Editorial

Creatine Kinase Release After Catheter-BasedCoronary Intervention

Richard Lim, MD, Kevin Zawacki, MD, and Warren K. Laskey, * MD

Elevation of total creatine kinase (CK) or myocardialisoenzyme (CK-MB) activity has been recorded in up to20% of successful percutaneous angioplasty (PTCA)procedures (Table I) [1–5]. This observation—in theabsence of overt myocardial infarction—has not beenuniversally accepted to indicate an adverse prognosis[1–3]. Conversely, it has been suggested that transientin-laboratory vessel closure is associated with adverselong-term outcome only if CK is elevated [6]. Althoughsubclinical CK rises after otherwise straightforward coro-nary intervention may differ fundamentally from sponta-neous non-Q wave myocardial infarction, there has beena recent spate of reports raising a flag of caution about theprognostic significance of CK-MB release without clini-cally apparent explanation [4,5,7,8]. Just how concernedshould the interventional community be?The Beth Israel group [3] found that angiographic

abnormalities (dissection, side-branch occlusion, throm-bus, transient no-reflow) could be identified in.40% ofpatients with raised CK-MB. Only 13 of 558 cases (2.3%)had a rise in CK-MB greater than 5 times the upper limitof normal. This was associated with a trend (P5 0.08)towards decreased survival whereas multivessel and veingraft disease, reflecting more advanced atherosclerosis,remained independent predictors. Multivariate analysisconfirmed that multivessel disease and depressed ejectionfraction (LVEF) were the strongest predictors of reducedsurvival, consistent with early observations of the naturalhistory of coronary disease.Subclinical CK-MB release is more common after

directional atherectomy (DCA) than balloon PTCA (19vs. 8%) [9], and in vein graft intervention than nativevessel procedures largely because of the potential fordistal embolization [10]. In the CAVEAT database(n5 1,012), of 60 patients with abrupt vessel closure,55% had raised CK$ 23 or CK-MB $ 33 [4].Regression analysis showed these enzyme indices to bepredictive of all-cause 1-year mortality when only base-line characteristics were considered (P5 0.038) but not

when procedural mechanical complications were entered(P5 0.055).The Cleveland Clinic reported that patients who had

CK $ 23 normal were a higher risk group with a greaterincidence of recent myocardial infarction, unstable an-gina, thrombotic or complex lesions, vein grafts, andDCAprocedures [5].Although LVEF,40%andmultives-sel disease were similarly distributed in all groups, theprevalence of three-vessel disease and inoperable diseasewas not stated. Most of the cardiac mortality occurred inthe first year. Significant multivariate correlates of car-diac death were CK elevation (odds ratio 2.19) and veingraft procedures (odds ratio 2.09). In a subgroup analysisfocusing on raised CK-MB only in those with total CK,23 normal [7], multivessel, vein graft, or DCA proce-dures and thrombus-associated lesions were again morefrequent. The strongest correlates with a raised CK-MBwere DCA followed by the occurrence of at least onein-lab complication: side-branch compromise, transientin-lab vessel closure, or a greater residual stenosis. Forthe entire population (n5 4,461), the annual cardiacmortality rate was 2–3% in the first year, then 1–2% inyears 2–5 and 0–0.2% beyond 5 years [7]. For the groupwith raised CK-MB (n5 708), theabsoluteincrease incardiac mortality risk was of the order of only 1%, with amultivariate risk ratio of 1.27. It is not reported whatproportion of cardiac deaths were sudden, arrhythmic, oroccurred in the context of acute infarction or progressiveheart failure. Neither is it clear how follow-up of patientswith small CK rises should differ from usual manage-ment.

Division of Cardiology, Department of Medicine, University ofMaryland School of Medicine, Baltimore, Maryland

*Correspondence to: Dr. Warren K. Laskey, Cardiac CatheterizationLaboratory, University of Maryland Hospital, 22 South Greene Street,Baltimore, MD 21201-1595.

Received 21 January 1997; Accepted 29 January 1997

Catheterization and Cardiovascular Diagnosis 41:117–119 (1997)

r 1997 Wiley-Liss, Inc.

