Slow flow and the no-reflow phenomenon are feared complications after percutaneous coronary interventions (PCIs). In general terms, both phrases refer to impaired epicardial coronary flow and myocardial perfusion despite patency of the epicardial arteries during PCI. Slow flow and no-reflow usually manifest as a failure of the affected artery to opacify after angioplasty or stenting of the occluded segment during acute myocardial infarction (AMI) (no-reflow), or as a reduction in flow in the affected artery after PCI of a nonoccluded segment. No-reflow is associated with a worse prognosis and has been shown to be an independent predictor of death, MI, and impaired left ventricular function.1-5 Several key pathophysiological processes, usually in combination, are believed to be responsible for this complication, including distal embolization of atherothrombotic debris, thrombus formation, and endothelial dysfunction of the distal arteriolar and capillary bed, including endothelial desquamation and microcirculatory vasospasm.6 The incidence of this complication varies with the type of PCI, being highest in the setting of primary PCI, saphenous vein graft (SVG) intervention, and rotational atherectomy (Table 1).7 Several management strategies have undergone evaluation in trials with variable success rates, and continued understanding of this phenomenon suggests that prevention might be better than the cure in most settings.8

PATHOPHYSIOLOGY
An understanding of the pathophysiology of slow flow and no-reflow is critical in understanding the various preventive and treatment strategies. The no-reflow concept was first described in animal brain ischemic models in 1967.9 Brains of rabbits exposed to long periods (>2.5 minute) of ischemia did not have normal blood flow restored when the ischemia was relieved. This was pathologically correlated with changes in brain microvasculature that impeded normal flow to brain cells.10,11 Kloner et al demonstrated a similar phenomenon in canine hearts, in which prolonged periods (>90 minutes) of proximal coronary occlusion were associated with only partial restoration of coronary flow despite removal of the coronary occlusion.11 Electron microscopy of the coronary microvasculature within the no-reflow zones showed significant capillary damage with endothelial swelling and intraluminal protrusions, which could occlude the capillary lumen. Other studies highlighted the role of intravascular plugging with fibrin, platelets, leukocytes, and atherothrombotic debris as potential contributors to the no-reflow phenomenon.12-16 The etiology of no-reflow and slow flow in any patient is, therefore, likely multifactorial, with endothelial damage in the microvasculature during ischemia and distal embolization of microparticles during reperfusion, resulting in diminished myocardial perfusion. This complex interaction is illustrated in Figure 1.

DIAGNOSIS OF SLOW FLOW AND NO-REFLOW
Slow flow and no-reflow with impaired myocardial perfusion can be diagnosed angiographically or by using adjunctive imaging modalities that can quantify myocardial perfusion, such as myocardial contrast echocardiography. Angiographically, the most widely used schemes to describe coronary flow and myocardial perfusion, both qualitatively and semiquantitatively, include the TIMI blood flow grades, the corrected TIMI frame count (TFC), and the myocardial blush grade (MBG).17-19 These schemes are summarized in Table 2.

The TIMI coronary flow grade was introduced by the TIMI study group in 1985 as a simple, qualitative tool to assess angiographic coronary flow rates to gauge the efficiency of thrombolytic therapy.17 Coronary flow is graded on a scale of 0 through 3 depending on flow characteristics, as summarized in Table 2. Improved TIMI grades have been shown to be correlated with improved outcomes.20,21 No-reflow is traditionally defined as TIMI grade 0 or 1, and slow flow is defined as TIMI grade 2 in this scheme.17 The TFC method, first described by Gibson et al, provided a semiquantitative method of assessing coronary flow.22 The number of angiographic frames for contrast to reach a specified distal segment in the coronary artery with cineangiography performed at 30 frames per second through a 6-F catheter was designated the TFC. The distal landmarks and normal reference ranges are summarized in Table 1. A further correction is made in the TFC for the left anterior descending artery (LAD), given its longer length relative to the other coronary arteries, by dividing the TFC in the LAD by a factor of 1.7, which yields the corrected TFC (cTFC). Normal coronary and microvascular function usually yield a cTFC of <20, a slow flow of cTFC of 20 through 40, and a no-reflow cTFC of >40.21 The prognostic significance of the cTFC was studied in an analysis of patients enrolled in the TIMI studies, in which it was shown to be an independent predictor of mortality.22

The concept of MBG was developed as a means of describing myocardial perfusion at the level of the capillary, in addition to describing epicardial artery flow.18 Myocardial microvascular perfusion, as assessed by an MBG score, has been shown to be one of the strongest predictors of mortality after primary PCI, independent of infarct artery patency.23 MBG is scored 0 to 3, as summarized in Table 2. In this scheme, true no-reflow would correlate with an MBG of 0 and 1, and slow flow would correspond with an MBG of 2. Of course, the accuracy of these three methods depends on several factors, such as amount of contrast injected, length of injection, and fluoroscopic time, as well as systemic blood pressure. For example, a contrast injection rate increase of more than 1 mL/s by hand injection can decrease the cTFC by two frames.24

Adjunctive imaging modalities that can assess myocardial perfusion and have found clinical utility in identifying no-reflow zones include myocardial contrast echocardiography,25,26 nuclear imaging,27,28 contrast-enhanced MRI,29,30 and PET imaging.31 However, despite the availability of these adjunctive imaging modalities, the diagnosis of coronary slow flow and no-reflow after PCI remains largely an angiographic one. Importantly, no-reflow must be suspected clinically if there is a lack of ST-segment resolution after PCI.

