Prognostic significance of myocardial enzyme release after coronary interventions

Prognostic Significance of Myocardial Enzyme ReleaseAfter Coronary Interventions

Dennis Kelly, 1 MD, and Rohit Arora, 2* MD

Mild to moderate periprocedural elevation in CK with concurrent CK MB elevation result inincreased subsequent myocardial infarction and mortality. However the potential risksthat percutaneous revascularization interventions pose must be evaluated in light therisks of alternative procedures and the risks of continued medical management. Prospec-tive clinical trials examining the relationship of periprocedural enzyme elevations to longterm prognosis will need to address this issue. Cathet. Cardiovasc. Intervent. 46:292–302,1999. r 1999 Wiley-Liss, Inc.

Key words: creatine kinase; troponin; angioplasty; revascularization

INTRODUCTION

Elevation of cardiac enzymes has been noted in5%–20% of patients who have undergone percutaneouscoronary interventions [1–15]. Creatine kinase (CK) andcreatine kinase MB (CK MB) elevations have been thecornerstone of diagnosis of acute myocardial infarction;however, the significance of elevated myocardial en-zymes after percutaneous coronary intervention has beenless clear. Initial studies suggested that elevations in CKand CK MB after successful percutaneous transluminalcoronary angioplasty (PTCA) and other interventionaltechniques are not clinically significant, but furtherstudies have suggested that even mild elevations of CK,with concomitant elevation of CK MB, are associatedwith an adverse prognosis. These studies are summarizedin Tables I and II.

MATERIALS AND METHODS

Early Studies of the Relationship Between CK MBElevation and Outcome

Oh at al. [1] measured CK MB levels 6 and 24 hr aftersuccessful balloon angioplasty in 128 patients and notedvalues above normal in 20% of them. A total of 220consecutive patients were reviewed for the study. Angio-plasty was successful (more than 40% luminal improve-ment in stenosis) in 161 patients. Excluded from the studywere 33 patients, 16 in whom serial CK MB determina-tions were not performed and 17 of whom underwentPTCA during evolving myocardial infarctions (MI) orreceived multiple direct countershocks. Patients with CKMB elevations had a higher incidence of chest pain,recent MI, postinfarction angina, and branch vesselclosure during angioplasty. Enzyme elevations (meanCK 5 179 U/L, mean CK MB5 9%) were not associated

with increased cardiac morbidity and mortality after amean follow-up time of 10 months.

Klein et al. [2] studied the incidence and significanceof creatine kinase elevations associated with successfulcoronary angioplasty. Patients with major in-hospitalcomplications, including death, resuscitation from car-diac arrest, Q-wave myocardial infarction, and emer-gency bypass surgery, were excluded from the study.Those who had undergone MI within the last 36 hr werealso excluded. Of the 272 patients included in the studygroup, successful angioplasty (improvement of luminaldiameter narrowing to less than 50% of a contiguousnormal vessel, no in-hospital complications, completeresolution of clinical manifestations of ischemia) wasobtained in 249 (92%).

Levels of CK, CK MB, or both, were abnormallyelevated in 38 (15%) patients. Three patterns of abnormalenzymes were identified: 15 patients with CK. 200 IU/Land CK MB . 5% (group 1), 4 patients with CK.200IU/L and CK MB , 4% (group 2), and 19 patients withCK , 200 IU/liter and CK MB. 5% (group 3). Therewere significantly more clinical events (chest pain, hypo-tension, arrhythmia, EKG changes) in group 1 (87%) ascompared with groups 2 and 3 (43% combined). Of the 38patients with abnormally elevated enzymes, 24 of them

1Department of Medicine, Columbia Presbyterian Medical Cen-ter, New York2Department of Cardiology, Columbia Presbyterian Medical Cen-ter, New York

*Correspondence to: Dr. Rohit Arora, Columbia Presbyterian MedicalCenter, 2 HS-1CC, 177 Fort Washington Avenue, New York, NY10032.

