Periprocedural myonecrosis following percutaneous coronary intervention

INTRODUCTION — Percutaneous coronary intervention (PCI) is associated with a small but significant incidence of serious procedural complications such as death, stroke, life-threatening bleeding or large myocardial infarction (MI). Periprocedural myocardial necrosis, which can range from a low-level elevation of cardiac biomarkers (periprocedural myocardial injury) to a large MI, is the most common complication. (See "Periprocedural complications of percutaneous coronary intervention".)

With advances in technology, particularly the use of coronary stents, the incidence of early, major cardiac events of death and large MI (both non-ST and ST elevation MI) have fallen to less than 3 percent, even in complex multivessel PCI [1,2]. However, the frequency with which any periprocedural myocardial injury is detected has increased, especially with the development of more sensitive biomarkers of myocardial damage/necrosis.

This topic will discuss the risk factors as well as the incidence, diagnosis, prognosis, mechanisms, prevention and treatment of periprocedural myonecrosis.

RISK FACTORS — The most commonly associated patient-related risk factors are older age (in most studies >65 years), the extent of coronary disease, the presence of preprocedural acute coronary syndrome (including unstable angina), and preprocedural elevation of cardiac markers [3]. Other factors include a history of prior coronary artery bypass graft surgery, prior myocardial infarction (MI), low ejection fraction, diabetes, and smoking. The presence of a thin fibrous cap or increased lipid core on intravascular imaging is also a predictor of a periprocedural MI [4,5]. A preprocedural elevation of inflammatory markers such as high sensitivity C-reactive protein is associated with a two- to fourfold increase in periprocedural MI [6]. Percutaneous coronary intervention of degenerated saphenous vein grafts, multivessel interventions, and complex lesions, particularly those with evidence of thrombus, are also associated with an increased risk. Other procedural factors associated with postprocedural MI include the number and length of the stents.

INCIDENCE — Serum creatine kinase MB fraction (CK-MB) is elevated above the upper limit of normal (ULN) in 10 to 38 percent of patients after an uncomplicated percutaneous coronary intervention (PCI) [7-14], and elevations more than three times the ULN, which are considered to represent an infarction large enough to be associated with short-term complications [10], in 7 to 18 percent [9,14-16]. In the American College of Cardiology National (United States) Cardiovascular Data Registry, there were over 200,000 patients without an acute coronary syndrome or elevated baseline CK-MB who underwent PCI between January 2004 and March 2007. Of these, 8 percent had a peak CK-MB more than three times the ULN. Typically, CK-MB is not measured and has been replaced by cardiac troponin.

An elevation of cardiac troponin above the upper limit of normal following PCI has been noted in as many as 50 percent of patients undergoing PCI [7,9,17,18]. Cardiac troponins are a more sensitive marker than CK-MB for smaller amounts of myocardial damage and elevated values after PCI with or without stenting are more common than increases in serum CK-MB [19-22]. In an analysis from the Mayo Clinic PCI registry, approximately 20 percent of patients with normal preprocedural CK-MB and cardiac troponin T (cTnT) values had an isolated postprocedural elevation in serum cTnT [22]. (See "Troponin testing: Clinical use".)

MECHANISMS — Elevations of cardiac biomarkers of necrosis can be due to a number of factors including embolization of atheroma or thrombus, side branch occlusion, no reflow, epicardial or microvascular spasm, or stent thrombosis. With elevations of creatine kinase MB fraction >5 to 8 times the upper limit of normal, distal vessel occlusion from a large embolus, acute stent thrombosis, or major side branch occlusion are usually responsible [23,24]. Periprocedural MI due to a side branch occlusion is the most common cause (60 percent) and has the lowest associated mortality [25].

Smaller increases in cardiac biomarkers are likely due to microembolization of thrombotic or atherosclerotic material. Evidence for microembolization comes from magnetic resonance imaging studies that have shown small, irreversible myocardial injury in patients with elevated cardiac markers following percutaneous coronary intervention (PCI) [23,26]. Since the size of the infarcts in this setting is small, these minor elevations have been felt to be markers of more severe coronary atherosclerosis that is responsible for the poorer prognosis in these patients. In addition, an enhanced inflammatory state (as evidenced by an elevated high sensitivity C-reactive protein) can predispose patients to thrombosis as well as vasospasm, and is felt to play a role as well [6].