SLOW-FLOW AND NO-REFLOW IN AMI
PCI in the setting of AMI is associated with high rates of distal embolization due to the relatively high thrombus burden associated with plaque rupture and coronary occlusion. The sequelae of distal embolization results in reduced myocardial perfusion and increased myocyte damage, which portends a worse prognosis.32 Macroscopic distal embolization may be seen in up to 16% of patients undergoing primary PCI,32 and suboptimal tissue perfusion may be seen in 20% to 40% of patients despite restoration of TIMI 3 epicardial flow.18,33 A number of strategies may be employed to prevent slow flow and no-reflow during primary PCI. First, given the central role of duration of ischemia in the pathogenesis of impaired flow, primary PCI should be performed as soon as possible to limit ischemia reperfusion injury. In the catheterization laboratory, two technologies have emerged as potentially beneficial in improving epicardial and myocardial perfusion: adjunctive pharmacotherapy with glycoprotein IIb/IIIa inhibitors (GPIIb/IIIa) and mechanical devices to prevent distal embolization.

GPIIb/IIIa inhibitors block the final common pathway in the platelet activation and aggregation cascade, and as such, exert a powerful antithrombotic effect. Abciximab remains the most studied agent in this class in the treatment of AMI. In the Abciximab before Direct Angioplasty and Stenting in Myocardial Infarction Regarding Acute and Long-Term Follow-up (ADMIRAL) trial, upstream use of abciximab resulted in a higher rate of TIMI 3 flow after primary PCI compared to placebo in patients with STEMI undergoing primary PCI (95.1% vs 86.7%; P=.04) and was associated with reduced major adverse cardiac events (MACE) at 30 days (6% vs 14.6%; P<.01).34 The Controlled Abciximab and Device Investigation to Lower Late Angioplasty Complications (CADILLAC) trial, by comparison, did not demonstrate a benefit with abciximab on final TIMI 3 flow in patients with STEMI undergoing primary PCI.35 However, abciximab was only given at the time of PCI in the CADILLAC trial, compared to upstream administration in the ADMIRAL trial. Other studies have demonstrated specifically the beneficial impact of using GPIIb/IIIa inhibitors during primary angioplasty on coronary microvascular flow using the coronary flow wire measurements36 and myocardial contrast echocardiography.37 This strongly suggests that the beneficial effect of abciximab results, at least partly from reduction of no-reflow zones in the myocardium. Moreover, a recent meta-analysis of all trials of abciximab in STEMI (11 trials; 27,115 patients) showed that abciximab administration during primary angioplasty is associated with a significant mortality reduction.38 These data from randomized controlled trials confirm improved epicardial flow, better tissue perfusion with less no-reflow phenomenon, and improved clinical outcomes with abciximab use in STEMI, and therefore make a compelling case for the use of abciximab as a standard of care in patients undergoing primary PCI.

The use of adjunctive mechanical devices to prevent distal embolization during primary PCI appears intuitive. Several devices have now been evaluated in randomized clinical trials,39-58 the results of which are briefly summarized in Table 3. As illustrated in Table 3, a number of devices have been tested, generally in small trials that used surrogate endpoints as the primary outcome measure. Most trials were generally underpowered to detect a mortality benefit and failed to do so. The results of many of these randomized trials were summarized in a recent meta-analysis (21 trials, 3,721 patients) by De Luca et al,45 which showed that adjunctive mechanical devices to prevent distal embolization in patients with AMI treated with primary PCI were associated with higher rates of postprocedural TIMI 3 flow and MBG 3, as well as less distal embolization.59 However, despite these improvements in epicardial flow and myocardial perfusion, no benefit was noted in terms of 30-day mortality. Although the reasons for this discrepancy in trial findings are not clear, it highlights the need for larger trials with higher-risk patients and longer-term follow-up to optimally define the role of adjunctive mechanical devices in primary PCI. Until such data are available, routine use of adjunctive devices to prevent distal embolization during primary PCI remains a controversial and unresolved issue.

A number of vasodilator agents have been shown to improve surrogate endpoints, such as TIMI flow rate, corrected TIMI frame counts, and wall motion scores, among others, when used as an adjunct in treating AMI. Such vasodilator agents include adenosine, verapamil, nicorandil, and sodium nitroprusside.1,60-63 However, the results of the Acute Myocardial Infarction Study of Adenosine (AMISTAD) trials highlight the pitfalls in accepting these surrogate endpoints. The AMISTAD studies investigated the utility of adenosine in primary PCI. In the first (and smaller) AMISTAD study, which was not powered to evaluate clinical endpoints, a 3-hour intravenous infusion of adenosine (70 µg/kg per minute) resulted in a relative reduction in infarct size of 33% in patients treated with thrombolysis.63 This result formed the basis of the larger AMISTAD-II study (n=2,118), which was powered to evaluate clinical endpoints in patients treated with either thrombolysis or primary PCI.64 Although a significant 57% relative reduction in infarct size was again demonstrated with the 70 µg/kg per minute infusion, the study did not show any benefit in clinical endpoints, including mortality rates. In this instance, improvement in validated surrogate endpoints did not appear to translate into meaningful clinical benefits. An exception in this category would appear to be nicorandil, which was shown to significantly reduce the primary clinical endpoint of death or heart failure (6.5% vs 16.4%; P=.05) when administered as a single intravenous dose of 12 mg in a 368-patient randomized study of acute STEMI patients undergoing primary PCI.60 Therefore, although some of the results are encouraging, there would not appear to be sufficient evidence to recommend routine use of any vasodilator agents during primary PCI. Their use should be reserved for the treatment of no-reflow when preventive measures have failed.

