Myocardial damage during percutaneous interventions for non-ST-elevation acute coronary syndromes

Abstract

The prognostic significance and pathophysiological mechanisms underlying elevations in cardiac enzymes in patients with non-ST-segment elevation acute coronary syndromes (ACS) post-percutaneous coronary intervention (PCI) is a matter of debate. The few available data, derived mainly from sub-analyses of large randomized trials and from small prospective observational studies, suggest that patients with ACS who undergo PCI have an increased risk for procedural myocardial damage which, in turn, is associated with an adverse clinical outcome. Although the pathophysiology of post-PCI myocardial damage is multifactorial, the embolization of debris or calcified plaque material, or exposure of thrombogenic material at intravascular sites seems to play a key role, as shown by mechanistic studies that demonstrate a close relationship between post-procedural enzyme release and abnormal tissue perfusion. Several pre-procedural treatment strategies using antithrombotic therapies have evolved in an attempt to lower the rate of myocardial damage related to the performance of PCI in ACS patients. Major trials that evaluated the use of glycoprotein (GP) IIb/IIIa inhibitors during PCI in patients with ACS have suggested that maximum benefit is obtained in patients with increased troponin levels and in patients undergoing PCI, reducing the incidence of cardiac enzyme release after the procedure. However, a number of lingering unsolved issues concerning which agent should be used and the most appropriate timing and dosage remain to be explored. Mechanistic and clinical findings suggest that an early invasive strategy with upstream GP IIb/IIIa inhibitors may yield more favourable outcomes than downstream strategies.

Introduction

Complications of percutaneous coronary intervention (PCI), and coronary stenting in particular, are well characterized. Death, myocardial infarction (MI), and the need for emergent or urgent repeat revascularization are all known possible outcomes of PCI.¹ Although these acute complications are rare, closer scrutiny of myocardial damage during PCI has revealed elevations in levels of serum creatine kinase (CK) and its sub-fraction CK-myocardial bound (CK-MB) in up to 26% of patients after otherwise technically successful procedures.^2,3 Cardiac troponins are more specific and sensitive markers of myocardial damage than either CK or CK-MB. Elevation of troponins is an independent predictor of an adverse outcome among patients presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACS).⁴ It is generally believed that elevated troponins in this setting indicate the presence of a thrombus at culprit lesions, and such an elevation may thus be a marker for consequent thromboembolization at distal vascular beds.^5–7 This may occur not only spontaneously, but also when the artery is directly manipulated via balloon angioplasty, stenting, or other endovascular therapeutic techniques. However, the prognostic significance and pathophysiological mechanisms underlying post-PCI cardiac enzyme elevations in this setting remain unclear.

Prognostic impact of post-PCI cardiac enzyme elevation in NSTE-ACS

Interpretation of post-procedural troponin elevation is problematic in patients with NSTE-ACS because it is difficult to demonstrate definitively that post-procedural troponin release is solely a result of the procedure rather than a reflection of pre-PCI troponin levels. Few studies have examined the prognostic impact of troponin elevation following PCI in patients with NSTE-ACS. Fuchs et al.⁸ evaluated 132 patients with NSTE-ACS who had positive baseline troponin I (TnI) and underwent PCI >48 h from admission. Patients with TnI re-elevation had significantly higher in-hospital mortality (9.8 vs. 0%; P=0.016) and a higher 6-month cumulative death rate (24 vs. 3.7%; P=0.001) than in those with no elevation in troponin levels. By multivariate analysis, TnI re-elevation was an independent predictor of 6-month cumulative mortality.

In a prospective sub-study of the SYMPHONY (Sibrafiban Versus Aspirin to Yield Maximum Protection from Ischemic Heart Events Post-acute Coronary Syndromes) and second SYMPHONY trials,⁹ which randomized patients with NSTE-ACS to receive aspirin or sibrafiban, biomarkers of myocardial damage were measured in 481 patients undergoing PCI. Patients with post-procedural troponin elevation were at increased risk for death or MI at 90 days of follow-up (10.6 vs. 4.2%; P=0.005).

In a smaller study, Nageh et al.¹⁰ demonstrated that patients with unstable angina who underwent PCI and had post-procedural cardiac TnI above baseline levels had a significant increase in long-term major adverse cardiac events compared with those whose troponin levels remained unchanged or fell below baseline 24 h after the procedure (80 vs. 8.6%, respectively). The increased event rate in this study was mainly driven by repeat revascularization procedures.

