EDITORIAL COMMENT
Periprocedural myocardial infarction and mortality
Causality versus association*
Brahmajee K. Nallamothu, MD, MPH* and
Eric R. Bates, MD, FACC*,*
* Division of Cardiovascular Diseases, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan, USA
* Reprint requests and correspondence: Dr. Eric R. Bates, B1 238 Taubman Center, 1500 East Medical Center Drive, Ann Arbor, Michigan 48109, USA.
ebates{at}umich.edu
In this issue of the Journal, Ioannidis et al. (1) report the results of a meta-analysis of seven studies on creatine kinase-MB isoenzyme (CK-MB) elevation after percutaneous coronary intervention (PCI) and its relationship to subsequent mortality. As in earlier reports, the authors confirmed a significant relationship between peri-procedural CK-MB elevation >3 x the upper limit of normal (ULN) and subsequent mortality. Additionally, they also found that patients with CK-MB elevation between 1 to 3 x ULN, which usually occurs with no associated clinical event, were at increased risk for late mortality. The latter finding extends the previous debate regarding the clinical significance of asymptomatic biomarker release (2,3).
Our comments focus on four key elements of this study: 1) its theoretical background; 2) its methodologic strengths and limitations; 3) the biologic plausibility of its findings; and 4) its clinical implications for prevention and therapy.
 |
Background
|
|---|
In 1991, Klein et al. (4) first reported that although CK elevation occurred in 15% of patients after otherwise-successful balloon angioplasty, it appeared to have no significant impact on in-hospital outcomes. Over the last decade, numerous investigators have studied this phenomenon in PCI registries (5–9) and clinical trial cohorts (10,11), extending the analyses to different patient populations and interventional devices, more cardiac-specific biomarker assays (CK-MB and cardiac troponins), and longer follow-up periods. From this body of work, a number of important generalizations can be made: - When routinely measured, biomarker release after PCI is common, occurring in 5% to 30% of cases: most of these are minor releases.
- Biomarker release is associated with several patient (age, acute coronary syndrome), angiographic (multivessel disease, saphenous vein graft intervention, intracoronary thrombus), and procedural (non-balloon device use) factors.
- Large elevations in biomarker release (e.g., CK-MB release >5 to 8 x ULN) are independently associated with late mortality.
- Small elevations in biomarker release have been inconsistently associated with late mortality.
Understandably, expert panels have varied in their interpretation of the clinical importance of these findings. Some have recommended the routine measurement of CK-MB (or other biomarkers) after PCI (12,13), whereas others suggest measurement only if driven by evidence of: 1) angiographic complications during PCI (i.e., side-branch occlusion), or 2) clinical ischemia (angina, arrhythmia, hypotension) (14,15). Many (12,14) have agreed that the threshold of >3 x ULN for CK-MB elevation, despite being somewhat arbitrary, should be used to define a peri-procedural myocardial infarction. A notable exception to this standard is the consensus statement from the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction (13). This committee recommended that any rise above normal for CK-MB or cardiac troponins in the setting of PCI be considered a myocardial infarction. The meta-analysis by Ioannidis and colleagues (1) supports this recommendation. Yet, the new American Heart Association Diagnostic and Interventional Catheterization Committee recommendation (15) raising the CK-MB diagnostic threshold to 5 to 8 x ULN may be more clinically relevant in the context of more recent data.
|
Methodological issues
|
|---|
Meta-analyses are generally reserved for pooling the results of randomized clinical trials (RCTs), where bias between the groups of patients being observed is minimized by study design. Combining the results of observational studies, although statistically feasible, is less common and has several theoretical disadvantages: 1) variable definitions of risk markers and outcomes; 2) widespread differences in the "quality" of the studies; and 3) a limited ability to adjust for potential sources of confounding between risk markers and outcomes.
The study by Ioannidis et al. (1) combined the results of seven published studies that included a total of 23,230 patients. The studies were reported between 1994 and 2002, included asymptomatic patients (with four studies specifically excluding patients with major complications after PCI), involved the use of a wide variety of devices, and used variable assays and protocols for the measurement of CK-MB after PCI. Overall, the authors found the incidence of peri-procedural CK-MB elevation to be 31% with the risk of late mortality rising proportionately with increasing biomarker elevations. Importantly, this risk was present even when the degree of CK-MB elevation was only 1 to 3 x ULN, suggesting a "dose-response" relationship between biomarker release and subsequent mortality. By pooling results from the seven studies, the authors were able to increase the statistical power needed to detect this smaller, yet potentially clinically important outcome.
