INTRODUCTION — Coronary artery reperfusion after acute ST-elevation myocardial infarction (STEMI) improves patient outcomes. Reperfusion can be achieved by primary percutaneous coronary intervention (PCI) or fibrinolysis. Primary PCI is preferred if it can be performed within 90 minutes (from arrival to the emergency department of the primary PCI center) to 120 minutes (from arrival of transferring hospital). (See "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy".)
Issues related to suboptimal reperfusion after primary PCI (including no reflow) will be reviewed here (see 'No reflow' below). Other issues related to primary PCI are discussed separately. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome" and "Primary percutaneous coronary intervention in acute ST-elevation myocardial infarction: Periprocedural management" and "Acute ST-elevation myocardial infarction: Selecting a reperfusion strategy".)
DEFINITION — For patients who have undergone primary PCI, suboptimal reperfusion of the distal myocardial bed is defined as a Thrombolysis in Myocardial Infarction flow grade <3 (table 1). This angiographic assessment is made by evaluating the flow of contrast material beyond the site of PCI into the distal vessel.
CAUSES — Suboptimal reperfusion after primary PCI may be caused by either epicardial coronary artery obstruction or no reflow/microvascular dysfunction.
Primary PCI with stent placement leads to a patent coronary artery at the site of proximal obstruction in more than 95 percent of cases. However, epicardial obstruction may be due to:
●Persistent stenosis
●Persistent thrombus
●Intramural hematoma
●Side-branch occlusion
●Epicardial coronary artery spasm
In the 232 patients (7 percent) with a final Thrombolysis in Myocardial Infarction flow grade ≤2 in the PAMI trials, persistent stenosis >50 percent, thrombus, and dissection were present in 28, 26, and 40 percent, respectively [1]. These complications of PCI are discussed in detail separately. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Coronary artery complications'.)
Microvascular dysfunction/no reflow are discussed below. (See 'Mechanisms' below.)
CLINICAL RISK FACTORS — Risk factors for a final Thrombolysis in Myocardial Infarction (TIMI) flow grade ≤2 after PCI include (table 1) [1]:
●Age ≥70 years
●Diabetes
●Longer time to reperfusion
●Pre-PCI TIMI flow grade ≤1
●Left ventricular ejection fraction <50 percent
●Saphenous vein culprit lesion [2]
●Large thrombus burden
●Left anterior descending coronary artery PCI
Patients who present with heart failure also appear to be more likely to have suboptimal reperfusion after primary PCI. In a report of 1548 patients, there was a significant correlation between Killip class (table 2) and postprocedural TIMI flow grade ≤2 [3]. (See "Risk factors for adverse outcomes after ST-elevation myocardial infarction", section on 'Killip class'.)
A clinical correlate of suboptimal reperfusion is incomplete ST-segment elevation resolution. In a series of 1005 consecutive patients with STEMI who were treated with primary PCI, 42 percent had incomplete ST-segment elevation resolution (defined as ≥1 mm ST-segment elevation after PCI) [4]. Independent predictors of incomplete resolution were anterior MI, Killip class 3 to 4 (table 2), and TIMI flow grade <2 before PCI and <3 (3 represents normal flow) after PCI. Incomplete ST-segment elevation resolution was an independent predictor of mortality and also predicts adverse outcomes in patients treated with fibrinolytic therapy. (See "Diagnosis and management of failed fibrinolysis or threatened reocclusion in acute ST-elevation myocardial infarction", section on 'Primary failure'.)
NO REFLOW — Some patients do not recover normal myocardial perfusion distal to the site of proximal obstruction despite the absence of epicardial vessel obstruction. This phenomenon is called "no reflow" and is a predictor of worse outcome.
The no-reflow phenomenon is defined as a profound reduction in antegrade coronary blood flow (Thrombolysis in Myocardial Infarction [TIMI] flow grade ≤2 ) despite proximal vessel patency and the absence of dissection, spasm, or distal macroembolus, which is defined as a distal angiographic filling defect with an abrupt "cutoff" in one of the peripheral coronary artery branches of the infarct-related vessel, distal to the site of PCI [5-7]. It is presumed to reflect microvascular dysfunction and appears to be more common in patients with diabetes, as well as the risk factors presented above [8,9] (see 'Clinical risk factors' above). In addition, the likelihood of severe microvascular dysfunction is increased with a longer time from symptom onset to reperfusion [10,11].
