  12. 12.
    Jang HJ, Koo BK, Lee HS, Park JB, Kim JH, Seo MK, Yang HM, Park KW, Nam CW, Doh JH, Kim HS (2013) Safety and efficacy of a novel hyperaemic agent, intracoronary nicorandil, for invasive physiological assessments in the cardiac catheterization laboratory. Eur Heart J 34(27):2055–2062CrossRefGoogle Scholar
  13. 13.
    Lee JM, Kato D, Oi M, Toyofuku M, Takashima H, Waseda K, Amano T, Kurita A, Ishihara H, Lim WH, Doh JH, Nam CW, Tanaka N, Koo BK, Tanaka N (2016) Safety and efficacy of intracoronary nicorandil as hyperaemic agent for invasive physiological assessment: a patient-level pooled analysis. EuroIntervention 12(2):e208–e215CrossRefGoogle Scholar
  14. 14.
    Takami H, Sonoda S, Muraoka Y, Sanuki Y, Kashiyama K, Fukuda S, Oginosawa Y, Tsuda Y, Araki M, Otsuji Y (2017) Impact of additional intracoronary nicorandil administration during fractional flow reserve measurement with intravenous adenosine 5′-triphosphate infusion. J Cardiol 69(1):119–124CrossRefGoogle Scholar
  15. 15.
    Kobayashi Y, Okura H, Neishi Y, Higa T, Kobayashi Y, Uemura S, Yoshida K (2017) Additive value of nicorandil on ATP for further inducing hyperemia in patients with an intermediate coronary artery stenosis. Coron Artery Dis 28(2):104–109CrossRefGoogle Scholar
  16. 16.
    Nishi T, Kitahara H, Iwata Y, Fujimoto Y, Nakayama T, Takahara M, Sugimoto K, Kobayashi Y (2016) Efficacy of combined administration of intracoronary papaverine plus intravenous adenosine 5′-triphosphate in assessment of fractional flow reserve. J Cardiol 68(6):512–516CrossRefGoogle Scholar
  17. 17.
    Pijls NH (2013) Fractional flow reserve to guide coronary revascularization. Circ J 77:561–569CrossRefGoogle Scholar
  18. 18.
    Nishi T, Johnson NP, De Bruyne B, Berry C, Gould KL, Jeremias A, Oldroyd KG, Kobayashi Y, Choi DH, Pijls NHJ, Fearon WF, CONTRAST Study Investigators (2017) Influence of contrast media dose and osmolality on the diagnostic performance of contrast fractional flow reserve. Circ Cardiovasc Interv. CrossRefPubMedGoogle Scholar
  19. 19.
    Kobayashi Y, Johnson NP, Zimmermann FM, Witt N, Berry C, Jeremias A, Koo BK, Esposito G, Rioufol G, Park SJ, Nishi T, Choi DH, Oldroyd KG, Barbato E, Pijls NHJ, De Bruyne B, Fearon WF, CONTRAST Study Investigators (2017) Agreement of the resting distal to aortic coronary pressure with the instantaneous wave-free ratio. J Am Coll Cardiol 70(17):2105–2113CrossRefGoogle Scholar
  20. 20.
    Kawai Y, Hisamatsu K, Matsubara H, Dan K, Akagi S, Miyaji K, Munemasa M, Fujimoto Y, Kusano KF, Ohe T (2009) Intravenous administration of nicorandil immediately before percutaneous coronary intervention can prevent slow coronary flow phenomenon. Eur Heart J 30(7):765–772CrossRefGoogle Scholar
  21. 21.
    Hashimoto K, Kinoshita M, Ohbayashi Y (1991) Coronary effects of nicorandil in comparison with nitroglycerin in chronic conscious dogs. Cardiovasc Drugs Ther 5(1):131–138CrossRefGoogle Scholar
  22. 22.
    Nakae I, Quan L, Hashimoto K, Sugimoto Y, Tsutamoto T, Kinoshita M (1994) Mechanism of the vasodilatory action of nicorandil on coronary circulation in dogs. Cardiovasc Drugs Ther 8(1):137–145CrossRefGoogle Scholar

Copyright information

© Springer Japan KK, part of Springer Nature 2018

Authors and Affiliations

  • Takeshi Nishi
    • 1
  • Hideki Kitahara
    • 1
  • Yoshihide Fujimoto
    • 1
  • Takashi Nakayama
    • 1
  • Kengo Nagashima
    • 3
  • Hideki Hanaoka
    • 2
  • Yoshio Kobayashi
    • 1
  1. 1.Department of Cardiovascular MedicineChiba University Graduate School of MedicineChibaJapan
  2. 2.Clinical Research Center, University HospitalChiba University School of MedicineChibaJapan
  3. 3.Department of Global Clinical ResearchChiba University Graduate School of MedicineChibaJapan

Personalised recommendations