Apple, Fred S.

Jaffe, Allan S.

Katus, Hugo A.

Lindahl, Bertil

Mueller, Christian

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CURRENT OPINIONWhy all the struggle about CK-MB and PCI?Allan S. Jaffe1, Fred S. Apple2*, Bertil Lindahl3, Christian Mueller4,and Hugo A. Katus51Cardiovascular Division, Gonda 5, Mayo Clinic and Medical School, 200 First St. SW, Rochester, MI 55905, USA; 2Hennepin County Medical Center and University of Minnesota,Minneapolis, MI, USA; 3Department of Medical Sciences and Uppsala Clinical Research center, Uppsala University, Uppsala, Sweden; 4University Hospital, Basel, Switzerland; and5Universita¨tsklinikum Heidelberg, Heidelberg 69120, GermanyReceived 1 August 2011; revised 21 November 2011; accepted 20 December 2011; online publish-ahead-of-print 11 January 2012IntroductionCardiovascular medicine has, in general, enthusiastically embracednew technologies and used them per appropriate guidelines.However, one area in which this has not been as much the casehas been with cardiac troponin (cTn). There has been reluctanceto use cTn at the suggested 99th percentile of the upper referencerange (URL).1 Part of this reluctance reflects a lack of comfort withthe large number of increases seen with such a sensitive probe thatchallenge clinicians.2 However, the reluctance to utilize cTn prop-erly has distorted the utility of cTn in many areas,1,2 but perhaps ithas caused the greatest confusion in the area of post-PCI biomark-er increases as attested to by recent articles.3– 5 In this area, thereluctance to give up the paradigms of the past and to use cTnper guidelines has led to confusion and inaccurate conclusions inarticles published even in our most prestigious journals. This edi-torial from a group of researchers knowledgeable in this areaattempts to articulate some of the difficulties with the interpreta-tions thus far posed and suggest how proper use of cTn canachieve a better understanding in this important area. It does notand cannot answer all of the questions going forward but progressis only possible if we understand and properly interpret the datathat presently exist.A recent article in this area published in JACC3 is an excellentexample of the problems in this area. It was followed by an editorialthat misconstrues most of the important concepts.4 The article uti-lized MR imaging post-PCI to visualize areas of cardiac injury puta-tively related to the procedure. Because they used a good andsensitive cTn assay and the recommended cut-off values, theyfound that more increases in CK-MB were associated findings ofdelayed hyperenhancement than with cTn. However, they then con-cluded that CK-MB increases were more significant. The problemswith this logic are several. First, it is not surprising that increasesof CK-MB are more apt to be detected by MR imaging; CK-MB ismuch less sensitive than cTn and so more myocardial injury isrequired and thus MR imaging detects larger areas of hyperenhance-ment. The authors acknowledge this in the results section by indicat-ing that higher cTn values would have provided similar results toCK-MB. Does that mean that the increases of cTn not seen werenot related to cardiac injury? Of course not! MR imaging is less sen-sitive than cTn and therefore patients with small increase in cTn maynot manifest hyperenhancement. The only challenge to this assertionutilized a very insensitive cTn assay and an excessively high cut-offvalue6 that was unmasked by calling the authors (A.S.J. personalcommunication). In addition, if plaque emboli are the aetiology ofthe injury, it may be sufficiently diffuse that it does not cause hyper-enhancement because the areas of injury are not sufficiently conflu-ent.7 Finally, we have no data to suggest that MR detectable defectsworsen prognosis more than non detectable ones.Most importantly, we contend that present data do not supportthe contention that post-PCI biomarker increases imply an adverseprognosis when the analysis includes the baseline cTn value used assuggested by guidelines.8 This later point underlies the confusionarticulated in the JACC editorial.4 The concept of post-PCIinjury developed prior to the development of cTn. The initialstudies suggested that if one had a normal CK-MB at baselineand then an increase post-intervention, it was associated with anadverse prognosis.9 We do not take issue with the design or inter-pretation of those studies, but would point out that there was con-troversy at the time about how minor amounts of necrosis couldcause an adverse prognosis.10 In hindsight, those concerns weremore right than wrong and now the use of cTn has helped us tounderstand the reason for the results that were reported. Inmost of the initial studies, the likelihood of a stable baselinevalue was presumed but, in retrospect, it is clear that was improb-able because so many of the patients presented acutely. Now, withacute presentations, in many patients cTn measurements arealready rising.11 Knowing that cTn is rising confirms