Incidence — Attainment of TIMI 3 flow (table 1) is much more common with primary PCI than fibrinolysis. The incidence of no reflow has varied widely and depends in part upon the method used for detection and possibly interobserver variability. Using the criterion of TIMI flow grade ≤2 without macrovascular obstruction, the incidence of no reflow during PCI has ranged from 4 to 7 percent in some studies [1,12] and 12 to 25 percent in others [13,14]. Even higher rates have been noted with other modalities that can assess microvascular flow: 29 percent using the TIMI myocardial perfusion grade [15] and 34 to 39 percent using myocardial contrast echocardiography [10,16]. (See 'Detection' below.)
The likelihood of no reflow correlates with the severity of myocardial damage during the infarct and TIMI flow. Reported predictors of no reflow are Killip class, the number of Q waves, the wall motion score on echocardiogram, and the presence of TIMI flow grade 0 on the initial coronary angiogram [3,17]. (See "Primary percutaneous coronary intervention in acute ST elevation myocardial infarction: Determinants of outcome", section on 'Time from symptom onset'.)
On the other hand, preinfarction angina appears to attenuate the no-reflow phenomenon, suggesting a protective effect from ischemic preconditioning [17]. (See "Myocardial ischemic conditioning: Pathogenesis" and "Myocardial ischemic conditioning: Clinical implications".)
Mechanisms — Multiple factors probably contribute to no reflow, all of which ultimately result in microvascular dysfunction. These include distal embolization of plaque and/or thrombus, myocardial necrosis, reperfusion injury resulting from oxygen free radical production, release of active tissue factor from the dissected plaque, and vasoconstriction secondary to alpha adrenergic tone, thromboxane A2, or serotonin released from platelets [5,16,18-21].
The role of distal embolization was suggested in an intravascular ultrasound study that evaluated total plaque volume before and after primary PCI [22]. Plaque volume decreased after the procedure in all patients, but a significantly greater decrease in plaque volume was seen in patients with inadequate reflow. Plaque volume after PCI also correlated with the corrected TIMI frame count.
Similar findings have been noted in patients with stable angina undergoing PCI. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Distal embolization'.)
Detection — In clinical studies using angiographic parameters, no reflow has been defined as a TIMI flow grade (a visual estimate) ≤2 (table 1) in the absence of macrovascular obstruction [13,14]. However, microvascular perfusion may also be reduced in patients with TIMI flow grade 3 and may occur concomitantly with epicardial vessel obstruction.
We rarely use the following methods to assess microvascular perfusion:
●TIMI frame count, which is the number of cine-frames required for the contrast material to reach a distal coronary landmark or the TIMI myocardial perfusion grade (or myocardial blush grade) [15,23,24].
●A coronary Doppler flow wire can be used to assess no reflow. Doppler flow measurements reveal a characteristic pattern of both systolic retrograde flow and rapid deceleration of diastolic flow in vessels with no reflow [25-27]. In comparison, a residual stenosis is characterized by slow diastolic flow velocity, prolonged diastolic deceleration time, and a smaller diastolic/systolic flow velocity ratio. (See "Clinical use of coronary artery pressure flow measurements".)
●Myocardial contrast echocardiography [16,28] and contrast-enhanced cardiovascular magnetic resonance [10,29,30] have been used to detect no reflow. Both have the advantage of also defining the extent of myocardium affected. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Infarct detection and sizing'.)
Prevention — Possible approaches to preventing the no-reflow phenomenon include the use of thrombectomy, distal embolic protection, direct stenting, systemic infusion of glycoprotein (GP) IIb/IIIa inhibitors, and intracoronary infusion of vasodilating or antithrombotic/thrombolytic agents. Among these, only direct stenting has been shown to improve outcomes.
Direct stenting — We perform direct stenting without predilation of the culprit lesion when possible for multiple reasons. It may reduce or prevent no reflow. The role of direct stenting in STEMI patients is discussed separately. (See "Primary percutaneous coronary intervention in acute ST-elevation myocardial infarction: Periprocedural management", section on 'Direct stenting'.)