Received 18 November 1997; Revision accepted 21 September 1998

Catheterization and Cardiovascular Interventions 46:292–302 (1999)

r 1999 Wiley-Liss, Inc.

had an apparent clinical event that occurred in thelaboratory. In-laboratory clinical events were more com-mon in group 1 (87%) but occurred frequently in group 3(53%). The cause of enzyme elevation could be inferredangiographically in 26 patients. Enzyme elevations wereattributed to coronary branch occlusion (7), intimaldissection with transient vessel closure (11), saphenousgraft embolism (4), coronary spasm (2), and thrombosis(2). No clinically important sequelae were recognizablein any group at hospital discharge.

Unlike most of the other studies considered in Tables Iand II, the studies by Oh et al. [1] and Klein et al. [2] donot demonstrate a relationship between elevation of CKMB and adverse outcome. In the report by Oh et al. [1],there were no deaths in the study population, whereas theother study populations considered in Table I had long-term death rates of 1%–8% for controls. This studypopulation also had a lower average age, less multivesseldisease, and was relatively small. There were so fewpatients with elevated CK MB (n5 24) that each death inthis group would have resulted in an increase in the deathrate of approximately 4%, which is the magnitude of thedifferences measured between groups in several of thestudies appearing in Table I. The study by Klein et al. [2]is limited by the fact that patients were not followedbeyond discharge from the hospitalization in which theintervention occurred. Both of these studies demonstratedthat clinical events that appear to be of little consequenceare often associated with elevation of CK MB and that acause for CK MB elevation is not clearly identifiable in asubstantial proportion of patients.

Large prospective trials evaluating new approaches torevascularization and new antithrombotic therapies pro-vided large databases that were later examined forrelationships between elevation of CK/CK MB andmortality. Kugelmass et al. [3] examined the incidenceand clinical consequences of CK MB elevation in aconsecutive series of 565 patients who had successfuldirectional coronary atherectomy (DCA; n5 274) orstenting (n5 291) and were followed for a mean of 2years. Serum CK MB levels were obtained for all patientsimmediately and 1 day after procedure. A total of 64(11.5%) were found to have sustained a postproceduralelevation of CK MB with a median peak of 29 IU/liter(2.9 times the upper limit of normal). Patients withpostprocedural CK MB elevations were older, tended tohave a greater prevalence of hypertension, and were morelikely to have undergone atherectomy than stent place-ment. There was no difference between the two groupswith respect to unstable angina at the time of intervention,diabetes mellitus, remote prior MI, smoking history, LVfunction, serum cholesterol, or gender. Angiographiccharacteristics correlating with elevation in postproce-dural CK MB include the presence of multivessel disease,coronary thrombus, treatment of a de novo lesion asopposed to a restenotic lesion. As a group, patients withpostprocedural CK MB elevation did not have a higherincidence of significant clinical events (death, MI, repeatvascularization) during the follow-up period. Those withCK MB elevation were divided into three groups: mild(10–30 IU/liter), moderate (31–50 IU/liter), and greater(. 50 IU/liter). Those in the greater CK group (13, 2.3%

TABLE I. Studies Populations and Results

Study Year Procedurea Definition of elevated enzymes Number of patients

Oh et al. [1] 1985 PTCA, successful CK MB. 2% of total CK 128Klein et al. [2] 1991 PTCA, successful CK MB. 5% of total CK 249Kugelmass et al. [3] 1994 DCA or stenting, successful CK MB. 1–53 ULN (10–50 IU/L) 565

CK MB . 53 ULN (.50 IU/L)Moscucci et al. [4] 1993 DCA or PTCA, successful and unsuccessful CK MB. 10 IU

CK MB . 40 IU664

Harrington et al. [5] 1995 DCA or PTCA, successful and unsuccessful CK MB. 33 ULN 1,012Abdelmeguid et al. [6] 1995 DCA or PTCA, successful with and without

transient vessel closureTotal CK . ULN 4,836

Abdelmeguid et al. [7] 1996 DCA or PTCA, successful 2–53 ULN.53 ULN

4,664

Abdelmeguid et al. [8] 1996 DCA or PTCA, successful CK 100–180 IU/LCK MB . 4%

4,484

CK 181–360 IU/LCK MB . 4%

Kong et al. [9] 1996 PTCA, DCA stenting, rotoblator CK. 125 IU/LCK MB . 4%

2,812

Redwood et al. [10] 1996 DCA, rotablator ELCA CK MB 1–43 ULNCK MB . 43 ULN

1897

Tardiff et al. [11] 1996 PTCA and CABG CK MB 1–33 ULNCK MB 3–103 ULN

2,432

aPTCA5 percutaneous transluminal coronary angioplasty; DCA5 dierectional coronary atherectomy; ELCA5 excimer laser angioplasty; ULN5 upperlimit of normal; IU/L 5 international units/liter.