The mechanism for a periprocedural ST-elevation MI (STEMI) is most commonly due to acute stent thrombosis or abrupt closure of the vessel, resulting in complete occlusion of the vessel. Less frequently, it is due to embolization of large thrombus or atheroma with distal vessel occlusion. Embolization is more common in degenerated saphenous vein graft interventions than in native vessel interventions.

Distal embolization can contribute to the "no-reflow" phenomenon after PCI, which is thought to reflect microvascular dysfunction since there is evidence of myocardial ischemia and reduced antegrade coronary flow but without epicardial stenosis or occlusion or loss of a distal branch. In a report of patients undergoing PCI for a non-ST-elevation acute coronary syndrome, those with a postprocedural cardiac troponin I (cTnI) elevation were significantly more likely to have reduced tissue-level perfusion than those without a cTnI elevation [27]. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'No reflow'.)

The relationship between periprocedural elevation of serum biomarkers (non-ST-elevation MI [NSTEMI]) and distal microembolization was studied in 52 patients who underwent elective PCI for stable coronary artery disease [28]. Using intracoronary Doppler guidewire detection of emboli, the total number of microemboli during all phases of the intervention (eg, device advancement over Doppler wire, predilation, stent deployment, and postdilation) was significantly higher in patients with periprocedural NSTEMI compared with those without (27 versus 16). Microemboli were detected in all but 1 of the 52 patients and were seen most often during stent deployment.

The relationships between the presence and effects of distal embolization and plaque composition were evaluated in a study of 44 patients with stable angina undergoing PCI [29]. Distal embolization was detected by the number of high-intensity transient signals (HITS) using a Doppler guidewire, plaque composition was evaluated using Virtual Histology intravascular ultrasound (Volcano Therapeutics, Inc), and the impact of distal embolization was assessed using measurement of coronary flow velocity reserve (CFVR). Patients in the highest tertile of HITS had a significantly larger necrotic core area compared with patients in lower tertiles. In addition, there was a small but significant negative correlation between HITS and CFVR after PCI.

Similar findings have been noted in patients with STEMI. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'Mechanisms'.)

The primary mechanism of injury after PCI in saphenous vein grafts is distal embolization [30,31]. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Embolic protection devices'.)

DIAGNOSIS — In patients who have not presented with an acute ischemic syndrome, postprocedure cardiac troponin (cTn) is not routinely measured in the absence of signs or symptoms of ischemia or complications. In those patients who have signs or symptoms of ischemia, it may be the result of myocardial injury with cell necrosis due to periprocedural events such as coronary dissection, occlusion of a major coronary artery or a side-branch, disruption of collateral flow, slow flow or no-reflow, distal embolization, or microvascular plugging. In patients with percutaneous coronary intervention (PCI)-related myocardial injury, cTn values will rise. The more sensitive the cTn assay used, the higher the percentage of patients who will have detectable myocardial injury. The level of myocardial injury (cTn value) that should qualify as a periprocedural MI has been debated for many years [22,32-40]. Two issues have caused significant discussion:

●The value of cTn above which an MI would be said to have occurred (in patients with normal baseline values). The tension in this area is attributable in large part to the fact that a definition that allows for a high degree of sensitivity for the diagnosis of myocardial necrosis will likely have a low specificity for events that are clinically meaningful; the converse is also true. Unlike a type I MI (acute coronary syndrome), many experts have recommended that a diagnosis of a periprocedural MI be made only if the level of the biomarker is associated with a worse outcome [32]. Their concern is that small increases from baseline in biomarker levels after PCI are expected (microembolization is an example) and do not necessarily represent a complication or a condition for which management needs to change.

●The difficulty in interpreting postprocedure elevations in patients with elevated baseline values of cTn.

The 2018 Fourth Universal Definition of Myocardial Infarction formulated by a joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Health Federation task force arrived at the following definition, which addresses these two (and other) concerns [40]: an elevation of cTn values more than five times the 99^th percentile upper reference limit (URL) in patients with normal baseline values. In patients with elevated preprocedure cTn in whom the cTn levels are stable (≤20 percent variation) or falling, the postprocedure cTn must rise by >20 percent. However, the absolute postprocedural value must still be at least five times the 99th percentile URL. In addition, one of the following is required:

●New ischemic ECG changes.