what is difficultto ascertain with CK-MB; that it, too, likely is rising. Thus, what wascalled a normal CK-MB in these studies belied the fact that thevalue was already starting to rise, albeit slowly and from a relativelylow baseline.Cardiac troponin solves this problem but only if one interpretsthe values properly. If one uses high cut-off values for the baseline,this effect may be missed. However, once it is recognized that thebaseline value is rising, it becomes clear that distinguishing* Corresponding author. Tel: +1 507 284 1648, Fax: +1 507 266 0228, Email: jaffe.allan@mayo.eduPublished on behalf of the European Society of Cardiology. All rights reserved. & The Author 2012. For permissions please email: journals.permissions@oup.comEuropean Heart Journal (2012) 33, 1046–1048doi:10.1093/eurheartj/ehr502subsequent rises from the initial insult from those due to PCI is im-possible regardless which biomarker one uses. The use of theproper reference value at baseline is essential to detect this situ-ation. Some data suggest that most post-PCI increases are dueto increases induced prior to the PCI because it is almost exclu-sively those who have increased cTn at baseline who manifestmarked increases (greater than three-fold) of either cTn orCK-MB post-PCI.11 Thus, perhaps most of the myocardial injuryis related to the initial insult although it is hard to exclude an add-itional component due to re-perfusion of an already injured area ordue to new interventional complications.12,13 An appreciation ofthis fact has been lost in many studies because so many studieshave not used the recommended cut-off values at baseline (seebelow). One could of course argue that any increase is adverse,but the critical question is at what level, if any, does it become clin-ically significant (see below).It is well understood that, in patients with ACS, an increased cTnmarks patients at accentuated risk.14 cTn increases mark moreadverse coronary anatomy, more unstable plaque, more throm-bosis, more endothelial dysfunction, or all in combination.14 Re-cently, similar data in patients with stable disease have beenpresented; i.e. increases of cTn are common and prognostically im-portant with or without intervention.15,16 Consequently, the infor-mation provided by cTn is available prior to PCI. Because CK-MB isless sensitive, increases lag behind cTn so some of CK-MBincreases are only detectable post PCI. Appreciation of this prog-nostic information at baseline critically depends on the use of theproper cut-off value (the 99th percentile URL) because this valuemaximizes the prognostic value. Values above this and many beloware indicative of myocardial injury because most assays cannotmeasure normal values.8 If one uses a higher cut-off value, onediminishes this prognostic effect. A good example of this is arecent analysis using the value at the 10% coefficient of variation(CV) instead of the 99th percentile value. This value is higherthan the 99th percentile URL. In a large cohort with baselinevalues ,10% of the CV value, increases rising to above thatvalue were reported to have prognostic importance.17 However,these values are abnormal and likely were rising pre-PCI andthere is known prognostic significance to this value as well.18With high-sensitivity assays, we now know that values in thatrange are well above the true normal values. Unfortunately, theuse of cut-off values above the 99th percentile value to define a‘normal’ baseline value is common practice. In one recentmeta-analysis,5 it was claimed that all the baseline values were‘normal,’ but if one reviews the individual manuscripts, none ofthe papers cited used the 99th percentile value with a reasonablysensitive cTn assay. It was not until 2008 that an analysis using the99th% URL was reported.19 When the 99th percentile cutoff wasused to determine a normal baseline, increases at baseline abovethis level provided substantial prognostic information but neithervalues of cTn nor CK-MB post-PCI regardless of their magnitudehad prognostic significance. The only marginally significant analysiswas the short-term analysis of patients with normal values (lessthan the 99th percentile value) at baseline and isolated increasesof cTn post-PCI. The P-value for a short-term adverse prognosticsign was 0.05. However, 2/3 of the events in this group occurredsecondary to non-cardiac causes in patients with severe non-cardiac co-morbidities. There was no signal for cardiac complica-tions. The recent analysis by Cavellini is similar despite the factthat they used a cut-off value slightly higher than the 99th percent-ile.20 The lack of prognostic value of post-PCI biomarker increasesalso recently was reported from the Acuity trial.21 What thismeans is that interventional cardiologists have been at least partial-ly right in saying that a good intervention, even if associated withsmall amounts of necrosis, is not associated with an adverse prog-nosis. Most importantly, well-done interventions in the absence