How strongly can we believe the conclusion that minor CK-MB elevations are associated with late mortality? One of the major limitations of this study is the fact that summary risk estimates reported were unadjusted. Because the influence of confounding is most crucial when the overall association between a risk marker and outcome is small, this is particularly important in the case of minor CK-MB elevations. Without proper adjustment for patient, angiographic, and procedural factors known to be associated with both CK-MB elevation and worse long-term survival, it is impossible to know whether biomarker release after PCI is simply a marker of disease severity or directly responsible for subsequent mortality. Determining independent association is a critical first step in understanding whether any epidemiological relationship is causal and this usually requires a prospective RCT. Unfortunately, none have been performed on this topic.
|
Biologic plausability
|
|---|
Another crucial step in establishing causality depends on understanding how well a relationship correlates with a pre-existing body of knowledge. Not until Ricciardi et al. (16) demonstrated that mild CK-MB elevations after PCI were related to discrete microinfarctions detected by contrast-enhanced magnetic resonance imaging was it clear that biomarker release was directly related to myocardial necrosis and not just due to profound ischemia from transient coronary artery occlusion during PCI. Several potential mechanisms have been postulated for causing PCI-related myocardial necrosis, including: 1) distal embolization, 2) the no-reflow phenomenon, 3) transient vessel closure from dissection or spasm, and 4) side-branch occlusion. Importantly, it appears that myocardial necrosis often occurs when PCI is otherwise "successful" with no clinically detectable complications.
However, the more difficult relationship to understand, from a standpoint of biologic plausibility, is how minor CK-MB elevations after PCI can lead to increased mortality several years after the procedure as suggested by the study by Ioannidis et al. (1) and earlier reports (5,6). Previous theories suggest that CK-MB elevations might lead to a heightened adrenergic or inflammatory state post-PCI or induce long-term arrhythmic instability from an infarct substrate even in the absence of substantial myocardial damage (12). In addition, it has been proposed that minor elevations may represent microembolization and compromise of potential distal collateral channels (2).
More recently, others (17,18) have suggested that plaque characteristics, including total atherosclerotic burden or plaque instability, are related to peri-procedural CK-MB elevations; thus, biomarker release after PCI actually "selects" for those patients with complex plaques who are at the highest risk for recurrent events. This suggestion appears to be more consistent with recent data from Ellis et al. (8) that identified an early four-month high-risk period of events for patients with any PCI-related CK-MB release in addition to a late mortality risk beyond 12 months. Interestingly, they also suggested that high inflammatory states and high-risk clinical features (such as incomplete revascularization and congestive heart failure) amplified risk in patients with peri-procedural CK-MB release. This appears to indicate that biomarker elevations, especially mild elevations, may be risk markers for disease or lesion severity and not causal mediators of late mortality.
|
Clinical implications
|
|---|
From a clinical perspective, there are two practical questions for interventional cardiologists: 1) how can we minimize PCI-related biomarker elevations, and 2) should those with biomarker elevations be treated differently from those with normal biomarker levels after PCI?
Despite whether one believes that minor biomarker elevations are clinically important or not, minimizing such elevations after PCI is a reasonable goal because they represent myocardial necrosis. It is well established that glycoprotein IIb/IIIa inhibitors reduce the incidence of biomarker elevations after PCI, although of interest to this debate, there is no impact on six-month mortality (19). Other therapies believed to reduce the extent of CK-MB elevations include pre-procedural drug therapies, such as beta-blockers (20) and statins (21), and intraprocedural therapies, such as ischemic preconditioning (22) and intracoronary adenosine (23). However, data on these therapies have been sparse overall and, in the case of beta-blockers (24), conflicting. Recently, distal protection devices have been shown to substantially lower the incidence of biomarker release after PCI in saphenous vein graft interventions (25). When possible, the avoidance of atherectomy devices, which increase the risk of biomarker release, should also be considered.
If PCI-related biomarker elevation does occur, should these patients be treated as if they had had a spontaneous acute coronary syndrome? Extended monitoring of patients with minor elevations is unlikely to be beneficial. Two studies (7,8) showed no significant differences in in-hospital events between those patients with CK-MB elevation 1 to 5 x ULN and patients with no CK-MB elevation.
No RCTs have been performed to evaluate specific therapies in patients with biomarker release after PCI. There is evidence that these patients have a higher inflammatory state and potentially might benefit from more aggressive statin use (26). Also, these individuals may represent a high-risk subgroup of patients that would obtain the greatest benefit from prolonged dual anti-platelet therapy with aspirin and clopidogrel. Beta-blockers and angiotensin-converting enzyme inhibitors may also be appropriate to reduce arrhythmic instability and improve remodeling after myocardial necrosis.