Roe et al.¹¹ evaluated 6164 patients from the GUSTO-IIb (Global Use of Strategies to Open Occluded Coronary Arteries IIb), PURSUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy), and PARAGON (Platelet IIb/IIIa Antagonism for the Reduction of Acute Coronary Syndrome Events in a Global Organization Network International) A and B trials, who underwent PCI during the initial hospitalization to assess the impact of peri-procedural CK-MB elevations on clinical outcomes. Peak CK-MB levels after PCI were analysed both continuously and categorically. A significant relationship was found between higher levels of peak CK-MB elevation after PCI and an increased risk of adverse outcomes. The negative prognostic impact of peri-procedural myocardial damage was confirmed by multivariate analysis that also adjusted for angiographic and procedural factors known to be significant predictors of mortality.¹¹

In summary, patients with ACS who undergo PCI have an increased risk for procedural myocardial damage. Although these patients can benefit from early coronary interventions, those who have increased cardiac enzymes after PCI have a worse prognosis than those who do not. Peri-procedural cardiac enzyme elevation may reflect greater cumulative myocardial damage in ACS patients with spontaneous myocardial necrosis and may partly explain the adverse consequences of post-admission infarctions.¹² Although larger prospective studies are needed to determine the ideal thresholds and markers for the classification of spontaneous and peri-procedural infarctions in patients with ACS, long-term risks of myocardial necrosis appear to be similar irrespective of the mechanism of ischaemic injury.

Pathophysiology of post-PCI troponin elevation in NSTE-ACS

Despite the demonstrated association between peri-procedural myocardial necrosis and mortality in the setting of NSTE-ACS, the pathophysiological mechanisms underlying cardiac enzyme elevation and subsequent adverse clinical outcomes remain controversial. Peri-procedural necrosis is often caused by procedural complications such as side-branch occlusion, abrupt closure, or coronary dissection, and a correlation between lower rates of procedural success and higher cardiac enzyme release after PCI has been demonstrated.¹² In addition, greater atherosclerotic plaque burden has been shown to be associated with an increased likelihood of peri-procedural cardiac enzyme release, and so CK-MB or troponin release after PCI may also be markers of a more active atherosclerotic process and, by themselves, independent predictors of a poor outcome.^13,14 However, mechanical manipulation during PCI or stent implantation can lead to embolization of debris or calcified plaque material, or exposure of thrombogenic material at intravascular sites.⁵ Embolization also includes microparticulate atheromatous material and this has been routinely demonstrated through the use of embolus capture devices.⁵

Finally, mechanisms other than mechanical embolization, such as capillary oedema, inflammation, and vasospasm mediated by the release of vasoconstrictors, may play at least some role.¹⁵ Previous angiography studies have shown that patients with NSTE-ACS and an elevated troponin level on presentation have more extensive coronary artery disease and more complex lesions, and more often demonstrate impaired thrombolysis in MI (TIMI) flow and thrombi at the site of a culprit lesion than those without elevated troponin levels.^7,16 Okamatsu et al.,⁷ using coronary angioscopy, found the presence of a coronary thrombus to be the only independent factor that distinguished between troponin-positive and troponin-negative patients (88 vs. 37%; P<0.0005), even when the incidence of complex plaque was equally high in the two groups (64 vs. 68%; P=0.77). Furthermore, recent studies have suggested that biomarker release in patients with NSTE-ACS is associated with impaired tissue-level perfusion, which, in turn, is associated with an adverse clinical outcome.^17,18

We recently tried to verify the hypothesis that post-PCI-elevated TnI levels in high-risk patients with NSTE-ACS may be associated with abnormal tissue-level perfusion by examining the relationship between elevations in troponin and tissue-level perfusion as assessed using the corrected TIMI frame count, TIMI myocardial perfusion grade (TMPG), and myocardial contrast enhancement by intracoronary myocardial contrast echocardiography (MCE).¹⁹ We found abnormal tissue perfusion in a high percentage of patients (59%) before PCI, and post-procedural cardiac TnI elevation was associated with an additional abnormal tissue-level perfusion, even in those patients with epicardial TIMI grade 3 flow at the completion of the intervention.¹⁹ TMPG 0/1 after PCI was observed more frequently in patients with post-procedural cardiac TnI elevation (43 vs. 7%; P<0.02). Cardiac TnI levels were higher in patients with TMPG 0/1 than in patients with TMPG 2/3 (5.3±2.7 vs. 1.5±1.3 ng/ml; P<0.0001). Patients with post-procedural cardiac TnI elevation also presented a significantly lower number of perfused segments on MCE (59 vs. 81%; P<0.02), as well as a lower MCE score index (0.65±0.38 vs. 0.89±0.21; P<0.02).¹⁹ These data provide a potential pathophysiological link between impaired tissue-level perfusion, myocardial damage, and adverse clinical outcome.