SLOW FLOW AND NO-REFLOW IN SVG PCI
SVG PCI is associated with high rates of distal atherothromboembolism due to graft degeneration, higher atherosclerotic and thrombotic burden, and a softer plaque composition.65 A high incidence of no-reflow (approximately 8%), as well as a high incidence of periprocedural MI (up to 28%), has been reported with SVG PCI.7 Because patients with SVG tend to have a higher burden of coronary disease and impaired left ventricular function, they have a tendency to have a particularly adverse prognosis after these distal embolic complications.66 Therefore, prevention of distal embolization in SVG PCI is a relatively more important goal.

Several embolic protection devices have demonstrated efficacy in reducing atheroembolic complications during SVG interventions. The pivotal Saphenous Vein Graft Angioplasty Free of Emboli Randomized (SAFER) trial randomized 801 patients undergoing SVG PCI to conventional stenting versus stenting over the PercuSurge GuardWire (Medtronic CardioVascular, Santa Rosa, CA) distal balloon protection device.67 A substantial reduction in 30-day MACE (16.9–9.6%) and no-reflow (8.3% to 3.3%) was noted in this study. This single trial established distal protection in eligible SVG lesions as a standard of care. The EPI FilterWire distal protection device (Boston Scientific Corporation) was shown to be noninferior with respect to 30-day MACE to the PercuSurge GuardWire in a 656-patient, head-to-head randomized comparison68 and is thus an acceptable alternative. Several other devices have since been shown to be noninferior to either the GuardWire or the FilterWire EX (Boston Scientific Corporation) in randomized controlled trials. Figure 2 provides a summary of the trials of devices to prevent distal embolization in SVG PCI. Figure 3 shows embolic debris retrieved from an SVG intervention case. Predicting which SVGs are more prone to distal embolization remains a challenge,69,70 and therefore, embolic protection in all cases in which device deployment is feasible should be considered the standard of care. Importantly, despite significant benefits with these devices compared to placebo, the MACE rate still remains approximately 10%, as illustrated in Figure 2, and suggests either the need for better distal embolic protection, or perhaps another mechanism for the high rates of distal myocardial damage.

GIIb/IIIa inhibitors have not been shown to reduce atheroembolic complications in SVG interventions.71,72 Limited data are also available for a small number of pharmacological agents other than GPIIb/IIIa inhibitors in preventing no-reflow in SVG PCI. Intragraft adenosine did not reduce the incidence of no-reflow in a retrospective study of 143 patients undergoing SVG PCI.73 In the Vasodilator Prevention of No-Reflow (VAPOR) randomized study, a significant reduction in no-reflow was noted with 200 µg of intragraft verapamil, with no-reflow observed in none of the patients in the treatment arm compared to one third of the patients in the control group.74 However, this small study consisted of only 22 patients. Fischell et al reported a low incidence of no-reflow (2.4%) in an observational registry of 83 consecutive SVG PCIs performed without distal embolic protection, all of which received intragraft nicardipine at a dose of 200 to 300 µg.75 Although the available data are limited and not sufficient to support the routine use of these medications for the prevention of slow or no-reflow during SVG PCI, these results are promising. Given that MACE rates with SVG PCI remain approximately at 10%, even with the use of embolic protection devices, it is feasible that these agents may find a role as adjunctive therapy with embolic protection devices in SVG PCI in the future.

SLOW FLOW AND NO-REFLOW IN ROTATIONAL ATHERECTOMY
Rotational atherectomy is associated with a high rate of slow flow and no-reflow, with the incidence of no-reflow up to 16%.76,77 The pathogenesis of this relates mainly to distal embolization of particulate debris generated during rotational atherectomy76,77 but also to platelet activation with burr rotation.78 It is more common in longer and heavily calcified lesions.76,77 Several precautions related specifically to procedural technique are recommended to prevent no-reflow, including avoiding speeds above 150,000 rpm, avoiding drops in burr speeds of more than 5,000 rpm, beginning with a smaller burr size (burr:artery ratio <0.6 or a burr size of 1.25 to 1.5 mm), and limiting runs to short intervals (20–30 seconds).78-80 The Cocktail Attenuation of Rotational Atherectomy Flow Effects (CARAFE) study established the standard of continuous flushing of the treated vessel with a saline solution containing verapamil, glycerlyl trinitrate, and unfractionated heparin.81 Recent studies have suggested that nicorandil in the flush solution may be more effective in reducing no-reflow compared to verapamil.82,83 Although GPIIb/IIIa inhibitor use during rotational atherectomy has been shown to reduce periprocedural myonecrosis,84,85 caution must be exercised with up-front administration given the risk of coronary perforation.

MANAGEMENT OF SLOW FLOW AND NO-REFLOW
When slow flow and no-reflow are encountered in the catheterization laboratory after PCI, the mainstay of treatment is pharmacologic. A systematic and algorithmic approach is suggested in Table 4. As an important first step, the operator must exclude a mechanical cause, such as coronary spasm, dissection, or thrombus formation, as a cause of impaired flow. Attention to supportive treatment for the patient should also be emphasized because patients frequently experience chest pain, hypotension, and cardiac dysrhythmias. There is limited evidence for a small number of vasodilator agents that have been shown to improve coronary flow in this setting. At least one of these agents should be administered because the ability to reverse slow flow and no-reflow has been shown to have important prognostic implications.86 Table 5 summarizes the commonly used vasodilators in the catheterization laboratory. For refractory slow flow and no-reflow, we advocate ongoing supportive treatment with GPIIb/IIIa inhibitors, intra-aortic balloon pump, and ionotropic support as required.