●Development of new pathological Q waves.

●Imaging evidence of new loss of viable myocardium or new regional wall motion abnormality in a pattern consistent with an ischemic etiology.

●Angiographic findings consistent with a procedural flow-limiting complication such as coronary dissection, occlusion of a major epicardial artery or a side branch occlusion/thrombus, disruption of collateral flow, or distal embolization.

Other definitions for periprocedural MI exist, generally using higher thresholds of biomarker elevation [41-43].

The task force also made the following recommendation: When a cTn value is elevated but ≤5 x 99^th percentile URL after PCI and the cTn value was normal before the PCI, or when the cTn value is >5 x 99^th percentile URL in the absence of ischemic, angiographic, or imaging findings, the term “myocardial injury” should be used.

New Q waves — The development of new pathological Q waves occurs in approximately 0.5 percent of PCI cases and is usually due to acute stent thrombosis (also called abrupt closure in the absence of a stent) [9]. (See "Coronary artery stent thrombosis: Incidence and risk factors" and 'Electrocardiogram' below.)

Recommendations for biomarker measurement — We do not routinely obtain a baseline cTn in patients undergoing PCI. However, in situations where it is anticipated that cTn will be obtained after the procedure, it is advisable to obtain a baseline value so that the postprocedural result can be properly interpreted. (See 'Diagnosis' above.)

Similarly, we do not routinely obtain a postprocedural cTn. However, in patients with suspected ischemia (ie, prolonged chest pain, side branch occlusion, recurrent ischemia, flow-limiting dissection, no-reflow, intracoronary thrombosis, or hemodynamic instability), cTn should be measured serially [44]. We suggest obtaining two biomarkers (using the same biomarker as used before the procedure) starting at three to six hours after PCI and separated by at least three to six hours apart in patients when reinfarction is suspected.

PROGNOSIS — Biomarkers of cardiac injury (troponin or creatine kinase MB fraction [CK-MB]) can be elevated after percutaneous coronary intervention (PCI), as a consequence of PCI or an elevation present before PCI. The available evidence, in the aggregate, suggests that biomarker elevation before PCI is the more important determinant of long-term mortality because it reflects more extensive disease, while both might play a role in in-hospital mortality. (See "Periprocedural complications of percutaneous coronary intervention", section on 'Predictors of mortality and major complications'.)

Cardiac troponin (cTn) measurement, as opposed to CK-MB, is the standard of care for prognostic (and diagnostic) purposes.

Based on available evidence, we conclude the following regarding the relationship between periprocedural elevations in biomarkers and prognosis:

●An elevated biomarker (using the universal criteria for MI) before the procedure is associated with an adverse prognosis.

●The prognostic implication of an elevated biomarker after PCI cannot be known unless the baseline value is taken into account. In patients with an elevated baseline, prognosis is more directly linked to the baseline value than the postprocedural value.

In patients with a normal baseline value, an elevated postprocedural troponin after an unsuccessful procedure or one with angiographic complications may be associated with adverse short- and long-term prognosis dependent on the degree of ischemia. After a seemingly uncomplicated procedure, there is even less certainty about the prognostic implications of a postprocedural rise in cTn.

There are no studies that inform us as to the optimal management of patients with an elevated biomarker. The authors and reviewers of this topic generally agree with the approach laid out below, but believe that the care of each patient with a positive cTn should be individualized:

●Patients with a baseline negative cTn and either a negative postprocedure value or no postprocedure value obtained are considered at low risk of cardiac events. Accordingly, in some institutions, they may be candidates for accelerated dismissal regimens, including same-day discharge.

The decision to do so should be based on comorbidities, the risk for other acute complications such as bleeding, and local practice.

●For patients with an elevated cTn either before or after the procedure, and especially if there are symptoms or complications of the procedure, overnight hospital stay is deemed to be prudent. The duration of hospitalization may be longer based on factors such as clinical stability, indication for PCI, outcome during the case, biomarker peak/trajectory, and the presence or absence of other acute processes.