In prognostic evaluation, risk ratio may obscure actualevent rates because it is simply a summary measure of thelikelihood of an adverse event. This ratio may thereforeappear significant even if the event rate in the group witha risk factor is low, as long as the event rate in the groupwithout the risk factor is lower. A positive predictivevalue allows us to quote a more meaningful risk estimateto our patients. In the Cleveland Clinic database [7],patients with raised CK-MB were 27% (95% confidenceinterval 2 to 60%) more likely than patients withoutraised CK-MB to suffer cardiac death over a mean of 36months. However, the vast majority of patients withraised CK-MB survived. No predictive values are re-ported by the Cleveland Clinic investigators; from theKaplan-Meier survival curves, however, the positivepredictive value of elevated CK-MB is estimated to beonly 2–3% at 1 year and 3–5% at 2 years [7]. At facevalue, this would imply that a 40-year-old man with agood left ventricle will have a 3–5% chance of cardiacdeath within 2 years if his technically successful DCA forsingle vessel disease results in a raised CK-MB. Con-versely, an 80-year-old woman with diabetes, LVEF 25%,diffuse three-vessel disease, previous CABG3 4 (redotwice), and a normal CK-MB despite intervention on herlast remaining 12-year-old vein graft, would still beexpected to have a guarded prognosis although a 97%

negative predictive value would give her an optimisticchance of being alive at 2 years.These data, in common with earlier analyses, derive

from interventional practices and outcomes that are nolonger applicable to the current era. The rapid evolutionof interventional approaches to patients presenting withacute coronary syndromes, new devices, more refinedtechniques, and adjunctive pharmacotherapy have dramati-cally altered the landscape. The reported associationsbetween elevated CK/CK-MB activities, procedural fac-tors and outcome may lose statistical significance when,as in current practice, the prevalence of ‘‘high-risk’’procedures increases. Furthermore, virtually all studieshave been retrospective and thus suffer from some bias inthe sampling of blood for enzyme activities.No retrospective analysis can control for all factors

influencing outcome, nor be sensitive enough to detect allinteractions between various factors. Multiple sources ofco-linearity exist; baseline left ventricular function, le-sion complexity, previous revascularization, whether thereis a stent or surgical option, choice of device, ease ofprocedure, success and completeness of revasculariza-tion, residual disease, CK release, and outcome are notunrelated. Other factors that may determine CK releaseinclude the viability of myocardium subtended by targetvessel, degree of collateralization, diabetes mellitus,

TABLE I. Elevation of Total Creatine Kinase or Myocardial Isoenzyme Activity in PTCA Procedures

Reference nTimingof CK Threshold

No..threshold(%) Mortality

Significantcovariates Comments

Oh et al. [1]1979–82

128 $33 in 24 h CKMB$2% 25 (20) 0% at mean 10 m Periprocedural chestpain

MI within 1 mSide-branch occlusion(32%)

Retrospective

Klein et al. [2]1989–90

249 q 6 h for 24 h CK$200 IU/L orCKMB $4%

38 (15) 0% at hospital dis-charge

Prospective; in-labevent in 63%

Kugelmasset al. [3]1988–92

558(DCA 271)(Stent 287)

23 in 24 h CKMB$10 IU/L 64 (11.5) 12.5% (cardiac) atmean 2 years

Advanced ageFemale genderDCA use

Retrospective; Veingraft intervention in27%; thrombus in31%; side-branchocclusion in 16%;slow reflow in 25%

Harringtonet al. [4]1991–92

1,012(DCA 512)(PTCA 500)

q 12 h for 24 h CKMB$33 orCK $23

112 (11) 4.4% (all-cause) at1 year

Retrospective; nativevessels only

Abdelmeguidet al. [5]1984–91

4,664 $23 in 24 h CK$23 184 (4) 5.9% (cardiac) at1 year

Vein graft proceduresThrombotic lesionsComplex lesionsIn-lab vessel closureSide-branch compro-mise

DissectionDistal embolizationVasopressors forhypotension

Retrospective; onlyvein graft proce-dures a multivariatecorrelate of cardiacdeath