In terms of vasodilator therapies for slow flow and no-reflow, the two most studied agents are adenosine and verapamil, with the evidence for their use derived from both animal studies and small clinical studies. Calcium-channel blockers have been shown to attenuate no-reflow in both laboratory animal models87,88 and clinical studies,89-91 putatively on the basis of vasodilation of the distal microcirculation. In a prospective study of verapamil for the treatment of no-reflow, approximately 90% of patients demonstrated prompt response to verapamil with improvements in TIMI flow grade and corrected TIMI frame count.7 In another prospective study of no-reflow in 36 SVG lesions, intragraft verapamil was associated with improved flow in all patients.92 However, in another study, intracoronary verapamil was not superior to conservative treatment (including intracoronary nitrates) in improving coronary flow, as measured by cTFC in patients with established no-reflow.1 Importantly, in a recent study comparing intracoronary verapamil and adenosine for slow flow and no-reflow prophylaxis in patients with acute coronary syndromes, verapamil was associated with hypotension and complete heart block lasting up to 3 hours in 18% of patients.91

Adenosine is commonly used to manage no-reflow, and has also been shown to attenuate no-reflow in both laboratory animal models93 and clinical studies.63,64,94,95 In a canine model, intracoronary adenosine infusion after prolonged coronary occlusion resulted in significantly improved regional myocardial flow.93 The putative benefit of adenosine was attributed to a combination of distal vasodilatation, decrease in neutrophil count, and preservation of endothelial structure. Sringdola et al and Fischell et al demonstrated the efficacy of rapid 24-µg boluses of intragraft adenosine in reversing established no-reflow in SVG intervention.73,96 Because adenosine has a short half-life and is not associated with prolonged hypotension and conduction disturbances, as described previously with verapamil, it is the agent that is favored at our institution.

Nitroglycerine is frequently administered to exclude underlying spasm as a cause of no-reflow. Although this is an appropriate step, once spasm has been excluded, there is no evidence to support the use of nitroglycerine in reversing no-reflow, and it is most operators' experience that its administration is not useful.9

There are limited data for other agents, which might be beneficial, that are not as widely used for the treatment of no-reflow and are therefore not discussed in detail here. These agents include nitroprusside,97 nicardipine,98 nicorandil,99 papaverine,100 and epinephrine.101 Other agents that have undergone trials and have been shown to have limited efficacy in treating no-reflow include urokinase,102 streptokinase,103 and tissue-type plasminogen activator.104

CONCLUSION
Slow flow and no-reflow result from a complex interaction of several pathophysiological processes. Prevention of impaired flow in patients at highest risk remains the best strategy. In AMI, timely reperfusion should be achieved, and GPIIb/IIIa agents should be strongly considered in all patients. Adjunctive mechanical devices to prevent distal embolization during AMI should be considered in patients with a high thrombus burden, although the clinical benefits of these devices have not been clearly established in primary PCI at present. In SVG PCI, distal protection of all suitable grafts should be employed. Procedural precautions aimed at preventing impaired flow states should be employed during rotational atherectomy. When slow flow or no-reflow is encountered after PCI, vasodilatory agents shown to improve epicardial and myocardial flow after the occurrence of this complication should be administered in an effort to improve myocardial perfusion, as this may improve prognosis. The best approach to slow flow and no-reflow in the present day remains one that incorporates the philosophy "prevention is better than the cure."

Sandhir Prasad, MBBS, FRACP, is from MonashHeart, Monash Medical Centre, in Melbourne, Australia. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Prasad may be reached at +03 9594 6666; sprasad@bigpond.net.au.

Ian T. Meredith, MBBS, PhD, FRACP, FACC, FSCAI, is from MonashHeart, Monash Medical Centre, in Melbourne, Australia. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Meredith may be reached at +03 9594 6666; ian.meredith@myheart.id.au.