Evidence from elevated CK-MB studies — Although current guidelines recommend cTn as preferred to CK-MB for diagnosis of myocardial infarction (MI) in all instances, including periprocedural, many of the studies that evaluated the prognosis of periprocedural biomarker elevation have used CK-MB. However, CK-MB is no longer measured routinely after PCI. The following studies illustrate the range of findings.

●A report from the EVENT registry of unselected patients undergoing PCI evaluated the relationship between periprocedural MI (defined as a peak CK-MB >3 X ULN) and one-year mortality [15]. After excluding patients with elevated pre-PCI CK-MB and ST-elevation MI, there were 5961 patients. After multivariable adjustment, periprocedural MI was independently associated with one-year mortality (adjusted hazard ratio 1.84, 95% CI 1.17-2.89). However, in a time-period specific analysis, the adjusted hazard ratio was significantly greater only for 30-day mortality, but not between one month and one year.

●Over 60 studies have shown that the greater the elevation of CK-MB after the PCI (either percutaneous transluminal coronary angioplasty or stenting), the greater the subsequent mortality [3,9,10,17,45-51]. While elevations of more than 8- and 10-fold the ULN have been associated with increased death or death and MI, the evidence on the impact of lesser degrees of elevation (>1x to >3x ULN) on mortality is less robust [9,17,45-51]. In these studies, the baseline CK-MB was taken into account. However, it appears that the critical level is the pre-PCI cardiac troponin (cTn) value, which, because cTn is so much more sensitive than CK-MB, is often elevated. If cTn is increasing, the CK-MB value will also be increasing, although this increase may be more difficult to appreciate because CK-MB is a less sensitive marker.

If one uses the appropriate cut-off value of the 99^th percentile upper reference limit in the analysis, the prognostic importance of pre-PCI elevations is substantial and renders the post-PCI values of substantially less importance [33]. Unfortunately, only one study has used this approach [18]. In that study, there was marginal significance to the short-term prognosis driven by mostly non-cardiac events. A 2012 report indicates that it may be possible to define criteria for a declining and then rising pattern of CK-MB that identifies peri-PCI myocardial injury associated with adverse events in the long term [35]. Additional details concerning the metrics of this approach and analysis are needed.

Evidence from elevated troponin studies — The results with cTn have been conflicting, with some studies showing long-term prognostic significance [52-54] and others not [21,46,55,56]. We believe the following studies provide the best evidence of the relationship between a periprocedural rise in troponin and subsequent mortality:

●In a meta-analysis of 15 studies including over 7500 patients with normal baseline troponin levels, troponin elevation occurred in 29 percent of the procedures [7]. Using the Joint European Society of Cardiology/American College of Cardiology Foundation/American Heart Association/World Health Federation Task Force definition discussed above, PCI-related MI occurred in about half. The following findings were noted:

•Elevated cTn was associated with a significantly increased risk of in-hospital major adverse cardiovascular events (the composite of all-cause death, MI, repeat target vessel PCI, and coronary artery bypass grafting) (odds ratio [OR] 11.29, 95% CI 3.00-42.48) or death (OR 7.16, 95% CI 1.95-26.27).

•cTn above the cut-off for MI was reported in a subset of patients (n = 2359) from four studies. In an unadjusted analysis, patients with PCI-related MI had a significantly increased risk of death (OR 2.25, 95% CI 1.26-4.00) at 26-month follow-up. An increase of the cTn below the cut-off was not associated with major adverse cardiovascular events, but this finding may have been due to a relatively small sample size. (See 'Diagnosis' above.)

●A review of 2352 patients who underwent PCI assessed the predictive value of baseline and postprocedural troponin (and CK-MB) concentrations [38]. Baseline troponin elevations were present in 733 patients (31 percent) and were associated with worse short- and long-term outcomes. When these elevations were taken into account, neither postprocedural troponin nor CK-MB elevations added to the long-term prognostic significance. Postprocedural elevations or increases in the degree of elevation correlated only with in-hospital complications.

●A subsequent study from the Mayo Clinic, which evaluated only patients with normal preprocedural levels of cTnT (and CK-MB), found that the 20 percent of patients with a postprocedural elevation of troponin had a significantly lower estimated three-year survival compared with those with normal troponin (86.9 versus 93.2 percent) [22]. The risk of in-hospital death was low irrespective of cTnT status.