Postprocedural Enzyme Elevations 293

of the treatment population, 20% of those with elevatedCK MB), showed a trend toward a reduction in survival(less than 50% at 36 months,P 5 0.08), whereas survivalin the other groups was not significantly different than inthose without enzyme elevation.

A similar result was obtained by Moscucci et al. [4].They reported that among 326 patients treated withdirectional atherectomy and 338 patients treated withPalmaz-Schatz stents, only those with a postprocedureCK MB level greater than 40 U (4% of patients) had a

higher 2-year mortality (15%) than the rest of the studygroup. Those with CK MB elevations from 10 to 40 U(8% of patients) had a similar mortality (8%) to thosewith CK MB , 10 U (7.3% mortality). The rates ofnon–Q-wave infarction were 17.4% for atherectomy,7.9% for stenting.

Both of these studies suggest that a specific level of CKMB elevation is associated with adverse long-term out-come but differ from other studies in Table I in that thelevels associated with adverse outcomes were relativelyhigh. Details of the population studied by Moscucci et al.[4] are limited given that the report is an abstract.Baseline characteristics such as age, ejection fraction, andproportion of patients with multivessel disease are similarin the study by Kugelmass et al. [3] in comparison tostudies demonstrating adverse outcomes with lower lev-els of CK MB elevation. The rate of cardiac death in thecontrol group was similar to that in other studies in TableI and the mean CK elevation was higher than that in thestudy by Kong et al. [9]. Rates of in-laboratory complica-tions were similar in the different studies. Nonetheless,the total number of patients with CK MB elevation andthe number of adverse events in those patients is rela-tively few in the studies by Kugelmass et al. [3] andMoscucci et al. [4] in comparison to later studies. Giventhat moderate postprocedural CK MB elevation correlateswith an adverse prognosis, as was observed in laterstudies, there may have been too few patients in thesestudies to detect a small decrease in cardiac survival inthose with CK MB elevation in comparison to thosewithout CK MB elevation. The techniques used in thestudies by Kugelmass et al. [3] and Moscucci et al. [4] arelimited to stenting and DCA, whereas the other studiesutilized predominately DCA and PTCA. DCA has beenassociated with worse clinical outcome than PTCA [12],but it was utilized in the majority of studies in Tables Iand II and therefore is not likely responsible for differ-ences in the results of these studies. The outcomes ofthose who underwent stent placement as compared tothose who underwent DCA was not specifically noted inthe reports by Kugelmass et al. [3] and Moscucci et al.[4].

Studies Demonstrating Adverse Outcome WithMild to Moderate Elevations of CK MB

The above discussion alludes to the fact that theapparent inconsequential nature of mild to moderate CKand CK MB elevations has been questioned by a numberof more recent studies. Harrington et al. [5] examined thelong-term significance of postprocedural MI utilizingdata from the Coronary Angioplasty Versus ExcisionalAtherectomy Trial (CAVEAT), which is described below.The original study [12] involved a population of patientswith symptomatic heart disease felt to be suitable for

TABLE II. Study Population and Results

Follow-up periodDeaths %(controls)

Deaths %(elevated CK MB)

Oh et al. [1] CK MB. 2% of totalCK

Mean follow-up10 months 0 deaths 0 deaths

Klein et al. [2] CK MB . 5% of totalCK

No long-term follow-up ? ?Kugelmass et al. [3] CK MB. 1–53 ULN

(10–50 IU/L)9%

Mean follow-up CK MB. 53 ULN(.50 IU/L)

2 years 8% ,50%Moscucci et al. [4] 7.3% CK MB. 10 IU/L

8%Mean follow-up CK MB. 40 IU/L2 years 15%Harrington et al. [5] CK MB. 33 ULN

4.2%1-year follow-up 1.2%Abdelmeguid et al. [6] CK 181 to 540Mean follow-up 6.2%41 months 4.3% CK. 540

14.1%Abdelmeguid et al. [7] CK MB 2–53 ULN1-year follow-up 4.9%

1.8% CK MB. 53 ULN8.2%

Abdelmeguid et al. [8]Mean follow-up36 months

Difference between con-trol and highest cat-egory of CK elevationappears to be,3% onthe published survivalcurves.