  1. Resnic FS, Wainstein M, Lee MKY, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J. 2003;145:42-46.
  2. Kenner MD, Zajac EJ, Kondos GT, et al. Ability of the no reflow phenomenon during an acute myocardial infarction to predict left ventricular dysfunction at one-month follow-up. Am J Cardiol. 1995;76:861-868.
  3. Porter TR, Li S, Oster R, et al. The clinical implications of no-reflow demonstrated with intravenous perfluorocarbon containing microbubbles following restoration of Thrombolysis in Myocardial Infarction (TIMI) 3 flow in patients with acute myocardial infarction. Am J Cardiol. 1998;82:1173-1177.
  4. Gerber BL, Rochitte CE, Melin JA, et al. Microvascular obstruction and left ventricular remodeling early after acute myocardial infarction. Circulation. 2000;101:2734-2741.
  5. 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;36:1202-1209.
  6. Rezkella SH, Kloner RA. No-reflow phenomenon. Circulation. 2002;105:656-662.
  7. Piana RN, Paik GY, Moscucci M, et al. Incidence and treatment of "no-reflow" after percutaneous coronary intervention. Circulation. 1994;89:2514-2518.
  8. 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 Diagn. 2003;60:194-201.
  9. Majno G, Ames A III, Chiang J, et al. No reflow after cerebral ischemia. Lancet. 1967;2:569-570.
  10. Ames A III, Wright RL, Kowada M, et al. Cerebral ischemia II: the no-reflow phenomenon. Am J Pathol. 1968;52:437-447.
  11. Kloner RA, Ganote CE, Jennings RB. The "no-reflow" phenomenon after temporary coronary occlusion in the dog. J Clin Invest. 1974;54:1496-1508.
  12. Topol EJ, Yadav JS. Recognition of the importance of embolization in atherosclerotic vascular disease. Circulation. 2000;101:570-580.
  13. Seydoux C, Goy J-J, Davies G. Platelet and neutrophil imaging techniques in the investigation of the response to thrombolytic therapy and the no-reflow phenomenon. Am Heart J. 1993;125:1142-1147.
  14. Michaels AD, Gibson CM, Barron HV. Microvascular dysfunction in acute myocardial infarction: focus on the roles of platelet and inflammatory mediators in the no-reflow phenomenon. Am J Cardiol. 2000;85:50b-60b.
  15. Cuypers J, Matakas F. The effect of post ischemic hyperemia on intracranial pressure and the no-reflow phenomenon. Acta Neuropathology (Berlin). 1974;29:73-84.
  16. Sheridan FM, Cole PG, Ramage D. Leucocyte adhesion to the coronary microvasculature during ischemia and reperfusion in an in vivo canine model. Circulation.1996;93:1784-1787.
  17. The Thrombolysis in Myocardial Infarction (TIMI) trial, phase I findings: TIMI Study Group. N Engl J Med. 1985;312:932-936.
  18. van't Hof AW, Liem A, Suryapranata H, et al. Angiographic assessment of myocardial perfusion in patients treated with primary angioplasty for acute myocardial infarction: myocardial blush grade. Circulation. 1998;97:2302-2306.
  19. Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation. 1996;93:879-888.
  20. Simes RJ, Topol EJ, Holmes DR Jr, et al. Link between angiographic substudy and mortality outcomes in a large randomized trial of myocardial infarction. Importance of early and complete infarct artery reperfusion. GUSTO-I investigators. Circulation. 1995;91:1923-1928.
  21. Cannon CP, Sharis PJ, Schweiger MJ, et al. Prospective validation of a composite end point in thrombolytic trials of acute myocardial infarction (TIMI 4 and 5). Thrombosis in Myocardial Infarction. Am J Cardiol. 1997;80:696-699.
  22. Gibson CM, Murphy SA, Rizzo MJ, et al. Relationship between TIMI frame count and clinical outcomes after thrombolytic administration. Circulation. 1999;99:1945-1950.
  23. Stone GW, Peterson MA, Lansky AJ, et al. Impact of normalized myocardial perfusion after successful angioplasty in acute myocardial infarction. J Am Coll Cardiol. 2002;39:591-597.
  24. Dodge JT Jr, Rizzo M, Nykiel M, et al. Impact of injection rate on the Thrombolysis in Myocardial Infarction (TIMI) trial frame count. Am J Cardiol. 1998;81:1268-1270.
  25. Ilceto S, Marangelli V, Marchese A, et al. Myocardial contrast echocardiography in acute myocardial infarction: pathophysiological background and clinical applications. Eur Heart J. 1996;17;344-353.
  26. Lindner JR, Ismail S, Spotnitz WD, et al. Albumin microbubble persistence during myocardial contrast echocardiography is associated with microvascular endothelial glycocalyx damage. Circulation. 1998;98:2187-2194.
  27. Kondo M, Nakano A, Saito D, et al. Assessment of "microvascular no-reflow phenomenon" using technetium-99m macroaggregated albumin scintigraphy in patients with acute myocardial infarction. J Am Coll Cardiol. 1998;32:898-903.
  28. Faraggi M, Karila-Cohen D, Brochet E, et al. Relationship between resting 201T1 reverse redistribution, microvascular perfusion, and functional recovery in acute myocardial infarction. J Nucl Med. 2000;41:393-399.
  29. Bremerich J, Wendland MF, Arheden H, et al. Microvascular injury in reperfused infarcted myocardium: noninvasive assessment with contrast-enhanced echoplanar magnetic resonance imaging. J Am Coll Cardiol. 1998;32:787-793.
  30. Wu KC, Zerhouni EA, Judd RM, et al. Prognostic significance of microvascular obstruction by magnetic resonance imaging in patients with acute myocardial infarction. Circulation. 1998;97:765-772.
  31. Jeremy RW, Links JM, Becker LC. Progressive failure of coronary flow during reperfusion of myocardial infarction: documentation of the no-reflow phenomenon with positron emission tomography. J Am Coll Cardiol. 1990;16:695-704.