●In a report of nearly 5000 patients undergoing elective coronary stent placement between 2004 and 2007, MI was defined as the peak value between 6 and 24 hours normalized to the local diagnostic level for MI and values greater than three times the ULN were classified as an MI [57]. After adjustment for differences in baseline characteristics, elevated cTn (and CK-MB) was significantly associated with one-year mortality (hazard ratio 1.35). The mortality hazard for cTn, however, was found only for much higher elevations. Troponin more than 20 times the diagnostic level demonstrated similar mortality risk as CK-MB more than three times the ULN. The mortality association may be overestimated by the absence of baseline cTn elevation as a co-variate in the multivariable analysis.

●A study of 2365 patients who underwent elective PCI for stable coronary artery disease assessed the predictive value of baseline and postprocedural cTn (and CK-MB) concentrations and provided a possible explanation for the discrepant findings in previous studies [38]. Baseline cTn elevations had both short- and long-term prognostic significance. When these elevations were taken into account, postprocedural cTn (or CK-MB) elevations did not add to long-term prognostic significance. Postprocedural elevations or increases in the degree of elevation correlated only with in-hospital complications.

This was the first study to use the baseline cTn measurement (as recommended in guidelines) in the analysis along with sensitive contemporary cut-off values, but has been confirmed by a larger analysis [39]. The marginal significance for in-hospital events was driven by non-cardiac events.

●In a study of 5467 patients with non-ST elevation acute coronary syndromes enrolled in three randomized trials, there were 212 who experienced a procedure-related MI after five years [58]. There was no difference in the cardiovascular death rate between those who had a procedure-related MI and those who did not (hazard ratio 0.90, 95% CI 0.47-1.71). This may reflect the fact that as assay sensitivity has increased, the baseline sample, even if the guideline-derived cut-off values are not used, still reduces any effect of post-PCI elevations.

●In a study of 13,608 patients with acute coronary syndrome undergoing PCI, among the 600 patients who experienced a type 4a (periprocedural) MI in the TRITON-TIMI 38 trial (see "Acute non-ST-elevation acute coronary syndromes: Early antiplatelet therapy"), 490 had elevated biomarkers before the procedure. Patients with non-ST elevation MI (n = 335 with Type 4 MI) were enrolled and underwent PCI within 72 hours of qualifying symptoms of acute coronary syndrome, whereas patients with ST elevation MI (n = 155 with Type 4 MI) could be enrolled up to two weeks after presentation. Then, if the baseline CK-MB was normal or lower than the original value, a threefold elevation >ULN on two successive measurements or a fivefold elevation on a single sample post-PCI was associated with an increased risk of cardiovascular death at 180 days (3.2 versus 1.3 percent; adjusted hazard ratio 2.4, 95% CI 1.6-3.7). The rigorous approach taken in this study to discriminate periprocedural injury that was distinct from the qualifying ischemic syndrome may account for the ability to detect a significant risk relationship in this study. Application and refinement of this strategy in additional populations with acute coronary syndrome undergoing PCI will be important to understanding whether a similar approach will be valid with troponin-based definitions.

●In an analysis of 5772 patients with stable or descending cTn after PCI in two randomized trials among patients with non-ST elevation acute coronary syndrome, peak cTn and peak CK-MB were associated with one-year mortality. Comparing the adjusted probability of death by one year according to peak cTn and peak CK-MB, the adjusted risk of death was similar for a 60-fold elevation of cTn (4.9 percent) compared with threefold elevation of CK-MB (5.1 percent) [59].

●In a study of 5268 patients, both postprocedure cTnT and CK-MB mass levels were associated with three-month mortality. The optimal discriminant threshold for an increase in mortality for cTnT was 25 x ULN (HR = 4.53 [1.59-12.9]; p = 0.002), which was similar to 5 x ULN for creatine kinase-MB (HR = 4.31 (1.27 to 14.6) [60].

