No Reflow and Slow Flow

Associate Editors-In-Chief: Jennifer Giuseffi, M.D.; David M. Leder, M.D.

Background
The no reflow, or slow flow, phenomenon refers to inadequate myocardial perfusion with evidence of persistent myocardial ischemia of a target vessel following thrombolysis or percutaneous coronary intervention (PCI) without angiographic evidence of mechanical obstruction.

Prevalence
The prevalance of no flow and slow flow varies according to definition. It has been reported in anywhere from 11-30% of patients following thrombolysis or intervention in acute myocardial infarction. However, in routine, elective coronary intervention, the prevalence has been reported to be as low as 0.6-2%. This phenomenon appears to be more frequent during interventions on saphenous vein grafts (SVG) or thrombus containing lesions as well as during the use of rotational atherectomy.

Associations
Gender does not appear to play a role in this phenomenon, but it seems to occur more frequently in older patients and in those who did not experience pre-infarct angina. Admission hyperglycemia has also been associated with higher incidence of no reflow as well as worse outcomes. Lesions at high-risk for no reflow and slow flow include: diffuse atherosclerotic involvement, angiographic demonstrable thrombus, irregular or ulcerative lesions, and long lesions with large plaque volume.

Mechanism
The primary mechanism is micro-embolization of either plaque debris or thrombotic material to the distal micro-vasculature following balloon inflation or stent deployment. Another possible additional mechanism is arteriole vasospasm secondary to vasoactive agents, i.e. serotonin, adenosine diphosphate, thromboxane A2, released by the embolized platelet-rich atheromatous material. Other factors that may contribute as well include microvascular plugging with platelets or leukocytes, endothelial swelling, tissue edema compressing vasculature, oxidative stress and inflammation.

Clinical Implications
No reflow often appears suddenly, is associated with severe chest pain, ischemic ECG changes, and/or hemodynamic deterioration. This needs to be distinguished from slow flow, which can be caused by coronary dissection, macrothrombus formation, coronary vasospasm, or distal macroembolization.

The presence of no reflow is clinically important as its presence has been associated with a five to ten fold increase in mortality, as well as a high incidence of myocardial infarction (MI), left ventricular dysfunction, ventricular arrhythmias, early congestive heart failure and cardiogenic shock.

Goals of Treatment
Restore normal blood flow through epicardial coronary arteries & microvasculature to prevent persistence of myocardial ischemia. No reflow needs to be distinguished from slow flow resulting from coronary artery dissection, thrombus, coronary vasospasm, or residual stenosis. These etiologies must be excluded as part of the treatment of no reflow. Ultimately, the goals are to improve outcomes, relieve chest pain and alleviate myocardial ischemia.

Prophylaxis
When intervening on high-risk lesions (see above for description), limit the amount of instrumentation within the target vessel, which includes minimizing overaggressive balloon or stent expansion. In patients undergoing rotational atherectomy, shorter runs, slower speeds and smaller initial burr size with small stepwise increases in burr size should be employed to help prevent no reflow. In addition, a cocktail of heparin, nitroglycerin and calcium channel blockers (CCB) should be infused simultaneously. Adding two arteriolar vasodilators, i.e. nicardipine and adenosine, to the flush "cocktail" may be helpful in further reducing incidence of no reflow, however traditionally the CCB used is verapamil.

Thrombus aspiration catheters may be used in high-risk patients undergoing primary PCI for STEMI with occlusion or high thrombus burden. The EXPIRA study published in 2009 showed the use of a thrombus aspiration catheter in anterior STEMI patients improves myocardial perfusion, reduces infarct size by cardiac MRI and reduces cardiac death at nine months. Care should be exercised when aspirating in the proximal LAD or proximal circumflex locations so that clot does not go down the other adjacent artery.

Distal protection devices may be used in SVGs to prevent distal embolization of clot, debris, and vasoactive mediators. However, the Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) and the Protection Devices in PCI Treatment of Myocardial Infarction for Salvage of Endangered Myocardium (PROMISE) trials showed inconsistent results with regards to embolic protection devices in use for primary PCI of native vessels.

Systemic glycoprotein IIb/IIIa receptor antagonists are recommended as pre-treatment in patients presenting with unstable coronary syndromes undergoing PCI. The TITAN-TIMI 34 trial showed early initiation of eptifibatide in the emergency room prior to primary PCI improved myocardial perfusion without an increased risk of bleeding.

A recent study by Zhao JL et al in 2009 showed patients presenting with acute MI and hyperglycemia had lower incidence of no reflow if they were pretreated with HMG-CoA reductase inhibitors prior to angiography.