  32. Henriques JP, Zijlstra F, Otteranger JP, et al. Incidence and clinical significance of distal embolization during primary angioplasty for acute myocardial infarction. Eur Heart J. 2002;23:1112-1117.
  33. De Luca G, van't Hof AW, Ottervanger JP, et al. Unsuccessful reperfusion in patients with ST-segment elevation myocardial infarction treated with primary angioplasty. Am Heart J. 2005;150:557-562.
  34. Montalescot G, Barragan P, Wittenberg O, et al. Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction. N Engl J Med. 2001;344:1895-1903.
  35. Stone GW, Grines CL, Cox DA, et al. Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction. N Engl J Med. 2002;346:957-966.
  36. Neumann FJ, Blasini R, Schmitt C, et al. Effect of glycoprotein IIb/IIIa receptor blockade on recovery of coronary flow and left ventricular function after the placement of coronary-artery stents in acute myocardial infarction. Circulation. 1998;98:2695-2701.
  37. Petronio AS, Rovai D, Musumeci G, et al. Effects of abciximab on microvascular integrity and left ventricular functional recovery in patients with acute infarction treated by primary coronary angioplasty. Eur Heart J. 2003;24:67-76.
  38. De Luca G, Suryapranata H, Stone GW, et al. Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials. J Am Med Assoc. 2005;293:1759-1765.
  39. Napodano M, Pasquetto G, Sacco S, et al. Intracoronary thrombectomy improves myocardial perfusion in patients undergoing direct angioplasty for acute myocardial infarction. J Am Coll Cardiol. 2003;42:1395-1402.
  40. Lefevre T, Garcia E, Reimers B, et al. X-AMINE ST Investigators. X-sizer for thrombectomy in acute myocardial infarction improves ST-segment resolution: results of the X-sizer in AMI for negligible embolisation and optimal ST resolution (X AMINE ST) trial. J Am Coll Cardiol. 2005;46:246-252.
  41. Beran G, Lang I, Schreiber W, et al. Intracoronary thrombectomy with the X-sizer catheter system improves epicardial flow and accelerates ST-segment resolution in patients with acute coronary syndrome: a prospective, randomized, controlled study. Circulation. 2002;105:2355-2360.
  42. Antoniucci D, Valenti R, Migliorini A, et al. Comparison of rheolytic thrombectomy before direct infarct artery stenting versus direct stenting alone in patients undergoing percutaneous coronary intervention for acute myocardial infarction. Am J Cardiol. 2004;93:1033-1035.
  43. Ali A, Cox D, Dib N, et al. Rheolytic thrombectomy with percutaneous coronary intervention for infarct size reduction in acute myocardial infarction: 30-day results from a multicenter randomized study. J Am Coll Cardiol. 2006;48:244-252.
  44. Burzotta F, Trani C, Romagnoli E, et al. Manual thrombus aspiration improves myocardial reperfusion: the randomized evaluation of the effect of mechanical reduction of distal embolization by thrombus aspiration in primary and rescue angioplasty (REMEDIA) trial. J Am Coll Cardiol. 2005;46:371-376.
  45. De Luca L, Sardella G, Davidson CJ, et al. Impact of intracoronary aspiration thrombectomy during primary angioplasty on left ventricular remodeling in patients with anterior ST-elevation myocardial infarction. Heart. 2006;92:951-957.
  46. Dudek D, Mielecki W, Legutko J, et al. Percutaneous thrombectomy with the RESCUE system in acute myocardial infarction. Kardiologica Polska. 2004;61:523-533.
  47. Kaltoft A, Bottcher M, Nielsen SS, et al. Routine thrombectomy in percutaneous coronary intervention for acute ST-segment-elevation myocardial infarction: a randomized controlled trial. Circulation. 2006;114:40-47.
  48. Kondo H, Suzuki T, Fukutomi T, et al. Effects of percutaneous coronary arterial thrombectomy during acute myocardial infarction on left ventricular remodeling. Am J Cardiol. 2004;93:527-531.
  49. Ikari Y, Kawano S, Sakurada M, et al. Thrombus aspiration prior to coronary intervention improves myocardial microcirculation in patients with ST elevation acute myocardial infarction: the VAMPIRE study. Circulation. 2005;112(suppl II):659.
  50. Colombo P, Silva P, Bigi R, et al. Thrombus aspiration improves coronary flow and myocardial reperfusion in acute myocardial infarction: final results of the DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. Am J Cardiol. 2005;96(suppl):74H.
  51. Margheri M, Vittori G, Chechi T, et al. Thrombus aspiration with export catheter in ST elevation myocardial infarction. J Interv Cardiol. 2007;20:38-43.
  52. Stone GW, Webb J, Cox DA, et al. Enhanced Myocardial Efficacy and Recovery by Aspiration of Liberated Debris (EMERALD) Investigators. Distal microcirculatory protection during percutaneous coronary intervention in acute ST-segment elevation myocardial infarction: a randomized controlled trial. JAMA. 2005;293:1063-1072.
  53. Fujita N, Suwa S, Koyama S, et al. The efficacy of distal embolic protection device during an acute myocardial infarction: early and long-term results. Am J Cardiol. 2004;94(suppl 6A):34.
  54. Gick M, Jander N, Bestehorn HP, et al. Randomized evaluation of the effects of filter-based distal protection on myocardial perfusion and infarct size after primary percutaneous catheter intervention in myocardial infarction with and without ST-segment elevation. Circulation. 2005;112:1462-1469.
  55. Guetta V. The use of protective FilterWire to improve flow in acute MI (UPFLOW MI trial). Available from http://www.tctmd.com/csportal/appmanager/tctmd/epcoe?scrld=5
    &_nfbp=true&hdCon=1386217&_pageLabel=EPCenterContent&destld=6. Accessed March 2007.
