Coronary No-reflow Phenomenon: A Review of Therapeutic Pharmacological Agents

Document Type : Original Article


1 Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.

2 Cardiology Department, Razavi Hospital, Imam Reza International University, Mashhad, Iran.


Coronary no-reflow phenomenon (CNRP) is one of the leading catastrophic consequences of percutaneous coronary intervention (PCI). Although several preventive strategies have been advised, yet CNRP is not entirely controlled with pharmacological agents after diagnosis. This study is a review of therapeutic pharmacological agents used in various studies for post-PCI-CNRP. Several pharmacological agents have been introduced for reducing the burden of adverse outcome, before or during PCI. Although most of these agents have shown a remarkable effect on post-PCI CNRP incidence reduction, and it seems more powerful are still needed for a better validation of the results. It appears that intra lesion and distal intracoronary administrations would have a less systemic effect, and therefore may be safer than catheter injection. Moreover, adenosine, sodium nitroprusside, and calcium channel blockers are among the most routinely used methods. However, we believe that the best approach in treating or preventing no-reflow post-STMI might be combinational therapy. By the way, although there have been numerous studies on different agents capable of lessening the noreflow phenomenon, yet there is no exact guideline for choosing the most appropriate drug. A systematic review and meta-analysis on all available or practiced combinational pharmacotherapies to prevent PCI-related no-reflow are needed to suggest the most appropriate therapy.


1. Danesh Sani SH, Eshraghi A, Shahri B, Vejdanparast M. No-reflow phenomenon in patients with STelevation acute myocardial infarction, treated with primary percutaneous coronary intervention: a study of predictive factors. Journal of Cardio-Thoracic Medicine. 2014; 2 (4):221-226
2. Assali AR, Sdringola S, Ghani M, Denkats AE, Yepes A, Hanna GP, Schroth G, Fujise K, Anderson HV, Smalling RW. Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of “no reflow” phenomenon. Catheterization and Cardiovascular interventions. 2000; 51 (1):27-31
 3. Bouleti C, Mewton N, Germain S. The no-reflow phenomenon: state of the art. Archives of cardiovascular diseases. 2015; 108 (12):661-674
4. Kloner RA. No-reflow phenomenon: maintaining vascular integrity. Journal of Cardiovascular Pharmacology and Therapeutics. 2011; 16 (3-4):244-250.
 5. Rezkalla SH, Stankowski RV, Hanna J, Kloner RA. Management of no-reflow phenomenon in the catheterization laboratory. JACC: Cardiovascular Interventions. 2017; 10 (3):215-223.
6. Brosh D, Assali AR, Mager A, Porter A, Hasdai D, Teplitsky I, Rechavia E, Fuchs S, Battler A, Kornowski R. Effect of no-reflow during primary percutaneous coronary intervention for acute myocardial infarction on six-month mortality. American Journal of Cardiology. 2007; 99 (4):442-445
 7. Born GVR. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature. 1962; 194 (4832):927-929
8. Dhalla N, Pierce G, Panagia V, Singal P, Beamish R. Calcium movements in relation to heart function. Springer, 1982.
9. Post R, Merritt C, Kinsolving C, Albright C. Membrane adenosine triphosphatase as a participant in the active transport of sodium and potassium in the human erythrocyte. J biol chem. 1960; 235:1796-1802 10. Paller MS, Hoidal J, Ferris TF. Oxygen free radicals in ischemic acute renal failure in the rat. The Journal of clinical investigation. 1984; 74 (4):1156-1164
11. Barcin C, Denktas AE, Lennon RJ, Hammes L, Higano ST, Holmes DR, Garratt KN, Lerman A. Comparison of combination therapy of adenosine and nitroprusside with adenosine alone in the treatment of angiographic no‐ reflow phenomenon. Catheterization and cardiovascular interventions. 2004; 61 (4):484-491
12. Galiuto L. Optimal therapeutic strategies in the setting of post-infarct no reflow: the need for a pathogenetic classification. Heart. 2004 Feb; 90(2): 123–125.