How to mitigate post-PCI myocardial damage

A number of pre-procedural treatment strategies using antithrombotic therapies have evolved in an attempt to lower the rate of complications related to performance of PCI²⁰ in ACS patients. Pre-treatment with aspirin and unfractionated heparin is the bedrock of pharmacotherapy to lower procedural risk. In recent years, a number of new antithrombotic agents have been tested as pre-procedural treatments to minimize complications in conjunction with, or as substitutes for, aspirin and unfractionated heparin. Among these agents are the thienopyridines, glycoprotein (GP) receptor IIb/IIIa inhibitors, the low-molecular-weight heparins, and the direct thrombin inhibitor, bivalirudin. Although some clinical evidence supports the use of each of these agents as pre-treatment for the reduction of thrombosis-mediated PCI complications, most of the data available pertain to GP IIb/IIIa inhibitors. The results of major trials that evaluated the use of these agents during PCI in patients with ACS have suggested that maximum benefit is obtained in patients with increased troponin levels and in patients undergoing PCI, reducing the incidence of cardiac enzyme release after the procedure.²⁰ Although the usefulness of this therapeutic strategy has been convincingly demonstrated, a number of lingering unsolved issues concerning which agent should be used and the most appropriate timing and dosage remain to be explored. Patients with ACS may have a decreased response to antiplatelet agents,²¹ and tirofiban may be less effective than abciximab within 60 min after administration.²² Recently, Schneider et al.²³ have identified a tirofiban bolus of 25 µg/kg (followed by a maintenance infusion of 0.15 µg/kg per min) that achieves inhibition of platelet aggregation >85% for 60 min. However, the role of this regimen in high-risk patients with NSTE-ACS remains to be established.

Furthermore, there is uncertainty about whether GP IIb/IIIa inhibitors should be given just before PCI if an early (within 48 h) invasive strategy is planned in this setting. In fact, although the results of placebo-controlled trials in which upstream GP IIb/IIIa inhibition was initiated upon admission are encouraging, there are few other data to support the use of upstream GP IIb/IIIa inhibitors.²⁴ In the TACTICS-TIMI 18 (Treat Angina with Aggrastat and Determine Cost of Therapy with Invasive or Conservative Strategy—Thrombolysis in Myocardial Infarction 18) trial,²⁵ all patients received upstream GP IIb/IIIa inhibitor therapy and were randomized to either early invasive or early conservative treatment, so the design did not permit a definitive statement to be made as to whether upstream GP IIb/IIIa inhibition is helpful in patients who progress to an early invasive strategy. Also, there has been no randomized trial in which patients were actually randomized to receive upstream or downstream (in the catheterization laboratory) GP IIb/IIIa inhibitors. To address these issues, we recently compared the effects of upstream tirofiban vs. downstream high-dose bolus (HDB) tirofiban or abciximab on epicardial and tissue-level perfusion and TnI release in high-risk patients with NSTE-ACS treated with PCI.²⁶ The results showed that in this patient population, an upstream tirofiban regimen was associated with better tissue-level perfusion, both before and after intervention, and lower post-procedural cardiac TnI release compared with a downstream HBD tirofiban or abciximab regimen (9.4 vs. 30 vs. 38.7%, respectively; P=0.018).²⁶ In contrast, no significant difference was found with regard to tissue-level perfusion and cardiac TnI release between downstream HBD tirofiban and downstream abciximab.²⁶ These mechanistic findings, coupled with the clinical findings from the TACTICS-TIMI 18 trial,²⁵ suggest that the earlier initiation of tirofiban in addition to aspirin and heparin therapy in patients with NSTE-ACS, followed by routine angiography within 48 h and PCI as appropriate, may yield more favourable outcomes than downstream strategies.

Conclusion

According to current evidence, patients with ACS who undergo PCI have an increased risk for procedural myocardial damage. Although the pathophysiology of post-PCI myocardial damage is multifactorial, embolization of debris or calcified plaque material, or exposure of thrombogenic material at intravascular sites seems to play a key role as shown by mechanistic studies that demonstrate a close relationship between post-procedural enzyme release and abnormal tissue perfusion. Among the currently available antithrombotic therapies, GP IIb/IIIa inhibitors have the best potential for preventing post-PCI myocardial damage. Mechanistic and clinical findings suggest that an early invasive strategy with upstream GP IIb/IIIa inhibitors may yield more favourable outcomes than downstream strategies.

Conflict of interest: none declared.

References