  56. Lefevre T, Guyon P, Reimers B, et al. Evaluation of a distal protection filter device in patients with acute myocardial infarction: the DIPLOMAT study. Am J Cardiol. 2003;92(suppl 6A):37L-38L.
  57. Cura F, Garcia E, Trivi M, et al. Protection of distal embolization in high risk patients with acute ST-elevation myocardial infarction randomized controlled trial. Am J Cardiol. 2007;99:357-363.
  58. Noel B, Morice MC, Lefevre T, et al. Thromboaspiration in acute ST-elevation MI improves myocardial perfusion. Circulation. 2005;112(suppl II):519.
  59. De Luca G, Suryapranata H, Stone GW, et al. Adjunctive mechanical devices to prevent distal embolization in patients undergoing mechanical revascularization for acute myocardial infarction: a meta-analysis of randomized trials. Am Heart J. 2007;153:343-353.
  60. Ishii H, Ichimiya S, Kanashiro, et al. Impact of a single intravenous administration of nicorandil before reperfusion in patients with ST-segment elevation myocardial infarction. Circulation. 2005;112:1284-1288.
  61. Hang CL, Wang CP, Yip HK, et al. Early administration of intracoronary verapamil improves myocardial perfusion during percutaneous coronary interventions for acute myocardial infarction. Chest. 2005;128:2593-2598.
  62. Amit G, Cafri C, Yaroslavtsev S, et al. Intracoronary nitroprusside for the prevention of the no-reflow phenomenon after primary percutaneous coronary intervention in acute myocardial infarction. A randomized, double-blind, placebo-controlled clinical trial. Am Heart J. 2006;152:887.e889-e814.
  63. Mahaffey KW, Puma JA, Barbagaleta NA, et al. 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. J Am Coll Cardiol. 1999;34:1711-1720.
  64. 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;45:1775-1780.
  65. Webb JG, Carere RG, Virmani R, et al. Retrieval and analysis of particulate debris following saphenous vein graft occlusion. J Am Coll Cardiol. 1999;34:461-467.
  66. Hong MK, Mehran R, Dangas G, et al. Creatine kinase-MB enzyme elevation following successful saphenous vein graft intervention is associated with late mortality. Circulation. 1999;100:2400-2405.
  67. Baim D, Wahr D, George B, et al. Randomized trial of a distal embolic protection device during percutaneous intervention of saphenous vein aorto-coronary bypass grafts. Circulation. 2002;105:1285-1290.
  68. Stone G, Rogers C, Ramee S, et al. Distal filter protection during saphenous vein graft stenting: technical and clinical correlates of efficacy. J Am Coll Cardiol. 2002;40:1882-1888.
  69. Giugliano GR, Kuntz RE, Popma JJ, et al. Determinants of 30-day adverse events following saphenous vein graft intervention with and without a distal occlusion embolic protection device. Am J Cardiol. 2005;92:173-177.
  70. van Gaal WJ, Choudhury RP, Porto I, et al. Prediction of distal embolisation during percutaneous coronary intervention in saphenous vein grafts. Am J Cardiol. 2007;99:603-606.
  71. Mathew V, Grill DE, Scott CG, et al. The influence of abciximab use on clinical outcome after aortocoronary vein graft interventions. J Am Coll Cardiol. 1999;34:1163-1169.
  72. Roffi M, Mukherjee D, Chew DP, et al. Lack of benefit from intravenous platelet GPIIb/IIIa receptor inhibition as adjunctive treatment for percutaneous interventions of aortocoronary bypass grafts. Circulation. 2002;106:3063-3067.
  73. Sringdola S, Assali A, Ghani M, et al. Adenosine use during aortocoronary vein graft interventions reverses but does not prevent the slow-no reflow phenomenon. Cathet Cardiovasc Interv. 2000;51:394-399.
  74. Michaels AD, Appleby M, Otten MH, et al. Pretreatment with intragraft verapamil prior to percutaneous coronary intervention of saphenous vein graft lesions: results of the randomized, controlled vasodilator prevention on no-reflow (VAPOR) trial. J Invas Cardiol. 2002;14:299-302.
  75. Fischell TA, Subraya RG, Ashraf K, et al. Pharmacologic distal protection using prophylactic, intragraft nicardipine to prevent no-reflow and non-Q-wave myocardial infarction during elective saphenous vein graft intervention. J Invas Cardiol. 2007;19:58-62.
  76. Ellis SG, Popma JJ, Buchbinder M, et al. Relation of clinical presentation, stenosis morphology, and operator technique to the procedural results of rotational atherectomy and rotational atherectomy-facilitated angioplasty. Circulation. 1994;89:882-892.
  77. Hanna GP, Yhip P, Fujise K, et al. Intracoronary adenosine administered during rotational atherectomy of complex lesions in native coronary arteries reduces the incidence of no-reflow phenomenon. Cathet Cardiovasc Interv. 1999;48:275-278.
  78. Williams MS, Coller BS, Vaananen HJ, et al. Activation of platelets in platelet-rich plasma by rotablation is speed dependent and can be inhibited by abciximab (c7E3 Fab; Reopro). Circulation. 1998;98:742-748.
  79. Safian RD, Feldman T, Muller DW, et al. Coronary Angioplasty and Rotablator Atherectomy Trial (CARAT): immediate and late results of a prospective multicenter randomized trial. Cathet Cardiovasc Interv. 2001;53:213-220.
  80. Whitlow PL, Bass TA, Kipperman RM, et al. Results of the study to determine rotablator and transluminal angioplasty strategy (STRATAS). Am J Cardiol. 2001;87:699-705.
  81. Cohen BM, Weber VJ, Blum RR, et al. Cocktail attenuation of rotational atherectomy flow effects (CARAFE) study: pilot study. Cathet Cardiovasc Diagn. 1996;63(suppl):18J-24J.
  82. Iwasaki K, Samukawa M, Furukawa H, et al. Comparison of the effects of nicorandil versus verapamil on the incidence of slow flow/no reflow during rotational atherectomy. Am J Cardiol. 2006;98:1354-1356.