We strongly support the recommendation that CK-MB or troponin levels should be measured before and after PCI (12,13). Patients with periprocedural myocardial infarction have a worse prognosis than if biomarkers had remained normal and this knowledge may be clinically useful. In particular, patients with biomarker elevation >5 to 8 x ULN or new Q waves have had a clinically significant complication. However, it should be recognized that patient outcome and prognosis may be significantly improved by the revascularization procedure despite a small peri-procedural myocardial infarction. The benefit of revascularizing a stenotic artery causing progressive or unstable angina or moderate or severe myocardial ischemia should far outweigh the negative impact of a small, especially asymptomatic, biomarker elevation (13). This fact has been lost in the debate about small peri-procedural myocardial infarction because there has not been a control group without revascularization against which to compare long-term outcome. Age, clinical presentation, left ventricular function, atherosclerotic burden, completeness of revascularization, objective demonstration of myocardial ischemia, and risk factor control success remain the strongest proven prognostic indicators after successful PCI.
|
Footnotes
|
|---|
* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology. 
|
References
|
|---|
1. Ioannidis JPA, Karvouni E, Katritsis DG. Mortality risk conferred by small elevations of creatine kinase-MB isoenzyme after percutaneous coronary intervention. J Am Coll Cardiol 2003;42:1406–11
2. Abdelmeguid AE, Topol EJ. The myth of the myocardial ‘infarctlet’ during percutaneous coronary revascularization procedures. Circulation. 1996;94:3369–3375[Free Full Text]
3. Holmes DR Jr., Berger PB. Troponisms, necrosettes, enzyme leaks, creatinine phosphokinase bumps, and infarctlets. What's behind this new lexicon and what does it add? Circulation. 2001;104:627–629[Free Full Text]
4. Klein LW, Kramer BL, Howard E, Lesch M. Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non–Q-wave myocardial infarction associated with coronary angioplasty. J Am Coll Cardiol. 1991;17:621–626[Abstract]
5. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG. Significance of mild transient release of creatine kinase-MB fraction after percutaneous coronary interventions. Circulation. 1996;94:1528–1536[Abstract/Free Full Text]
6. Kong TQ, Davidson CJ, Meyers SN, Tauke JT, Parker MA, Bonow RO. Prognostic implication of creatine kinase elevation following elective coronary artery interventions. JAMA. 1997;277:461–466[Abstract/Free Full Text]
7. Kini A, Marmur JD, Kini S, et al. Creatine kinase-MB elevation after coronary intervention correlates with diffuse atherosclerosis, and low-to-medium level elevation has a benign clinical course: implications for early discharge after coronary intervention. J Am Coll Cardiol. 1999;34:663–671[Abstract/Free Full Text]
8. Ellis SG, Chew D, Chan A, Whitlow PL, Schneider JP, Topol EJ. Death following creatine kinase-MB elevation after coronary intervention: identification of an early risk period: importance of creatine kinase-MB level, completeness of revascularization, ventricular function, and probable benefit of statin therapy. Circulation. 2002;106:1205–1210[Abstract/Free Full Text]
9. Nallamothu BK, Chetcuti S, Mukherjee D, et al. Prognostic implication of troponin-I after percutaneous coronary intervention. Am J Cardiol. 2003;91:1272–1274[CrossRef][Medline]
10. Harrington RA, Lincoff AM, Califf RM, et al. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol. 1995;25:1693–1699[Abstract]
11. The EPISTENT Investigators. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein IIb/IIIa blockade. Lancet. 1998;352:87–92[Medline]
12. Califf RM, Abdelmeguid AE, Kuntz RE, et al. Myonecrosis after revascularization procedures. J Am Coll Cardiol. 1998;31:241–251[Abstract/Free Full Text]
13. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the redefinition of myocardial infarction. J Am Coll Cardiol. 2000;36:959–969[Free Full Text]
14. Smith SC Jr., Dove JT, Jacobs AK, et al. ACC/AHA guidelines of percutaneous coronary interventions (revision of the 1993 PTCA guidelines)—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty). J Am Coll Cardiol. 2001;37:2215–2239[Free Full Text]