13. Mahaffey KW, Puma JA, Barbagelata NA, DiCarli MF, Leesar MA, Browne KF, Eisenberg PR, Bolli R, Casas AC, Molina-Viamonte V. Adenosine as an adjunct to thrombolytic therapy for acute myocardial infarction: results of a multicenter, randomized, placebo-controlled trial: the Acute Myocardial Infarction STudy of ADenosine (AMISTAD) trial. Journal of the American College of Cardiology. 1999; 34 (6):1711-1720
14. Ross AM, Gibbons RJ, Stone GW, Kloner RA, Alexander RW, Investigators A-I. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). Journal of the American College of Cardiology. 2005; 45 (11):1775-1780
15. Braunwald E. Mechanism of action of calcium-channel-blocking agents. New England Journal of Medicine. 1982; 307 (26):1618-1627
16. Verdecchia P, Reboldi G, Angeli F, Gattobigio R, Bentivoglio M, Thijs L, Staessen JA, Porcellati C. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention. Hypertension. 2005; 46 (2):386-392
17. Reffelmann T, Hale SL, Li G, Kloner RA .Relationship between no reflow and infarct size as influenced by the duration of ischemia and reperfusion. American Journal of Physiology-Heart and Circulatory Physiology. 2002; 282 (2):H766-H772
18. Abbo KM, Dooris M, Glazier S, O'Neill WW, Byrd D, Grines CL, Safian RD. Features and outcome of no-reflow after percutaneous coronary intervention. The American journal of cardiology.1995; 75 (12):778-782
19. Su Q, Li L, Liu Y. Short‐ term effect of verapamil on coronary no‐ reflow associated with percutaneous coronary intervention in patients with acute coronary syndrome: a systematic review and meta‐ analysis of randomized controlled trials. Clinical cardiology. 2013; 36 (8)
20. Zhao J-L, Yang Y-J, Cui C-J, You S-J, Wu Y-J, Gao R-L. Different effects of adenosine and calcium channel blockade on myocardial no-reflow after acute myocardial infarction and reperfusion. Cardiovascular drugs and therapy. 2006; 20 (3):167-175
21. Babbitt DG, Virmani R, Forman MB. Intracoronary adenosine administered after reperfusion limits vascular injury after prolonged ischemia in the canine model. Circulation. 1989; 80 (5):1388-1399
22. Grossi L, D'Angelo S. Sodium nitroprusside: mechanism of NO release mediated by sulfhydrylcontaining molecules. Journal of medicinal chemistry. 2005; 48 (7):2622-2626
23. Salvemini D, Currie MG, Mollace V. Nitric oxide-mediated cyclooxygenase activation. A key event in the antiplatelet effects of nitrovasodilators. The Journal of clinical investigation. 1996; 97 (11):2562-2568
24. Massoudy P, Zahler S, Barankay A, Becker BF, Richter JA, Meisner H. Sodium nitroprusside during coronary artery bypass grafting: evidence for an antiinflammatory action. The Annals of thoracic surgery. 1999; 67 (4):1059-1064
25. Ignarro LJ, Lippton H, Edwards JC, Baricos WH, Hyman AL, Kadowitz PJ, Gruetter CA. Mechanism of vascular smooth muscle relaxation by organic nitrates, nitrites, nitroprusside and nitric oxide: evidence for the involvement of S-nitrosothiols as active intermediates. Journal of Pharmacology and Experimental Therapeutics. 1981; 218 (3):739-749
 26. Leone AM, Porto I, De Caterina AR, Basile E, Aurelio A, Gardi A, Russo D, Laezza D, Niccoli G, Burzotta F. Maximal hyperemia in the assessment of fractional flow reserve: intracoronary adenosine versus intracoronary sodium nitroprusside versus intravenous adenosine: the NASCI (Nitroprussiato versus Adenosina nelle Stenosi Coronariche Intermedie) study. JACC: Cardiovascular Interventions. 2012; 5 (4):402-408
27. Benz S, Schnabel R, Weber H, Pfeffer F, Wiesner R, von Breitenbuch P, Nizze H, Schareck W, Hopt UT. THE NITRIC OXIDE DONOR SODIUM NITROPRUSSIDE IS PROTECTIVE IN ISCHEMIA/REPERFUSION INJURY OF THE PANCREAS1. Transplantation. 1998; 66 (8):994-999
28. Berg R, Buhari C. Treating and preventing no reflow in the cardiac catheterization laboratory. Current cardiology reviews. 2012; 8 (3):209-214
29. Wang HJ, Lo PH, Lin JJ, Lee H, Hung JS. Treatment of slow/no‐ reflow phenomenon with intracoronary nitroprusside injection in primary coronary intervention for acute myocardial infarction. Catheterization and cardiovascular interventions. 2004; 63 (2):171-176
 30. Kobatake R, Sato T, Fujiwara Y, Sunami H, Yoshioka R, Ikeda T, Saito H, Ujihira T. Comparison of the effects of nitroprusside versus nicorandil on the slow/no-reflow phenomenon during coronary interventions for acute myocardial infarction. Heart and vessels. 2011; 26 (4):379-384
31. Parham WA, Bouhasin A, Ciaramita JP, Khoukaz S, Herrmann SC, Kern MJ. Coronary hyperemic dose responses of intracoronary sodium nitroprusside. Circulation. 2004; 109 (10):1236-1243
32. Parikh KH, Chag MC, Shah KJ, Shah UG, Baxi HA, Chandarana AH, Naik AM, Shah JN, Shah HD, Goyal RK. Intracoronary boluses of adenosine and sodium nitroprusside in combination reverses slow/no-reflow during angioplasty: a clinical scenario of ischemic preconditioning. Canadian journal of physiology and pharmacology. 2007; 85 (3-4):476-482
 33. Coller BS. Platelet GPIIb/IIIa antagonists: the first anti-integrin receptor therapeutics. The Journal of clinical investigation. 1997; 99 (7):1467-1471
34. Eeckhout E, Kern M. The coronary no-reflow phenomenon: a review of mechanisms and therapies. European heart journal. 2001; 22 (9):729-739
35. Qin T, Xie L, Chen M-H. Meta-analysis of randomized controlled trials on the efficacy and safety of intracoronary administration of tirofiban for no-reflow phenomenon. BMC cardiovascular disorders. 2013; 13 (1):68 .
