Pursuing the goal to improve downstream myocardial tissue perfusion.

The coronary slow flow phenomenon is an angiographic finding characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Extensively studied both in the experimental and clinical setting, it was clearly associated with unfavourable clinical outcome and prognosis. Several hypotheses, including embolization of platelet-rich thrombi or atherosclerotic plaque debris that can ‘sludge’ the distal vessel, and release of vasoconstrictive substances causing intense vasospasm of the distal microcirculation, were advocated to justify this event in the context of percutaneous coronary intervention. If the principal mechanism of the slow flow phenomenon is vasoconstriction, this would explain the favourable response seen with intracoronary administration of calcium antagonists such as verapamil, or vasodilators such as nitroprusside, papaverine, and adenosine. Nicorandil, a nicotinamide ester, is a vasodilator agent approved as an antianginal agent, with a compound and balanced mechanism of action which relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cGMP levels as well as by a second mechanism resulting in activation of Kþ channels and hyperpolarization. Potassium channel opening effects a titratable and sustained dilating action on both coronary artery conductance and resistance vessels. Kawai et al. have provided evidence that a prophylactic bolus of 6 mg of nicorandil administered i.v. immediately prior to percutaneous coronary intervention (PCI) reduces the incidence of the slow flow phenomenon without any side effects. Conceptually, this strategy improves coronary flow and myocardial perfusion by dilating those vessels with loss of endothelial integrity and reducing capillary and arteriolar blockages resulting from the presence of leukocytes and atheroemboli. To test this hypothesis, the authors randomly assigned 408 patients to undergo i.v. administration of nicorandil or placebo on top of isosorbide dinitrate just 1 min before PCI. They used the incidence of slow flow established by means of the corrected TIMI frame count as the primary endpoint to assess the efficacy of the drug on distal perfusion. A total of nine (4.4%) patients receiving nicorandil, and 36 (17.8%) receiving placebo, experienced slow flow after angioplasty. Also, the corrected TIMI frame count was lower in the nicorandil group (10.5+ 5.6 vs. 12.8+7.4, P ,0.0001). Although not powered to show a difference in secondary endpoints, the study achieved consistent findings in patients presenting with either acute coronary syndrome or stable angina. In addition, serum assessment of cardiac enzymes from patients with acute myocardial infarction revealed a beneficial effect of nicorandil in the acute phase of ischaemia. This study raises some interesting points worthy of discussion. First, although the occurrence of slow flow is generally associated with reperfusive treatment of myocardial infarction, it could also represent a complication of the elective percutaneous treatment of stable angina in a substantial number of cases. In this case, the fragmentation of atherosclerotic plaque plays an important role, but a full understanding in this setting is probably lacking. Secondly, once it has been clarified that a number of pieces of evidence on the efficacy of different possible therapeutic approaches may be provided, including those on nicorandil, our attention should be shifted from research of the best drug to the identification of a protocol for a simple, safe, and repeatable administration. As a matter of fact, to date no clear guidelines on the management of slow flow are available, and current protocols which are too complex have often restricted the diffusion and standardization of adjuvant therapy. As a result, this complication is not treated in all cases and on a regular basis. Thirdly, a preventive approach could represent the best solution to the problem. In this context, nicorandil plays an interesting and somehow a particular role. When compared with adenosine, in fact, this drug not only improves coronary microvascular circulation, but also dilates