Thrombectomy — For patients undergoing primary PCI, we do not routinely perform manual thrombectomy (eg, thrombus aspiration, aspiration thrombectomy) [31]. However, there may be occasional instances in which clinical and angiographic characteristics make thrombectomy a reasonable choice.
The TOTAL [32], TASTE [33,34], and TAPAS [35,36] trials are the largest and best performed studies of manual thrombectomy in STEMI. These studies randomly assigned patients to routine manual thrombectomy followed by PCI or PCI alone. A 2017 individual patient meta-analysis of these three trials (n = 18,306) found no difference in the rates of cardiovascular death at 30 days (2.4 versus 2.9 percent; hazard ratio 0.84, 95% CI 0.70-1.01) [37]. Similarly, there was no difference at 30 days in the rate of stroke or transient ischemic attack (0.8 versus 0.5 percent; odds ratio 1.43, 95% CI 0.98-2.10).
With regard to mechanical (rheolytic) thrombectomy, the results of randomized trials do not show benefit in the aggregate [38-41]. A 2013 meta-analysis included seven trials (n = 1598) comparing mechanical thrombectomy to conventional PCI [36]. There was no significant difference between the two strategies in the incidence of death or major adverse cardiovascular events, but there was a trend toward a higher rate of all strokes with the former (1.3 versus 0.4 percent; risk ratio 2.74, 95% CI 0.93-8.01).
Distal embolic protection devices — We do not use a distal embolic protection device as routine adjunctive therapy to primary PCI with stenting in patients with acute STEMI in the native circulation. Distal embolic protection devices are increasingly used with PCI in saphenous vein grafts due to the substantial potential for embolization of both thrombus and atheromatous material. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Embolic protection devices'.)
The efficacy of a distal embolic protective device in acute STEMI was addressed in the multicenter EMERALD trial of 501 patients who presented within six hours of symptom onset and underwent primary PCI or rescue intervention after failed fibrinolysis in native coronary arteries [42]. The patients were randomly assigned to primary PCI alone or with a distal occlusion balloon and aspiration distal microcirculation system (eg, GuardWire, PercuSurge/Medtronic). Among the patients assigned to distal protection, aspiration was performed in 97 percent, and visible debris was retrieved from 73 percent.
Despite the removal of debris, there was no difference between the two groups in terms of the coprimary endpoints of ST-segment resolution at 30 minutes (63 versus 62 percent) and left ventricular infarct size (12.0 versus 9.5 percent). In addition, the secondary endpoint of major adverse cardiac events at six months was equivalent in the two groups (10 versus 11 percent). The lack of benefit persisted when only the 83 percent of patients undergoing primary PCI (not rescue) were evaluated and was seen in all subsets.
A lack of benefit was also noted in two later randomized trials (PROMISE and DEDICATION), which were of similar design but used a different distal embolic protection device (FilterWire) [43,44].
Potential mechanisms for the lack of benefit in these trials include smaller embolic burden than seen in saphenous vein grafts, embolization caused by crossing the lesion with the embolic protection device, delayed reperfusion due to the occlusive nature of the device, other nonembolic causes of microcirculatory dysfunction, difficulty protecting side branches, difficulty in detecting benefit against the background of established myocardial infarction, and embolization of vasoconstrictor materials not captured by the device [45-47].
Systemic glycoprotein IIb/IIIa inhibitors — Among patients undergoing primary PCI for acute STEMI, we do not routinely use systemic GP IIb/IIIa inhibitors for prevention of no reflow. (See "Acute ST-elevation myocardial infarction: Antiplatelet therapy", section on 'Intravenous agents'.)
Intracoronary infusions — Intracoronary infusions of adenosine, verapamil, streptokinase, or abciximab have been evaluated in small studies for their ability to improve myocardial reperfusion, prevent reperfusion injury, and salvage ischemic myocardium at the time of primary PCI. None of these agents is associated with a convincing improvement in outcomes (either myocardial flow or clinical) [48].
A 2013 systematic review and meta-analysis of nine small randomized trials of adenosine and one of verapamil found no evidence that either agent reduced short-term, all-cause mortality or nonfatal MI. In addition, there was an increase in the risk of adverse effects such as bradycardia or hypotension with adenosine [49]. This may reflect underpowering to demonstrate a treatment effect rather than a proven lack of efficacy. Moreover, the dihydropyridine calcium blocker nicardipine is used increasingly since bradycardia is avoided.