CK 100–180 IU/LCK MB . 4%

CK 181–360 IU/LCK MB . 4%

Kong et al. [9] CK. 125 IU/LMean follow-up CK MB. 4%42 months 7% 15%Redwood et al. [10] CK MB 1–43 ULNMean follow-up 3–4%1 year 1%Tardiff et al. [11] CK MB 1–33 ULNMean follow-up 2%30 days 2% CK MB 3–103 ULN

4%

294 Kelly and Arora

either atherectomy or angioplasty who were randomizedto either technique. The primary endpoint of the studywas angiographic restenosis, defined as stenosis of morethan 50% at 6 months after an initially successfulprocedure. A composite early clinical endpoint to assessthe safety of the procedures was prospectively defined toinclude death, emergency coronary artery bypass surgery,acute myocardial infarction, and abrupt vessel closureduring the period of hospitalization after randomization.A composite 6-month clinical endpoint including death,MI, CABG, and need for revascularization was alsoprospectively defined. Myocardial infarction was diag-nosed clinically at the participating site and was verifiedby a committee blinded to treatment assignment, on thebasis of appearance of new Q-waves or an increase in CKMB to more than three times the upper limit of normal forthe site. Evaluation by site investigators revealed thesuccess rate to be 96.4% for both DCA and PTCA groups.Angiographic review found a higher success rate foratherectomy than for angioplasty (89% vs. 80%,P ,0.001). Atherectomy led to a greater gain in the diameterof the vessel than angioplasty (1.05 vs. 0.86 mm,P ,0.001). However, there was a higher rate of myocardialinfarctions among patients undergoing atherectomy incomparison to those undergoing PTCA (6% vs. 3%,P 50.035). The rate of composite events defined above wasgreater in the atherectomy group as compared with theangioplasty group (11% vs. 5%,P , 0.001). At 6 months,the rate of stenosis as defined by the primary endpointwas 50% in the atherectomy group vs. 57% in theangioplasty group (P 5 0.006). Assessment of thecumulative clinical outcome of death, MI, CABG, andneed for subsequent coronary intervention revealed nosignificant difference between the two groups. There wasa statistically significant difference with respect to MI(clinical diagnosis), with an increased incidence noted inthe atherectomy group (7.6 vs. 4.4,P 5 0.04). Follow-upat 1 year [13] revealed that 11 patients died in the first 12months after atherectomy compared with 3 after angio-plasty. (2.2% vs. 0.6%, respectively,P 5 0.0350).Myocardial infarction rates subsequent to procedure werelow as two patients in each group had an MI between 6-and 12-month follow-up. Due to the excess periproce-dural infarction in the atherectomy group, the cumulativeMI rate (clinical diagnosis) was greater in this group at1-year follow-up (8.9% vs. 4.4%,P 5 0.005). There wereno differences in the rates of percutaneous or surgicalrevascularization at 1-year follow-up. In CAVEAT II[14], 305 patients with saphenous vein bypass graftlesions were randomized to PTCA or atherectomy. Theincidence of non–Q-wave MI and abrupt vessel closurewas higher in CAVEAT II than in CAVEAT I, which isfelt likely secondary to the higher risk of distal emboliza-tion during the treatment of diseased grafts vs. native

coronary arteries. The risk of complications after atherec-tomy was greater than after angioplasty in CAVEAT IIalso, but there were no significant differences in the ratesof death or myocardial infarction after 6 months offollow-up.