36. Mak K-H . Recovery of coronary flow and left ventricular function after abciximab. Circulation. 1999; 100 (22):e110-e110
37. Sun B, Liu Z, Yin H, Wang T, Chen T, Yang S, Jiang Z. Intralesional versus intracoronary administration of glycoprotein IIb/IIIa inhibitors during percutaneous coronary intervention in patients with acute coronary syndromes: A meta-analysis of randomized controlled trials. Medicine 2017;  96 (40).
38. Chiariello M, Gold HK, Leinbach RC, Davis MA, Maroko PR. Comparison between the effects of nitroprusside and nitroglycerin on ischemic injury during acute myocardial infarction. Circulation. 1976; 54 (5):766-773
39. Sai S, Louie F, Sitaram S, Arunachalam V. Impact of intracoronary administration of nitroprusside vs. nitroglycerine before balloon dilatation on slow reflow during percutaneous coronary intervention in patients with acute ST elevation myocardial infarction. Cardiovascular Revascularization Medicine. 2011; 12 (3):e15-e16
40. Kaumann A, Lemoine H. β 2-Adrenoceptor-mediated positive inotropic effect of adrenaline in human ventricular myocardium. Naunyn-Schmiedeberg's archives of pharmacology. 1987; 335 (4):403-411.
 41. Sato T, Sasaki N, O’Rourke B, Marbán E. Nicorandil, a potent cardioprotective agent, acts by opening mitochondrial ATP-dependent potassium channels. Journal of the American College of Cardiology. 2000; 35 (2):514- 518
42. Cahoon NJ.  Efficacy and mechanism of nicorandil in perioperative protection of skeletal muscle from ischaemia and reperfusion injury in a porcine model. University of Glasgow. 2012. In available:
43. Ito H, Taniyama Y, Iwakura K, Nishikawa N, Masuyama T, Kuzuya T, Hori M, Higashino Y, Fujii K, Minamino T. Intravenous nicorandil can preserve microvascular integrity and myocardial viability in patients with reperfused anterior wall myocardial infarction. Journal of the American College of Cardiology. 1999; 33 (3):654-660
44. Ishii H, Ichimiya S, Kanashiro M, Amano T, Imai K, Murohara T, Matsubara T. Impact of a Single Intravenous Administration of Nicorandil Before Reperfusion in Patients With ST-Segment–Elevation Myocardial Infarction. Circulation.2005; 112 (9):1284-1288
 45. Lim SY, Bae EH, Jeong MH, Kang DG, Lee YS, Kim KH, Lee SH, Yoon KH, Hong SN, Park HW. Effect of combined intracoronary adenosine and nicorandil on no-reflow phenomenon during percutaneous coronary intervention. Circulation Journal. 2004; 68 (10):928-932
46. Mizumura T, Nithipatikom K, Gross GJ. Infarct size-reducing effect of nicorandil is mediated by the KATP channel but not by its nitrate-like properties in dogs. Cardiovascular research. 1996; 32 (2):274-285 47. Tsubokawa A, Ueda K, Sakamoto H, Iwase T, Tamaki S-i. Effect of intracoronary nicorandil administration on preventing no-reflow/slow flow phenomenon during rotational atherectomy. Circulation journal. 2002; 66 (12):1119-1123
48. Piot C, Croisille P, Staat P, Thibault H, Rioufol G, Mewton N, Elbelghiti R, Cung TT, Bonnefoy E, Angoulvant D. Effect of cyclosporine on reperfusion injury in acute myocardial infarction. New England Journal of Medicine. 2008; 359 (5):473-481
49. Kucukcelebi A, Ozcan M. The beneficial effect of cyclosporin-A on the no-reflow phenomenon in rat skin island flaps. British journal of plastic surgery. 1992; 45 (7):512-514
50. Stangier J, Rathgen K, Stähle H, Gansser D, Roth W. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British journal of clinical pharmacology. 22007; 64 (3):292-303