15. Levine GN, Kern MJ, Berger PB, et al. Management of patients undergoing percutaneous coronary revascularization. Ann Intern Med. 2003;139:123–136[Abstract/Free Full Text]
16. Ricciardi MJ, Wu E, Davidson CJ, et al. Visualization of discrete microinfarction after percutaneous coronary intervention associated with mild creatine kinase-MB elevation. Circulation. 2001;103:2780–2783[Abstract/Free Full Text]
17. Kanaparti PK, Brown DL. Relation between coronary atherosclerotic plaque burden and cardiac enzyme elevation following percutaneous coronary intervention. Am J Cardiol. 2000;86:619–622[CrossRef][Medline]
18. Mehran R, Dangas G, Mintz GS, et al. Atherosclerotic plaque burden and CK-MB enzyme elevation after coronary interventions: intravascular ultrasound study of 2256 patients. Circulation. 2000;101:604–610[Abstract/Free Full Text]
19. Kong DF, Califf RM, Miller DP, et al. Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/IIIa integrin in ischemic heart disease. Circulation. 1998;98:2829–2835[Abstract/Free Full Text]
20. Sharma SK, Kini A, Marmur JD, Fuster V. Cardioprotective effect of prior beta-blocker therapy in reducing creatine kinase-MB elevation after coronary intervention: benefit is extended to improvement in intermediate-term survival. Circulation. 2000;102:166–172[Abstract/Free Full Text]
21. Herrmann J, Lerman A, Baumgart D, et al. Preprocedural statin medication reduces the extent of periprocedural non–Q-wave myocardial infarction. Circulation. 2002;106:2180–2183[Abstract/Free Full Text]
22. Laskey WK. Beneficial impact of preconditioning during PTCA on creatine kinase release. Circulation. 1999;99:2085–2089[Abstract/Free Full Text]
23. Desmet W, Dens J, Coussement P, Van de Werf F. Does adenosine prevent myocardial micronecrosis following percutaneous coronary intervention? The ADELINE pilot trial. Heart. 2002;88:293–295[Free Full Text]
24. Ellis SG, Brener SJ, Lincoff AM, et al. Beta-blockers before percutaneous coronary intervention do not attenuate postprocedural creatine kinase isoenzyme rise. Circulation. 2001;104:2685–2688[Abstract/Free Full Text]
25. Baim DS, 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[Abstract/Free Full Text]
26. Chan AW, Bhatt DL, Chew DP, et al. Relation of inflammation and benefit of statins after percutaneous coronary interventions. Circulation. 2003;107:1750–1756[Abstract/Free Full Text]
This article has been cited by other articles:
|
|
|
|
 
A. S.P. Sharp, A. Latib, A. Ielasi, C. Larosa, C. Godino, M. Saolini, V. Magni, R. T. Gerber, M. Montorfano, M. Carlino, et al.
Long-Term Follow-Up on a Large Cohort of "Full-Metal Jacket" Percutaneous Coronary Intervention Procedures
Circ Cardiovasc Interv,
October 1, 2009;
2(5):
416 - 422.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Sanchis, V. Bodi, J. Nunez, L. Mainar, E. Nunez, P. Merlos, E. Rumiz, G. Minana, X. Bosch, and A. Llacer
Efficacy of Coronary Revascularization in Patients With Acute Chest Pain Managed in a Chest Pain Unit
Mayo Clin. Proc.,
April 1, 2009;
84(4):
323 - 329.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. R. Bates
Aspirating and Filtering Atherothrombotic Debris During Percutaneous Coronary Intervention
J. Am. Coll. Cardiol. Intv.,
June 1, 2008;
1(3):
265 - 267.
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Bolognese, G. Falsini, F. Liistro, and P. Angioli
Myocardial damage during percutaneous interventions for non-ST-elevation acute coronary syndromes
Eur. Heart J. Suppl.,
October 1, 2005;
7(suppl_K):
K15 - K18.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Cavallini, S. Savonitto, R. Violini, G. Arraiz, M. Plebani, Z. Olivari, P. Rubartelli, S. Battaglia, L. Niccoli, G. Steffenino, et al.
Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study
Eur. Heart J.,
August 1, 2005;
26(15):
1494 - 1498.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Pasceri, G. Patti, A. Nusca, C. Pristipino, G. Richichi, G. Di Sciascio, and on behalf of the ARMYDA Investigators
Randomized Trial of Atorvastatin for Reduction of Myocardial Damage During Coronary Intervention: Results From the ARMYDA (Atorvastatin for Reduction of MYocardial Damage during Angioplasty) Study
Circulation,
August 10, 2004;
110(6):
674 - 678.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
Top
Background
Methodological issues