Harrington et al. [5] used regression models to evaluatethe predictive significance of postinterventional MI withrespect to several long-term outcomes. The outcomeswere a 30-day composite of death, bypass surgery, andrepeat intervention; death within 1 year; a 1-year compos-ite of death and late myocardial infarction (infarctionoccurring . 30 days postintervention); and a 1-yearcomposite of death, bypass surgery, repeat intervention,and late myocardial infarction. The investigators notedthat a core laboratory definition of myocardial infarctionbased on elevation of CK two or more times normal(where CK MB was not measured) or CK MB three ormore times normal resulted in a greater number ofmyocardial infarctions in both treatment arms (15.2%atherectomy vs. 6.8% PTCA,P 5 0.001). Using regres-sion analysis, core laboratory-defined myocardial infarc-tion was highly predictive of mortality, bypass surgery, orrepeat intervention within 30 days (P , 0.0001). Therewere no differences between treatment groups withregard to consequences of MI at 30 days. However, at1-year follow-up, MI was significantly predictive ofdeath when baseline characteristics were considered (P 50.038) and of borderline significance when baselinecharacteristics and procedural mechanical complicationswere considered (P 5 0.055).

Abdelmeguid et al. [6] examined long-term outcome oftransient, uncomplicated in-laboratory coronary arteryclosure in 88 of 4,863 consecutive patients undergoingeither angioplasty or atherectomy and found that theabove does not have an adverse long-term prognosis.However, elevation of CK and CK MB in this group ofpatients had prognostic implications. During a meanfollow-up period of 41 months, patients with a peak CKgreater than 180 IU/L (upper limit of normal) had an 8%incidence of cardiac death compared to a 4% incidence ofcardiac death for those with a peak CK less than 180IU/L. Cardiac mortality was shown to increase progres-sively with increasing peak CK values (6.2% for CK of181 to 540 IU/L, 14.1% for CK. 540 IU/L).

DCA was used more frequently in the group of patientswho experienced transient coronary artery closure than inthe control population (17% vs. 7%), but any difference inoutcome for DCA vs. PTCA in this patient populationwas not explored in this study. The population of patientsundergoing procedures at the same institution was furtheranalyzed in two additional studies exploring the relation-ship of CK MB elevation and outcome as follows.

Abdelmeguid et al. [7] examined the prognostic valueof CK elevations after atherectomy or angioplasty in a


group of 4,664 consecutive patients. Patients with postpro-cedural CK elevations between 2 and 5 times control withCK MB . 4% (group II) and CK elevations. 5 timescontrol with CK MB. 4% (group III) were found to haveincreased cardiac mortality after 1 year of follow-up(4.9% and 8.2%, respectively) as compared to patientswith postprocedural CK, 2 times control with unspeci-fied CK MB (group I, cardiac mortality5 1.8%, P ,0.001). There was no difference in noncardiac mortality.The patients were followed for a mean of 36 months.During this time period, the investigators noted a consis-tent increase in the frequency of cardiac deaths andcardiac hospitalizations for those patients in groups II andIII. There were no significant differences in clinicaldemographics in the three groups except for a higherincidence of recent MI (. 36 hr,, 2 weeks) and a higherincidence of rest angina in groups II and III. Differencesin morphological and procedural characteristics existed.In groups II and III, there was a significantly higherincidence of thrombus associated and complex lesions aswell as more severe initial stenoses. Procedures per-formed on venous grafts were more frequent in groups IIand III. Minor procedural complications such as transientvessel closure, side-branch compromise, coronary dissec-tion, coronary embolism, and hemodynamic instabilitywere significantly increased in groups II and III. Residualstenoses were not significantly different in the threegroups. There were no significant differences betweengroups II and III except that more directional atherectomywas done in group II and a higher incidence of eccentriclesions existed in group II. In summary, the patients ingroup III and even those in group II, who would notqualify as having had a non–Q-wave MI via someinterventional study criteria, clearly have a worse progno-sis than those with CK, 2 times control.

A more recent study by Abdelmeguid et al. [8]examined 4,484 patients who underwent successful PTCAor DCA and whose peak CK levels did not exceed twicenormal. Patients were divided into three groups accordingto the CK and CK MB levels after the procedure. Group 1(3,776 patients) had neither CK nor CK MB elevationafter the procedure (CK, 180, MB, 4%). Group 2 (450patients) had a peak CK level between 100 and 180 IU/L,with CK MB fraction. 4%. Group 3 (258 patients) had apeak CK level between 181 and 360 IU/L, with CK MBfraction. 4%. CK determination was done 6–12 hr afterthe procedure, the following day, and in the event ofischemic symptoms. The maximum value measured wastaken as the peak CK. Follow-up was available in 4,461(99.5%) patients with a mean duration of 36 months.Kaplan Meir curves demonstrated a difference betweengroups with and without elevated CK MB with respect tosurvival from cardiac death (P 5 0.036). Kaplan Meircurves demonstrated a difference between groups with