Treatment — The optimal management strategy for no reflow after the establishment of proximal coronary artery patency with PCI is unknown in part because no therapy has been shown to clearly improve outcomes.
Intracoronary vasodilator therapy has been evaluated; it has not been shown to improve clinical outcomes [14,50-53]. In small series, intracoronary verapamil was used with apparent success in treating no reflow [14,54]. Intracoronary nitroprusside at doses of 50 to 200 mcg has also shown promising results when given alone or with intracoronary adenosine [51-53,55]. In the absence of hypotension or when no reflow persists as a potential contributor to hypotension, we administer intracoronary vasodilators, favoring calcium channel blockers (eg, verapamil, diltiazem, or nicardipine) or nitroprusside. Improved effectiveness may be achieved with administering the vasodilator agents to the distal vessel via a microcatheter or angioplasty balloon.
For patients with hypotension and/or hypoperfusion, intravenous vasopressors, inotropic agents, and ventricular support devices such as intraaortic balloon pump or Impella may be of benefit. (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction", section on 'Summary and Recommendations'.)
Antithrombotic/fibrinolytic therapies — We do not routinely use intracoronary GP IIb/IIIa inhibitors or fibrinolytic drugs for the treatment of impaired microvascular perfusion. While there is no direct evidence of benefit, we believe it is reasonable to administer an intracoronary GP IIb/IIIa inhibitor to patients with evidence of no reflow (or giant thrombus).
Intracoronary GP IIb/IIIa inhibitors and streptokinase have been evaluated in randomized trials for their ability to improve microvascular perfusion in patients undergoing primary PCI. (See 'Systemic glycoprotein IIb/IIIa inhibitors' above.)
The following are representative trials of intracoronary abciximab from the stent era:
●In a trial of 534 patients randomly assigned to either intracoronary or intravenous bolus of abciximab after primary PCI with thrombus aspiration, there was no significant difference in the incidence of complete ST-segment resolution, which was the primary endpoint (64 versus 62 percent, respectively) [56]. However, the secondary endpoints of myocardial blush grade and enzymatic infarct size were better in the intracoronary infusion group.
●In a trial of 154 patients randomly assigned to either intravenous or intracoronary bolus of abciximab, both of which were followed by a 12-hour infusion, the primary endpoint of median infarct size at two days, as determined by magnetic resonance imaging (MRI), was significantly reduced in the group treated with intracoronary abciximab (15.1 versus 23.4 percent) [57]. The extent of microvascular obstruction seen on MRI and early ST-segment resolution were also significantly improved. There was also a trend toward fewer major adverse cardiovascular events. (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Infarct detection and sizing'.)
●A third trial of 50 patients evaluated the efficacy of intracoronary abciximab delivered either through the guiding catheter or a dedicated perfusion catheter at the site of occlusion [58]. Local intracoronary delivery significantly reduced the thrombus score after PCI, as determined by optical coherence tomography (4 versus 34 percent).
Given these limited data, abciximab or other GP IIb/IIIa inhibitors have rarely been used for intracoronary administration for treatment of no reflow. Abciximab is no longer available. The possible efficacy of low-dose intracoronary streptokinase (250,000 units) was compared with no additional therapy in a trial of 41 patients who had undergone successful PCI [59]. The TIMI frame count and multiple measures of microvascular perfusion (eg, coronary flow reserve, index of microvascular resistance, and collateral flow index) were significantly better in the streptokinase group at 48 hours. However, there was no significant difference between the two groups in left ventricular size or function at six months.
Vasodilator therapies — Intracoronary vasodilators such as adenosine, nitroprusside, and verapamil are of unproven benefit when given for slow coronary flow in STEMI, and we rarely use them. However, it is possible that the absence of benefit noted in studies is due to small size or suboptimal design. Better clinical outcomes are seen in patients with improvement in coronary flow, and there is general agreement within the interventional community that coronary flow often improves after the infusion of vasodilators such as calcium channel blockers, sodium nitroprusside, and adenosine.