Electrocardiogram — The development of a new Q wave is associated with a worse prognosis [9,61]. In an analysis from the BARI trial, the increase in mortality with new Q waves after balloon angioplasty persisted at five years (18.1 versus 5.4 percent for no new electrocardiogram changes, adjusted relative risk 4.6) [61]. The mortality rate was intermediate with ST segment elevation or depression or T wave abnormalities: 8.5, 8.9, and 6 percent, respectively.

PREVENTION — Multiple therapies for the prevention of periprocedural myocardial infarction (MI) have been evaluated and include, among others, antiplatelet drugs, statins, ischemic preconditioning, adenosine, beta blockers, and distal protection devices. These will be presented briefly here, but are discussed in detail separately with the exception of adenosine. Of these, none have sufficiently proven efficacy to recommend routine use prior to elective percutaneous coronary intervention (PCI) in stable patients. Pretreatment with antiplatelet therapy and statin may be considered in patients at high risk of periprocedural MI.

Antiplatelet therapy — The administration of an oral platelet P2Y₁₂ receptor blocker prior to elective PCI in patients with chronic coronary syndromes has been well studied. Dual antiplatelet therapy with aspirin and a platelet P2Y₁₂ receptor blocker can reduce complications, particularly periprocedural myonecrosis. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies".)

In patients with stable coronary artery disease undergoing PCI, clopidogrel is the best-studied oral platelet P2Y₁₂ receptor blocker. Administration of the loading dose of clopidogrel more than six hours before the procedure in the CREDO trial was associated with a significantly greater reduction in adverse events as compared to administration at the time of PCI [62]. Higher loading dose of clopidogrel (600 mg versus 300 mg) is also associated with greater and more rapid inhibition of platelet function and reduced major cardiac events in patients undergoing PCI [63]. In the ALPHEUS study, 1910 patients were randomly assigned to ticagrelor (180 mg loading dose and 90 mg twice daily thereafter for 30 days) or clopidogrel (300 to 600 mg loading dose and 75 mg daily thereafter for 30 days) [64]. There was no difference between the two groups in the rate of the primary composite outcome of PCI-related type 4 (a or b) MI (see "Diagnosis of acute myocardial infarction", section on 'Joint Task Force definitions') or major myocardial injury (cTn >5 x 99th percentile upper reference limit; 35 versus 36 percent; odds ratio 0.97, 95% CI 0.80-1.17). (See "Antithrombotic therapy for elective percutaneous coronary intervention: General use", section on 'P2Y12 receptor blockers'.)

In acute coronary syndrome (ACS) patients, the use of more potent P2Y₁₂ receptor blockers such as prasugrel and ticagrelor has been shown to reduce both short- and long-term adverse events and stent thrombosis [18,65]. In a post hoc analysis of the TRITON-TIMI 38 trial of 13,608 moderate- to high-risk ACS patients undergoing PCI, prasugrel significantly reduced the risk of periprocedural MI compared to clopidogrel (4.9 versus 6.4 percent respectively, hazard ratio 0.76, 95% CI 0.66-0.88) during a mean follow-up of 14.5 months [65].

Cangrelor, a potent, rapid-acting intravenous P2Y12 inhibitor has been studied in three large double-blind randomized trials (CHAMPION-PCI, CHAMPION-PLATFORM, and CHAMPION-PHOENIX). In a pooled analysis, compared with clopidogrel, cangrelor reduced the combined end point of death, MI, ischemic driven revascularization, or stent thrombosis at 48 hours. Since it can be given at the time of PCI, it may be useful in preventing periprocedural MI in patients who have not been pretreated with P2Y12 oral agents and are at increased risk for periprocedural MI [66]. (See "Antithrombotic therapy for elective percutaneous coronary intervention: Clinical studies", section on 'Cangrelor'.)

The addition of cilostazol to aspirin and clopidogrel also results in greater platelet inhibition and a reduction in MI and stent thrombosis [67,68].

Intravenous platelet glycoprotein IIb/IIIa antagonists have also been shown to reduce major adverse cardiac events in patients with non-ST elevation MI (NSTEMI) and ST elevation MI (STEMI). However, studies have shown less benefit and increased bleeding when added to dual-antiplatelet therapy with aspirin and clopidogrel. The American College of Cardiology/American Heart Association guidelines recommend that they be considered in addition to aspirin and clopidogrel in NSTEMI patients who are high risk, especially when there are delays to angiography or recurrent ischemia. It is reasonable to omit glycoprotein IIb/IIa agents when bivalirudin is used [69]. In addition, it is reasonable to use these agents in patients with a large thrombus burden, although there is little scientific evidence to support this approach. Routine upstream use prior to PCI is not currently recommended.