and without CK MB elevation with respect to subsequentMI (P 5 0.025) and freedom from major cardiac events(death, MI, bypass surgery, and repeat percutaneouscoronary intervention (P 5 0.009). A rise in CK MB wasa strong correlate of cardiac death (risk ratio 1.27,P 50.04) and subsequent myocardial infarction (risk ratio1.31,P 5 0.03). There was a trend toward more bypasssurgery, repeat percutaneous revascularization, and car-diac hospitalization in groups with elevated CK MB.Major ischemic complications (death, myocardial infarc-tion, and coronary revascularization) occurred more oftenin groups with elevated CK MB: group 1 (37.3%) vs.group 2 (43.3%) vs. group 3 (48.9%),P 5 0.01.Predictors of elevated CK MB included DCA (thestrongest predictor), multivessel interventions, and inter-ventions on vein grafts. In-laboratory minor clinicalevents (transient in laboratory vessel closure, side-branchcompromise, large dissection, hypotension requiring intra-venous vasopressors or intra-aortic balloon counterpulsa-tion, and coronary embolism) were associated with 20%of CK MB elevations. Although DCA was the strongestpredictor of elevated CK MB, DCA as an independentpredictor of poor prognosis was not assessed.

Kong et al. [9] reviewed 2,812 consecutive electivecoronary artery interventions and identified a case groupof 253 consecutive patients with postprocedural total CK(. 1.5 3 normal) and CK MB elevations and a controlgroup of 120 patients without CK elevation. After a meanfollow-up of 42 months in the case patients and 47months in the control patients, cardiac death occurred in15% of the cases and 7% of the controls. MI occurred in17% of the case patients and 9% of controls, and thecombined endpoint of cardiac death or subsequent MIoccurred in 23% of case patients vs. 14% of controlpatients. The patients were placed into three categoriesbased on the magnitude of CK elevations, including high(3.0 times normal), intermediate (1.5 to 3.0 times nor-mal), and low (.1.0 to ,1.5 times normal) and event-free survival curves for cardiac mortality, MI, andcombined endpoints were plotted. Cardiac mortalitydiffered significantly among the groups and was greatestfor patients in the high and intermediate subgroups.Significant differences between groups was seen withrespect to subsequent MI and the combined endpoint ofcardiac mortality or subsequent MI. There was no differ-ence in the incidence of repeat PTCA or CABG in casevs. control patients. Baseline characteristics of the caseand control patient groups were similar; however, priorCABG and hypertension were more common in the casegroup and a greater number of patients in the controlgroup underwent PTCA for unstable angina. Target lesioncharacteristics were generally more complex in the casegroup, and a greater percentage of procedures in the casegroup involved saphenous vein graft lesions. The devices

296 Kelly and Arora

used included balloon PTCA, directional atherectomy,extraction atherectomy, excimer laser PTCA, and adjunc-tive balloon PTCA. Devices were used in equal propor-tions in both case and control groups. Procedural compli-cations occurred more often in the case group, includingthrombus development (23% vs. 8%), major dissection(26% vs. 9%), side-branch occlusion (13% vs. 3%), anddistal embolization (15% vs. 1%). CK elevation predictedcardiac mortality independent of clinical variables, leftventricular ejection fraction, the extent and severity ofCAD, coronary lesion morphology, interventional de-vices, and procedural outcomes. Higher-peak CK andlower preprocedural left ventricular function were themost important predictors of cardiac mortality. CK eleva-tion had a relative risk of late cardiac mortality of 1.05 per100-U/L increment of CK.