118 Lim et al.

cardiogenic shock, intra-aortic counterpulsation, andwhether a ‘‘bailout’’ procedure occurred. Three-vesseldisease and poor LVEF should be forced into themultivar-iate analysis to determine whether CK release truly hasincrementalprognostic value. The prognostic impact ofLVEF ,40% and ‘‘multivessel disease’’ is different indifferent patient subsets: repeat angioplasty, first-timeangioplasty, redo CABG, and first-time CABG. Intu-itively, a fivefold elevation in CK-MB activity is worsethan a twofold rise, because CK-MB release impliesmuscle loss, which may be reflected in reduction ofLVEF. Therefore, the adverse prognosis associated withCK-MB release may simply reflect myocardial necrosiswhether subclinical or otherwise. Although any degree ofnecrosis is undesirable, a twofold CK-MB rise may bemore important—if myocardial reserve is already re-duced—than a fivefold rise in someone with well-preserved LVEF. When the measurement is continuous,receiver operating characteristic (ROC) analysis avoidsthe need to set an arbitrary dichotomous threshold, andmay help to determine appropriate ‘‘cut-points.’’ Howwell a prognostic index discriminates between patientswith and without adverse events can also be judged by thearea under the ROC curve.Future studies should progress from describing the

association in retrospect and attempt to prospectivelyvalidate the concern while testing whether adjunctivestrategies incorporating platelet IIB/IIIA receptor antago-nists, magnesium, stenting, and debulking can ameliorateCK-MB release. CK-MB release should certainly bedocumented prospectively in the evaluation of experimen-tal technology to address the scientific skepticism sur-rounding its clinical importance. Based on the availablepublished data, identifying a subclinical CK-MB rise as amajor complication after intervention [7] is prematureand, as previously cautioned [3], may distort the risk ratioin the evaluation of new devices. In all likelihood,CK-MB release is an epiphenomenon in high-risk pa-tients who can already be identified as such before (andduring) intervention. In such cases, the question shouldbe asked: Is there a better or safer alternative? If not, morecaution will be required, recognizing that the proceduralrisk is higher (and the patient and family appropriately

counseled), and the case should be undertaken only byexperienced operators. Some post-procedural cardiacdeaths, however, are not amenable to preventive mea-sures. We may know who is at higher risk of dyingbut—even as interventionists—we may not always be ina position to do very much about it.

REFERENCES

1. Oh JK, Shub C, Ilstrup DM, Reeder GS: Creatine kinase releaseafter successful percutaneous transluminal coronary angioplasty.Am Heart J 109:1225–1231, 1985.

2. Klein LW, Kramer BL, Howard E, Lesch M: Incidence and clinicalsignificance of transient creatine kinase elevations and the diagno-sis of non-Q wave myocardial infarction associated with coronaryangioplasty. J Am Coll Cardiol 17:621–626, 1991.

3. Kugelmass AD, Cohen DJ, Moscucci M, Piana RN, Senerchia C,Kuntz RE, Baim DS: Elevation of the creatine kinase myocardialisoform following otherwise successful directional coronary ather-ectomy and stenting. Am J Cardiol 74:748–754, 1994.

4. Harrington RA, Lincoff AM, Califf RM, Holmes DR Jr, BerdanLG, O’Hanesian MA, Keeler GP, Garratt KN, Ohman EM, MarkDB: Characteristics and consequences of myocardial infarctionafter percutaneous coronary intervention: Insights from the Coro-naryAngioplasty Versus ExcisionalAtherectomy Trial (CAVEAT).J Am Coll Cardiol 25:1693–1699, 1995.

5. Abdelmeguid AE, Ellis SG, Sapp SK, Whitlow PL, Topol EJ:Defining the appropriate threshold of creatine kinase elevationafter percutaneous coronary interventions. Am Heart J 131:1097–1105, 1996.

6. Abdelmeguid AE, Whitlow PL, Sapp SK, Ellis SG, Topol EJ:Long-term outcome of transient, uncomplicated in-laboratorycoronary artery closure. Circulation 91:2733–2741, 1995.

7. Abdelmeguid AE, Topol EJ, Whitlow PL, Sapp SK, Ellis SG:Significance of mild transient release of creatine kinase-MBfraction after percutaneous coronary interventions Circulation94:1528–1536, 1996.

8. Abdelmeguid AE, Topol EJ: The myth of the myocardial ‘‘infarct-let’’ during percutaneous coronary revascularization procedures.Circulation 94:3369–3375, 1996.

9. Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hofling B,Simonton CA, Masden RR, Serruys PW, Leon MB, Williams DO:A comparison of directional atherectomy with coronary angio-plasty in patients with coronary disease. N Engl J Med 329:221–227, 1993.

10. Hinohara T, Robertson GC, Selmon MR, Vetter JW, McAuley BJ,Sheehan DJ, Simpson JB: Directional coronary atherectomy:Complications and management. Cathet Cardiovasc Diagn (Suppl)1:61–71, 1993.

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