51. Spagnoli V, Klein E, Sideris G, Magkoutis N, Brumpt C, Bal Dit Sollier C, Henry P, Drouet L. Correlation between burst of thrombin and microvacular obstruction (no reflow) during ST Elevation Myocardial Infarction treated by primary percutaneous coronary Intervention. European Heart Journal. 2013; 34 (suppl_1):1608
52. Hale SL, Kloner RA. Dabigatran treatment: effects on infarct size and the no-reflow phenomenon in a model of acute myocardial ischemia/reperfusion. Journal of thrombosis and thrombolysis. 2015; 39 (1):50-54
53. Nauck MA, Meier JJ. Glucagon-like peptide 1 and its derivatives in the treatment of diabetes. Regulatory peptides. 2005; 128 (2):135-148
54. Chen WR, Tian F, Dai Chen Y, Wang J, Yang JJ, Wang ZF, Da Wang J, Ning QX. Effects of liraglutide on no-reflow in patients with acute ST-segment elevation myocardial infarction. International journal of cardiology. 2016; 208:109-114
55. Poupko JM, Baskin SI, Moore E. The pharmacological properties of anisodamine. Journal of Applied Toxicology. 2007; 27 (2):116-121
 56. Niu X, Zhang J, Bai M, Peng Y, Sun S, Zhang Z. Effect of intracoronary agents on the no-reflow phenomenon during primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction: a network meta-analysis. BMC cardiovascular disorders. 2018; 18 (1):3
57. Jun W, FAN G, Yunfa WJ.  Effect of intracoronary administration of anisodamine on slow reflow phenomenon following primary percutaneous coronary intervention in patients with acute myocardial infarction [J]. Journal of Clinical Cardiology. 2006; 1:008
58. Poeggeler B, Saarela S, Reiter RJ, TAN DX, CHEN LD, Manchester LC, BARLOW‐ WALDEN LR. Melatonin—a highly potent endogenous radical scavenger and electron donor: new aspects of the oxidation chemistry of this indole accessed in vitro. Annals of the New York Academy of Sciences. 1994; 738 (1):419-420
59. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y . Protective role of melatonin in cardiac ischemia‐ reperfusion injury: from pathogenesis to targeted therapy. Journal of pineal research. 2018; 64(3).
 60. Reiter RJ, Tan D-X. Melatonin: a novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovascular research. 2003; 58 (1):10-19
61. Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial— Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. The Lancet. 2003; 361 (9364):1149- 1158
62. Liu W, Zou Z, Jiang H, Li Q, Guo F, Wang Z, Zhu H. Clinical effect of preoperative high-dose atorvastatin against no-reflow after PCI. Experimental and therapeutic medicine. 2017; 13 (1):97-102
63. BriguoriC C, Visconti G, Focaccio A, Golia B, Chieffo A, Casteli A, et al.  Novel approaches for preventing or limiting events (Naples) II trial: impact of a single high loading dose of atorvastatin on periprocedural myocardial infarction. J Am Coll Cardiol. 2009 Dec 1;54(23):2157-63.
64. Eshraghi A, Talasaz AH, Salamzadeh J, Salarifar M, Pourhosseini H, Nozari Y, Bahremand M, Jalali A, Boroumand MA . Evaluating the effect of intracoronary N-acetylcysteine on platelet activation markers after primary percutaneous coronary intervention in patients with ST-elevation myocardial infarction. American journal of therapeutics. 2016; 23 (1):e44-e51
65. Andrews NP, Prasad A, Quyyumi AA. N-acetylcysteine improves coronary and peripheral vascular function. Journal of the American College of Cardiology. 2001;  37 (1):117-123
66. Weinbroum AA, Kluger Y, Abraham RB, Shapira I, Karchevski E, Rudick V. LUNG PRECONDITIONING WITH N-ACETYL-l-CYSTEINE PREVENTS REPERFUSION INJURY AFTER LIVER NO FLOW-REFLOW: A DOSE-RESPONSE STUDY1. Transplantation 2001; 71 (2):300-306