PROGNOSIS — The 4 to 7 percent of patients who do not achieve Thrombolysis in Myocardial Infarction (TIMI) 3 (normal) flow (figure 1A-B) after primary PCI have worse outcomes (table 1) [1,60]. The magnitude of this effect was illustrated in a report from the PAMI trials [1]. The 232 patients who had a final TIMI flow grade ≤2 after PCI (7 percent of all patients) had significantly higher rates of in-hospital mortality (15 versus 2 percent) and in-hospital major adverse cardiac events (20 versus 6 percent) than those with TIMI 3 flow [1]. At one year, significant differences persisted for mortality (23 versus 5 percent), major adverse cardiac events (37 versus 20 percent), and reinfarction (9 versus 4 percent). A similar significant increase in early (30-day) mortality with TIMI flow ≤2 was noted in the GUSTO-IIb trial (11.7 versus 1.5 percent with TIMI 3 flow) [60].
A higher rate of adverse outcomes has been noted in other studies in patients with no reflow, regardless of the method of detection [1,3,13,15,16,24,25,29,30,61,62]. These include increases in in-hospital heart failure and mortality (18 versus 0 percent) [61], left ventricular remodeling at six months [29,30,62], and mortality at one year [3]. In a study of 120 patients, the frequency of cardiac mortality (37 versus 10 percent) and the combined cardiac endpoint of recurrent MI, heart failure, malignant arrhythmia, or cardiac mortality continued to increase over a mean follow-up of almost six years [13].
Both the TIMI myocardial perfusion (TMP) grade and the presence of persistent ST-segment elevation are powerful predictors of prognosis [63,64]. This was illustrated in a review of 253 consecutive high-risk patients who underwent PCI on a native vessel [24]. The following findings were noted:
●A TMP grade on the last angiogram after revascularization of 0/1, indicating little or no tissue perfusion, was associated with a marked increase in mortality compared with TMP grades 2 and 3 at both 30 days (26 versus 10 and 4 percent) and one year (35 versus 13 and 9 percent).
●The adjusted odds ratio for cumulative mortality was 2.17 for a TMP grade of 0/1 and 3.61 for persistent ST elevation in more than two leads one hour after PCI.
●Among patients with a TMP grade of 0/1 or 2, cumulative mortality was much higher in patients who also had persistent ST elevation in more than two leads (47 versus 13 percent). The added value of persistent ST elevation is that it (but not the TMP grade) reflects the size of the area with endangered perfusion.
In contrast, the TIMI frame count, another measure of myocardial tissue perfusion, was not an independent predictor of outcomes.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: ST-elevation myocardial infarction (STEMI)".)
SUMMARY AND RECOMMENDATIONS
●Primary percutaneous coronary intervention (PCI) in patients with ST-elevation myocardial infarction (STEMI) establishes normal or near-normal antegrade blood flow, as assessed by the Thrombolysis in Myocardial Infarction (TIMI) flow grade 3 (table 1), in over 90 percent of cases. Suboptimal reperfusion is said to be present in the 4 to 7 percent of patients who do not achieve normal flow. (See 'Definition' above.)
Among those STEMI patients with TIMI flow grade <3 after PCI, most cases are due to no reflow, usually attributable to distal microvascular dysfunction, rather than proximal epicardial coronary artery obstruction. (See 'Causes' above and 'No reflow' above.)
●Direct stenting for the primary lesion is the only strategy that has been shown to reduce the risk of no reflow. However, direct stenting may not be possible in some cases. (See 'Direct stenting' above.)
●For most patients undergoing primary PCI, we suggest not routinely performing thrombus aspiration (Grade 2B). It is reasonable to use aspiration thrombectomy in patients with a large thrombus burden. (See 'Thrombectomy' above.)
●Distal embolic protection does not appear to protect against no reflow in the native coronary circulation but is effective in saphenous vein grafts. (See 'Prevention' above.)
●For patients with TIMI flow grade ≤2 due to persistent stenosis, thrombus, dissection, spasm, or distal macroembolism, treatment is directed at correcting the underlying problem. The optimal management strategy for no reflow after the establishment of proximal coronary artery patency with PCI is unknown. (See 'Treatment' above.)
●Patients with hypotension and/or hypoperfusion should be treated with the same approach used in other patients with cardiogenic shock following acute MI. (See "Prognosis and treatment of cardiogenic shock complicating acute myocardial infarction", section on 'Summary and Recommendations'.)
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