  83. Tsubokawa A, Ueda K, Sakamoto H, et al. Effect of intracoronary nicorandil administration on preventing no-reflow/slow flow during rotational atherectomy. Circulation. 2002;66:1119-1123.
  84. Lefkovits J, Blankenship JC, Anderson KM, et al. Increased risk of non-Q wave myocardial infarction after directional atherectomy is platelet dependent: evidence from the EPIC trial. Evaluation of c7E3 for the Prevention of Ischemic Complications. J Am Coll Cardiol. 1996;28:849-855.
  85. Koch KC, von Dahl J, Kleinhans E, et al. Influence of a platelet GPIIb/IIIa receptor antagonist on myocardial hypoperfusion during rotational atherectomy as assessed by myocardial Tc-99m sestamibi scintigraphy. J Am Coll Cardiol. 1999;33:998-1004.
  86. Lee CH, Wong HB, Tan HC, et al. Impact of reversibility of no reflow phenomenon on 30-day mortality following percutaneous revascularization for acute myocardial infarction—insights from a 1,328 patient registry. J Interv Cardiol. 2005;18:261-266.
  87. Watts JA, Hawes EM, Jenkins SH, et al. Effects of nisoldipine on the no-reflow phenomenon in globally ischemic rat hearts. J Cardiovasc Pharmacol. 1990;16:487-494.
  88. Villari B, Ambrosio G, Golino P, et al. The effects of calcium channel antagonist treatment and oxygen radical scavenging on infarct size and the no-reflow phenomenon in reperfused hearts. Am Heart J. 1993;125:11-23.
  89. Taniyama Y, Ito H, Iwakura K, et al. Beneficial effect of intracoronary verapamilon microvascular and myocardial salvage in patients with acute myocardial infarction. J Am Coll Cardiol. 1997;30:1193-1199.
  90. Fugit MD, Rubal BJ, Donovan DJ. Effects of intracoronary nicardipine, diltiazem and verapamil on coronary blood flow. J Invas Cardiol. 2000;12:80-85.
  91. Vijayalakshmi K, Whittaker VJ, Kunadian B, et al. Prospective, randomized, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes. Heart. 2006;92:1278-1284.
  92. Kaplan BM, Benzuly KH, Kinn JW, et al. Treatment of no-reflow in degenerated saphenous vein graft interventions: comparison of intracoronary verapamil and nitroglycerin. Cathet Cardiovasc Diagn. 1996;39:113-118.
  93. Olafsson B, Forman MB, Puett DW, et al. Reduction in reperfusion injury in the canine preparation by intracoronary adenosine: importance of the endothelium and the no-reflow phenomenon. Circulation. 1987;76:1135-1145.
  94. Marzilli M, Orsini E, Marraccini, et al. Beneficial effects of intracoronary adenosine as an adjunct to primary angioplasty in acute myocardial infarction. Circulation. 2000;101:2154-2159.
  95. Assali AR, Sdringola S, Ghani M, et al. Intracoronary adenosine administered during percutaneous intervention in acute myocardial infarction and reduction in the incidence of "no reflow" phenomenon. Cathet Cardiovasc Interv. 2000;51:27-31.
  96. Fischell TA, Carter AJ, Foster MT, et al. Reversal of "no-reflow" during vein graft stenting using high velocity boluses of intracoronary adenosine. Cathet Cardiovasc Diagn. 1996;39:113-118.
  97. Hillegass WB, Dean NA, Liao L, et al. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol. 2001;37:1335-1343.
  98. Huang RI, Patel P, Walinsky P, et al. Efficacy of intracoronary nicardipine in the treatment of no-reflow during percutaneous coronary intervention. Cathet Cardiovasc Interv. 2006;68:671-676.
  99. Sakata Y, Kodama K, Komamura K, et al. Salutory effect of adjunctive intracoronary nicorandil administration on restoration of myocardial blood flow and functional improvement in patients with acute myocardial infarction. Am Heart J. 1997;133:616-621.
  100. Ishihara M, Sato H, Tateishi H, et al. Attenuation of the no-reflow phenomenon after coronary angioplasty for acute myocardial infarction with intracoronary papaverine. Am Heart J. 1996;132:959-963.
  101. Skelding KA, Goldstein JA, Mehta L, et al. Resolution of refractory no-reflow with intracoronary epinephrine. Cathet Cardiovasc Interv. 2002;57:305-309.
  102. Field H, Lichstein E, Schacter J, et al. Early and late angiographic findings of the "no-flow" phenomenon following direct angioplasty as primary treatment for acute myocardial infarction. Am Heart J. 1992;123:782-784.
  103. Kloner RA, Alker KJ. The effect of streptokinase on intramyocardial hemorrhage, infarct size, and the no-reflow phenomenon during coronary reperfusion. Circulation. 1984;70:513-521.
  104. Kloner RA, Alker KJ, Campbell C, et al. Does tissue-type plasminogen activator have direct beneficial effects on the myocardium independent of its ability to lyse intracoronary thrombi? Circulation. 1989;79:1125-1136.
  105. Lee CH, Wong HB, Tan HC, et al. Impact of reversibility of no reflow phenomenon on 30-day mortality following percutaneous revascularization for acute myocardial infarction—insights from a 1,328 patient registry. J Interv Cardiol. 2005;18:261-266.
  106. Abbo KM, Dooris M, Glazier S, et al. Features and outcome of no-reflow after percutaneous coronary intervention. Am J Cardiol. 1995;75:778-782.
  107. Kuni H, Kijima M, Araki T, et al. Lack of efficacy of intracoronary thrombus aspiration before coronary stenting in patients with acute myocardial infarction: a multicenter randomized trial. J Am Coll Cardiol. 2005;46:246-252.
  108. Tahk S-J, Chae IH, Choi S-Y, et al. The effect of distal protection on the protection of microvascular integrity during primary stenting in AMI without glycoprotein IIb/IIIa inhibition. Circulation. 2004;110(suppl III):760.