Mazen K. Khalil, MD, FSCAI; Tamara Atkinson, MD, FSCAI; Faisal Latif, MD,FSCAI

Introduction

No reflow is a challenging complication of percutaneous coronary intervention (PCI). No reflow occurs mainly in ST segment elevation myocardial infarction (STEMI) and saphenous vein graft (SVG) PCI but can occur during elective PCI.1 No reflow, defined as thrombolysis in myocardial infarction (TIMI) flow grade < 3 and myocardial blush grade < 3, manifests as abnormal epicardial blood flow despite relief of coronary obstruction.2 Clinically, the patient can experience hemodynamic instability, ischemic symptoms, and ST elevation.3 The mechanism of no reflow is multifactorial with the primary cause being microvascular obstruction,1, 3 due to distal embolization of thrombus or debris, microvascular spasm, intravascular plugging from platelet microthrombi or leukocytes, or ischemia-reperfusion injury.1, 2, 4

This Tip of The Month (TOTM) will focus on the prevention and management of no reflow.

Risk Factors for No Reflow

Clinical risk factors3 include female sex, age > 65, hypertension, diabetes, hyperlipidemia, CHADS2-VASc score ≥ 3,5 delayed presentation to the cath lab for STEMI patients, mild to moderate renal insufficiency, and increased inflammatory markers. Angiographic risk factors include high thrombus burden, plaque composition,6 reperfusion time > 6 hours, SVG PCI, and lesions longer than 15 mm.1, 4

Strategies to Prevent No Reflow

Preventive strategies for no reflow should be an integral part of pre-PCI planning in patients with STEMI (especially delayed presentation and extensive thrombus), SVG PCI, and atherectomy.1, 4, 7

  1. Primary stenting (based on imaging guidance) and avoidance of high-pressure post dilatation should be considered, when possible, in patients with STEMI at high risk for no reflow.
  2. When using atherectomy, shorter burr runs (< 20 seconds), lower burr speeds (140,000 to 150,000 rpm), and avoidance of decelerations > 5,000 rpm are useful to reduce the risk of no reflow secondary to debris embolization.7
  3. Using an embolic protection device and pretreatment with intracoronary vasodilators should strongly be considered when performing an SVG PCI.

Treatment of No Reflow

When no reflow is suspected, other causes of vessel occlusion such as dissection, thrombus migration, and vasospasm should be excluded with imaging.7 Once vessel patency is confirmed, administer vasodilators liberally, ensure therapeutic activated clotting time (ACT), and provide hemodynamic support if needed (Impella, balloon pump, etc.). Management includes pharmacologic and nonpharmacologic measures, as listed in the table below.1, 4, 7

Pharmacologic Therapies1

Medication

Route

Dose

 

Adenosine

IC

IV

50–200 µg bolus

70 µg/kg/min

 

Verapamil

IC

100–250 µg bolus

 

Diltiazem

IC

400 µg bolus

 

Nicardipine

IC

50–200 µg bolus

 

Nitroprusside

IC

50–200 µg bolus

 

Epinephrine

IC

50–200 µg bolus

 

GP IIb/IIIa inhibitors

IV

 
 

   1. Abciximab

 

   1. Bolus: 0.25 mg/kg; IV infusion: 0.125 mg/kg/min

   2. Eptifibatide

 

   2. Bolus: 180 mg/kg; IV infusion: 2 mg/kg/min IV bolus: 25 mg/kg; IV infusion

   3. Tirofiban

 

   3. Bolus: 25 mg/kg; IV infusion: 0.15 mg/kg/min

Nonpharmacologic therapies1

Thrombectomy

 

High thrombus burden

  1. Intracoronary delivery of medications is ideally performed using a microcatheter or over-the-wire balloon in the distal coronary artery; this minimizes systemic side effects and ensures delivery to the microcirculation. A dedicated dual-lumen or thrombectomy catheter allows distal drug delivery without losing wire position.
  2. Medications can be administered in multiple boluses if no reflow persists and the patient is hemodynamically stable. Use of different vasodilators can be tried if the first one doesn’t achieve improvement in flow.
  3. Epinephrine use resulted in improved flow, ST segment resolution, and improved ejection fraction in no reflow refractory to conventional management, based on the RESTORE trial, which was a nonrandomized study.8
  4. Even though they improved vessel patency after no reflow during STEMI, adenosine and sodium nitroprusside did not improve mortality or heart failure. Although adenosine decreased the infarct size in the AMISTAD II trial,9 it was suggested to cause harm in the REFLO-STEMI trial;10 however, the dose of adenosine used in REFLO-STEMI was very high (1–2 mg).