ofbaseline injury rarely results in marked increases in biomarkers. It isonly when treating a recently damaged area that more markedincreases occur and they may be due mostly to the initial insultand not the intervention. What is associated with an adverse prog-nosis is more severe disease, which is what an increased biomarkerat baseline denotes. The necessary prognostic information is avail-able at baseline if one uses the proper metrics. Thus, in ouropinion, CK-MB no longer has a role in defining post-PCI injury.For now, cTn at baseline will provide all the prognostic informationthat is important. It is likely that there is some level of post-PCI cTnincrease, where a peri-procedural complication harms patients butthe frequency of those marked increases are likely infrequent andhard to study. One could argue that physicians should continue tomonitor cTn post-procedures for quality control purposes but notprognosis.As with any field, there are many questions posed by new dataand/or new interpretations of older data. This is certainly the casehere. We would point out the need to define the following:(1) There are data sets that could probe the frequency where aperi-procedural myocardial infarction (AMI) might have beendiagnosed despite the fact that PCI was delayed.(2) Other investigators could reanalyse their data sets using con-temporary assays and proper cut-off values to confirm orrefute our synthesis.(3) We suspect that novel high-sensitivity cTn assays will supportthe prior data detailed. However, this will only happen if theproper metrics are used.(4) There are some patients who have stable increases of cTneither due to chronic disease or because they are on thedown slope of the cTn time–concentration curve after anevent. The impact of a subsequent rise after PCI has not yetbeen defined in this group.(5) It may well be that if identical interventions were done, it mightbe that those without any injury at all (no cTn change) mighthave a better prognosis since any loss of myocardium is prob-ably adverse. However, it might take hundreds of thousands ofpatients to confirm this but it should be explored. Perhapsvery large data sets will allow us to define some level atwhich elevated post-PCI values are prognostically importanteven when they occur from a normal baseline value.(6) Using post-PCI cTn increases to probe the effects of newadjunctive interventions might be a wise investment in thefuture.(7) We should ask if increases in cTn post-procedure is of import-ance in other developing catheter-based interventions?In conclusion, it is time to move beyond the concept that post-PCICK-MB values are useful. Furthermore, it is time to give up theWhy all the struggle about CK-MB and PCI? 1047concept that post-PCI myocardial injury is an important endpoint.Some clinical trialists wish to retain it because it has served clinicaltrials well for many years. However, from a patient-oriented focus,prognostically, it is the increases of cTn at baseline that are import-ant. Likely, further increases post-PCI are indicative of cardiacinjury if the baseline value is normal but the data stronglysupport the idea that such increases rarely have prognostic import-ance. Should we call these biomarker increases AMIs despite thelack of prognostic significance? Should we measure biomarkerspost-PCI? If we choose to, what criteria should we employ? Ourfocus should be on questions like this and not on trying to justifyingthe retention of paradigms that no longer serve the clinical com-munity well.FundingA.S.J. has received consulting, research support and/or speakinghonoraria from most of the major diagnostic companies. F.S.A.has received consulting, research support and/or speaking honor-aria from most of the major diagnostic companies. B.L. has beenmember of the advisory board for Beckman Coulter, Philips, Radi-ometer and Siemens Diagnostics and has received lecture/consult-ing honoraria from Siemens Diagnostics and Roche diagnostics.C.M. received lecture honoraria from Abbott Diagnostics,Biosite, Brahms, Roche Diagnostics, and Siemens Diagnostics, andhe has received support from the Swiss National Science Founda-tion (PP00B-102853), the Swiss Heart Foundation, Abbott Diag-nostics, Biosite, Brahms, Nanosphere, Roche Diagnostics, andSiemens Diagnostics. H.A.K. holds a patent on the cardiac troponinT assay jointly with Roche Diagnostics.References1. Jaffe AS, Katus H. Acute coronary syndrome biomarkers–the need for more ad-equate reporting. Circulation 2004;110:104–106.2. Saenger AK, Jaffe AS. Requiem for a heavyweight: the demise of creatinekinase-MB. Circulation 2008;118:2200–2206.3. 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Prognosticsignificance of periprocedural versus spontaneously occurring myocardial infarc-tion after percutaneous coronary intervention in patients with acute coronarysyndromes: An analysis from the ACUITY trial. J Am Coll Cardiol 2009;54:477–486.A.S. Jaffe et al.1048

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