The importance of adequate and rapid platelet inhibition before PCI has also been shown in registry studies. Up to 30 percent of patients have inadequate inhibition of platelet function to clopidogrel (nonresponders). Using platelet function tests, such as the point of care VerifyNow TM test, lower rates of stent thrombosis, death, and MI have been demonstrated in patients who respond to dual therapy as compared to nonresponders [70]. Whether routine use of platelet function testing pre-PCI is of value in identifying and treating nonresponders is uncertain. Bedside genetic testing has also been demonstrated to identify patients with CP2C19 polymorphisms associated with clopidogrel nonresponse. Clinical trials have shown potential value in choosing the antiplatelet agent based on the results [71]. (See "Clopidogrel resistance and clopidogrel treatment failure".)

Statins — The concept that pretreatment with statins might decrease the incidence of periprocedural MI stems in part from the observation that patients with acute coronary syndromes (in which there is local inflammation in one or more coronary arteries) benefit from the early use of statins. It is felt that PCI induces vascular injury with associated platelet aggregation and thrombosis, as well as local inflammation.

Preprocedural statin therapy has been shown to prevent periprocedural MI in multiple randomized trials in patients with both stable and unstable coronary artery disease [72]. A randomized trial (Statins Evaluation in Coronary Procedures and Revascularization [SECURE-PCI]) in patients with acute coronary syndrome failed to show benefit for pretreatment, but in the subgroup of patients who had PCI there was a 28 percent reduction in 30-day major adverse cardiovascular event and periprocedural MI that was more pronounced in those with STEMI [73]. This issue is discussed in detail elsewhere. (See "Low-density lipoprotein-cholesterol (LDL-C) lowering after an acute coronary syndrome" and "Percutaneous coronary intervention with intracoronary stents: Overview".)

Adenosine — Adenosine induces dilation of the microvasculature, modulates inflammation, and has other mechanisms of action that might be useful in the periprocedural period. It has been evaluated as an adjunctive therapy to reperfusion for STEMI. (See "Reperfusion injury of the heart", section on 'Potential therapies'.)

In an open label study of the efficacy of adenosine in reducing periprocedural myonecrosis (defined as a creatine kinase MB fraction [CK-MB] rise above the upper limit of normal), 62 patients scheduled to undergo non-urgent PCI of de novo coronary lesions were randomly assigned to pretreatment with either 50 µg of intracoronary adenosine or no adenosine [74]. Intracoronary adenosine was associated with a significant reduction in myonecrosis (13 versus 39 percent, adjusted odds ratio 0.19, 95% CI 0.05-0.75) compared patients who received adenosine to those who did not. In addition, among patients with CK-MB elevations, the peak values were significantly lower in the adenosine group. Further studies are needed to confirm these results and to determine whether outcomes are improved. Administration of adenosine for the purpose of preventing periprocedural myonecrosis is not presently recommended.

Ischemic preconditioning — The role of remote ischemic preconditioning to prevent biomarker elevation is discussed separately. (See "Myocardial ischemic conditioning: Clinical implications", section on 'Percutaneous coronary intervention'.)

Distal protection devices — Distal embolic protection devices (DEPD) have been evaluated in two groups of patients undergoing PCI: patients with saphenous vein grafts and patients undergoing primary PCI.

The use of DEPD has been shown to reduce complications and periprocedural MI in PCI of degenerated saphenous vein grafts by preventing distal embolization of atherosclerotic debris [75]. Application in this setting depends on the location of the lesion to be treated. Typically, ostial or distal anastomotic lesions are not treated with DEPD because of inability to protect the distal vascular bed, or the concern of proximal embolization into the aorta. (See "Coronary artery bypass graft surgery: Prevention and management of vein graft stenosis", section on 'Embolic protection devices'.)

The use in native coronary disease has been not been shown to be effective in reducing periprocedural MI.