Outcome of Patients With No Reflow Phenomenon

No reflow leads to decreased five-year survival after STEMI11 (18.2% mortality in patients with no reflow compared to 9.5% in patients with normal flow). The increase in mortality secondary to no reflow was independent of other variables such as infarct size, multivessel disease, or Killip class.11 Larger infarct size was also noted in the no reflow group (15% of the left ventricle in the no reflow group compared to 8% in normal flow).11 In addition, no reflow has been associated with increased incidence of systolic heart failure and malignant arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, and high-degree atrioventricular [AV] block).12

Conclusion

In conclusion, no reflow leads to worse outcomes, especially in patients presenting with STEMI. The following tips are recommended to prevent and treat this PCI complication:

  1. Use preventive measures to reduce the risk of no reflow.
  2. Confirm the diagnosis of no reflow using intravascular ultrasound (IVUS).
  3. Avoid aggressive stent inflation/post-dilation.
  4. Use a microcatheter for distal delivery of vasodilator agents.
  5. Use multiple vasodilator agents for refractory no reflow as well as GP IIb/IIIa inhibitors.

 

References

  1. Caiazzo G, Musci RL, Frediani L, et al. State of the Art: No-Reflow Phenomenon. Cardiol Clin. 2020 Nov;38(4):563–573.
  2. Rezkalla SH, Kloner RA. No-reflow phenomenon. 2002 Feb 5;105(5):656–62.
  3. Jaffe R, Charron T, Puley G, et al. Microvascular obstruction and the no-reflow phenomenon after percutaneous coronary intervention. Circulation. 2008 Jun 17;117(24):3152–6.
  4. Rezkalla SH, Stankowski RV, Hanna J, et al. Management of No-Reflow Phenomenon in the Catheterization Laboratory. JACC Cardiovasc Interv. 2017 Feb 13;10(3):215–223.
  5. Huang X, Zheng W, Zhao XD, et al. CHA2DS2-VASc score predicts the slow flow/no-reflow phenomenon in ST-segment elevation myocardial infarction patients with multivessel disease undergoing primary percutaneous coronary intervention. Medicine (Baltimore). 2021 May 28;100(21):e26162.
  6. Tanaka A, Kawarabayashi T, Nishibori Y, et al. No-reflow phenomenon and lesion morphology in patients with acute myocardial infarction. 2002 May 7;105(18):2148–52.
  7. Klein LW, Kern MJ, Berger P, et al. Society of cardiac angiography and interventions: suggested management of the no-reflow phenomenon in the cardiac catheterization laboratory. Catheter Cardiovasc Interv. 2003 Oct;60(2):194–201.
  8. Navarese EP, Frediani L, Kandzari DE, et al. Efficacy and safety of intracoronary epinephrine versus conventional treatments alone in STEMI patients with refractory coronary no-reflow during primary PCI: The RESTORE observational study. Catheter Cardiovasc Interv. 2021 Mar;97(4):602–611.
  9. Ross AM, Gibbons RJ, Stone GW, et al. A randomized, double-blinded, placebo-controlled multicenter trial of adenosine as an adjunct to reperfusion in the treatment of acute myocardial infarction (AMISTAD-II). J Am Coll Cardiol. 2005 Jun 7;45(11):1775–
  10. Nazir SA, Khan JN, Mahmoud IZ, et al. The REFLO-STEMI (REperfusion Facilitated by LOcal adjunctive therapy in ST-Elevation Myocardial Infarction) trial: a randomised controlled trial comparing intracoronary administration of adenosine or sodium nitroprusside with control for attenuation of microvascular obstruction during primary percutaneous coronary intervention. Efficacy Mech Eval. 2016 Dec;3(9).
  11. Ndrepepa G, Tiroch K, Fusaro M, et al. 5-year prognostic value of no-reflow phenomenon after percutaneous coronary intervention in patients with acute myocardial infarction. J Am Coll Cardiol. 2010 May 25;55(21):2383–9.
  12. Morishima I, Sone T, Okumura K, et al. Angiographic no-reflow phenomenon as a predictor of adverse long-term outcome in patients treated with percutaneous transluminal coronary angioplasty for first acute myocardial infarction. J Am Coll Cardiol. 2000 Oct;36(4):1202–9.