OK-Flow. Sorry – No-Reflow
Coronary angioplasty (PCI) is probably the most important invasive therapeutic tool developed in cardiology in the last 30-40 years. As we know, it addresses to obtain reperfusion in ischemic heart disease and especially in acute myocardial infarction (AMI). Reperfusion in large coronaries is obtained in almost all cases. But – here comes the drama – reperfusion in the myocardium is less. Some authors believe that no-reflow (NR) is common in about 10% of interventions in AMI, others suggest a proportion of 60% (!) (1), while the solid study published a few years ago by Rezkalla (2) reports that 32% of coronary angioplasties in AMI are followed by the no-reflow phenomenon. These figures may be influenced by the diagnostic method used and we will make further comments on this subject.
No-reflow phenomenon is a serious problem which is caused by many reasons. Firstly, the prognostic impact of no-reflow is great and counterbalances the immense advantage of getting reperfusion in large coronaries. Secondly, we do not know the exact mechanism. Thirdly, current therapies are more or less disappointing (1, 3, 4).
The prognostic implications are important. Firstly, it is clearly demonstrated that the ejection fraction is lower, remodelling of the left ventricle is worth, consecutive heart failure is more severe and cardiac rupture more common after PCI in AMI in patients with NR comparatively to those without NR (1, 3). One simple explanation is that, if there is NR, repairing cells and humoral factors cannot enter in that area to promote healing. What is the most important, the prognostic importance of NR is huge. In patients with NR, the one-year and five-year risk of death is three and two times higher, respectively, than in those without NR (3).
The main diagnostic tools come from coronarography. TIMI Grade less than 3, Myocardial Blush Grade less than 3 or higher TIMI frame count are currently used to diagnose and try to quantify the no-reflow (1, 3). However, all these three methods are not perfect, because the complexity of the NR phenomenon develops after performance of coronarography in the acute phase. For this reason, magnetic nuclear resonance (MRI) is the best method to diagnose NR. It is demonstrated that up to 60% of patients with a TIMI or Blush score of 3 (means normal perfusion) have actally elements of no-reflow at MRI (3). Contrast echocardiography or scintigraphy may also be taken into account, but they do not have the diagnostic value of MRI.
The physiopatholgy of NR is complicated. The main mechanisms involved include myocardial edema developed during acute ischemia prior to reperfusion, which compresses the intramyocardial vessels, and reperfusion injury caused by the free radicals developed during ischemia and which damages the myocardium and microvessels once they are spread when reperfusion is restored or distal embolization of atheroma debris or platelet rich microthrombi are displaced by the baloon during the procedure (1, 3). If so different mechanisms are supposed to act, it is clear that a single therapy cannot be imagined.
Indeed, therapies for every of the imagined mechanisms were applied and unfortunately, not a single one succeeded in being significantly effective. Some benefit is obtained, however.
• Thrombus aspiration is a logical approach, in order to block supposed microemboli during baloon inflation. Aspiration of thrombi before PCI and stenting as well as using devices distal to the baloon to catch the microemboli showed no reduction of NR and no clinical benefit (1, 3, 4).
• Mechanical ischaemic postconditioning is based on experimental data showing that brief and repeated ischaemia provoked by baloon inflation immediately after reflow may significantly reduce the infarct size. Initial data on few patients suggested such a reduction by 40-50%. However, consecutive studies on large population of reperfused AMI showed no clinical benefit (3).
Pharmacological therapies were addressed to different supposed mechanisms.
• Adenosine is a potent arteriolodilator. It had initially good results in small trials, but later on, serious trials such AMISTAD II showed no clinical benefits. Adenosine was even injected in coronaries, with no effect.
Only some late small trials suggested reduced short term mortality (3).
• Glycoprotein IIb/IIIa inhibitors were supposed to act on microemboli produced by the distruction of the occluding thrombus of the large coronary. Small benefits were noted by using intracoronaru abciximab (2).
• Various calcium channel blockers were tried, including verapamil, diltiazem and nicardipine. The clinical benefit was small, but it was foud repeatedly (1-3).
• Sodium nitroprusside administered by intracoronary repeated small bolus injections showed benefit on major adverse events. Today it is considered the main pharmacologic adjunct, but hypotension should be drastically monitored (2, 3).
• Metoprolol has been also tested, with some promising results (3).
• Other pharmacologic therapies such as epinephrine, nicorandil, imatinib, cyclosporine A or liraglutide were tested on small groups of patients (1-3).
The most promising approach to reduce the no-reflow phenomenon seems to be the combination of mechanical and some pharmacological approaches adjunctive to the large coronary reperfusion procedure (1).
From all these, the only therapy able to fight no-reflow which is mentioned in the 2017 ESC STEMI Guidelines involves the use of abciximab as a bailout procedure in the postinterventional moments. But this is only a IIa C recommendation (5). The ACCF/AHA Guidelines for STEMI date back to 2013 (6). In the text it is mentioned that ”No-reflow is associated with a reduced survival rate”, thrombus aspiration and some pharmacological approachs for NR are mentioned in two phrases, both finishing with the assumptions ”without consistent effect” or ”not all studies have shown positive results” (6). In an American comment on the 2017 ESC Guidelines on STEMI, there are 10 points of observations. From these, the first seven make reference to PCI reperfusion, which may be a main therapeutic tool (7).
No mention of no-reflow in these comments. All the other European or American Guidelines on AMI in the last decade do not comment on the no-reflow phenomenon.
We may say that:
• PCI reperfusion is the main non-pharmacological tool in AMI (and probably the main therapy overall)
• In all cases, no-reflow appears (probably) during the procedure
• No-reflow consistently produces a worth prognosis and increased mortality
• Many possible mechanisms are supposed for NR, but no one is considered to be the main
• From the more than 10 therapies which have been tested, only one – abciximab – is mentioned as a IIaC bailout procedure in only one of the many European and American Guidelines on AMI in the last decade.
Interventional revascularization in AMI is the main therapeutic tool in AMI. The accompanying no-reflow is the main unconquered fortress.