Randomized trials have not shown routine benefit of DEPD in the setting of primary PCI for STEMI, even though the device removes a substantial amount of atheromatous debris. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'Distal embolic protection devices'.)

Thrombus aspiration — In the setting of acute STEMI, thrombectomy with aspiration of the occluding thrombus has been shown to reduce embolization, no reflow, and reduce infarct size and mortality in several randomized trials. However, two large multicenter trials (TASTE and TOTAL) of manual thrombectomy failed to show benefit and a meta-analysis of 17 trials (20,960 patients) also failed to show benefit and potential harm [76]. Accordingly, routine use of thrombectomy is not considered standard of care. It may still be of benefit in patients with a large thrombus burden as considered by the interventionalist. (See "Suboptimal reperfusion after primary percutaneous coronary intervention in acute ST-elevation myocardial infarction", section on 'Thrombectomy'.)

MANAGEMENT — The treatment of periprocedural myocardial infarction (MI) depends upon the underlying cause, whether or not the periprocedural MI is detected during or after the procedure. With acute stent thrombosis, immediate re-dilation of the occlusion with or without stenting is highly effective in reducing the size of the infarction. In patients with stent thrombosis, intravascular ultrasound should be strongly considered for evaluation of the pathophysiology and selecting optimal therapeutic strategies. (See "Coronary artery stent thrombosis: Clinical presentation and management".)

In the case of distal embolization of a thrombus, mechanical disruption and fibrinolytic agents can improve flow. With atheroembolic material, this is not usually effective, and when the vessel is large enough, stenting across the debris is sometimes possible. If vasospasm or slow flow is evident, then use of intracoronary vasodilators, such as calcium channel blockers, nitroglycerin, nitroprusside, nicorandil, or adenosine, can be helpful. Dissection and side branch occlusion can be treated with dilation and stenting of the occlusive lesions.

In most cases, a periprocedural MI is silent and not detected during the procedure, but recognized afterwards if cardiac enzymes are routinely measured. Supportive measures alone are adequate for modest elevations when no clinical events have occurred. With minor elevation of cardiac biomarkers and the absence of symptoms or complications, hospitalization does not need to be prolonged and no additional therapy is needed. For larger infarcts, such as Q wave infarcts and those meeting definitions of periprocedural MI, treatment should follow recommendations for secondary prevention after spontaneous ST-elevation MI and non-ST elevation MI [77]. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

SUMMARY AND RECOMMENDATIONS

●Percutaneous coronary intervention (PCI) is associated with a small but significant incidence of serious procedural complications such as death, stroke, life-threatening bleeding, or large myocardial infarction (MI). Periprocedural myocardial necrosis, which can range from a minor elevation of cardiac biomarkers of necrosis (periprocedural myocardial injury) to a large MI, is the most common complication. Approximately 20 percent of patients with normal preprocedural creatine kinase MB fraction and cardiac troponin T (cTnT) values had an isolated postprocedural elevation in serum cardiac troponin. (See 'Incidence' above.)

●Assessment of biomarkers relies on cardiac troponin elevation, as it is more sensitive. MI associated with PCI is arbitrarily defined by elevation of cTn values >5 x 99^th percentile upper reference limit (URL) in patients with normal baseline values (≤99^th percentile URL) or a rise of cTn values >20 percent if the baseline values are elevated and are stable of falling. In addition, either (i) symptoms suggestive of myocardial ischemia, or (ii) new ischemic electrocardiographic changes or new left bundle branch block, or (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow- or no-flow or embolization, or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality are required. (See 'Diagnosis' above.)

●An elevated cardiac biomarker before the procedure is associated with an adverse prognosis. Elevations after PCI may also carry a worse prognosis. Our approach to the use of biomarker testing before and after PCI is discussed above. (See 'Prognosis' above.)

●Multiple therapies for the prevention of periprocedural MI have been evaluated and include, among others, antiplatelet drugs, statins, ischemic preconditioning, adenosine, beta blockers, and distal protection devices. Of these, antiplatelet drugs and statins appear to have the greatest benefit. (See 'Prevention' above.)

●Cardiac troponin I or T should be measured in all patients with symptoms suggestive of an MI during or after PCI and in all patients with complicated procedures. (See 'Recommendations for biomarker measurement' above.)