Several studies have noted similar findings. Redwoodet al. [10] followed 1,897 patients for approximately 1year after undergoing new device angioplasty of nativecoronary arteries utilizing directional atherectomy (n5554), rotational atherectomy (n5 833), or excimer laserangioplasty (n5 510). A total of 26% of patients hadwhat was categorized as a minor CK MB elevation(greater than one time and less than or equal to four timesnormal), while 13% had a major elevation (CK MBgreater than four times normal). Minor CK MB elevationsresulted in similarly increased late mortality (3%–4% vs.1%) for each of the modalities. Other late events such asQ-wave MI, PTCA, and CABG were not associated withminor elevations in CK MB. Tardiff et al. [11] examinedpatients enrolled in GUSTO IIa (comparing heparin tohirudin in acute MI and unstable angina). Of 2,564patients enrolled in the study, 937 had a percutaneous orsurgical intervention during the index hospitalization. Arelationship between postprocedural enzyme elevation inthese patients and outcome at 30 days was examined.Those with no enzyme elevation had a mortality of 2%and combined infarction and mortality rate of 4%. Forpatients with enzyme elevations in the one to three timesnormal range, the values were 2% and 9%, respectively.For patients with CK MB elevations greater than threetimes normal, the values were 4% and 14%, respectively.

The patient populations in CAVEAT [12,13], in thestudies by Abdelmeguid et al. [6,7,8] and in the study byKong et al. [9], were similar with respect to patient age,proportion of patients with multivessel disease, andejection fraction. The cases and controls were wellmatched although some differences did exist as notedabove. Less is known about the populations examined byRedwood et al. [10] and Tardiff et al. [11], given thatthese presentations are in abstract form. All of thesestudies are limited by the fact that they are retrospectivein nature and therefore are subject to many potentialsources of bias. Examples of potential bias includes

patient selection, increased enzyme sampling of moreclinically ill patients, and a lack of standardization in thetechniques of revascularization as well as in preproce-dural and postprocedural medical regimens. Nonetheless,the results are not inconsistent with what is known aboutCK MB elevations in the setting of overt clinical ischemiaand these results raise concerns about the safety ofsuccessful percutaneous interventions.

Glycoprotein IIb/IIIa Inhibitors

In the EPIC trial [15], administration of a chimericmonoclonal antibody Fab fragment (abciximab) directedagainst the platelet glycoprotein IIb/IIIa receptor duringangioplasty resulted in a reduction of major ischemicevents in high-risk patients. Patients who were consid-ered to be at risk for increased complications duringballoon angioplasty or directional coronary atherectomybecause of evolving myocardial infarction, unstable an-gina, or unfavorable demographic or lesion morphologicfeatures were considered eligible for the study. Theprimary endpoint of the study was a prespecified compos-ite of any of the following events in the first 30 days afterrandomization: death from any cause, nonfatal myocar-dial infarction, coronary artery bypass grafting or repeatPTCAfor acute ischemia, insertion of a coronary endovas-cular stent because of procedural failure, or placement ofan intra-aortic counterpulsation pump to relieve refrac-tory ischemia. In-hospital myocardial infarction criteriaincluded development of a new Q-wave or CK MB morethan three times the upper limit of normal, representingan increase of 50% or more over the previous valley.Diagnostic criteria of a subsequent myocardial infarctionin patients who entered the study with an acute, evolvingmyocardial infarction were more complicated [15]. Par-ticipants received 325 mg of aspirin daily with the firstdose given at least 2 hr before the procedure. Intravenousheparin was administered during the procedure to achievean activated clotting time of at least 300 sec. Patientswere then randomly assigned to one of three patientgroups: placebo bolus plus a subsequent 12-hr placeboinfusion, a 0.25-mg/kg bolus of abciximab with a subse-quent 12-hr placebo infusion, or a 0.25-mg/kg bolus ofabciximab with a subsequent 12-hr infusion of abciximabat 10 µg/min. The group that received a bolus ofabciximab experienced a 16% reduction in the compositeendpoint as compared to placebo, while the group thatreceived both infusion and bolus experienced a 35%reduction in the composite endpoint as compared toplacebo. There was no difference with respect to death inthe group receiving abciximab as compared to controls at30 days. However, nonfatal MI occurred in 8.6% of theplacebo recipients as compared to 6.2% in the groupreceiving abciximab bolus only and 5.2% of the groupreceiving both bolus and infusion of abciximab (P 5


0.013). There was a significant difference in emergencyPTCA, 4.5% vs. 3.6% vs. 0.8%, respectively. There wasan increase in bleeding complications and transfusions inthe treated groups. A follow-up study at 6 months noted a23% reduction of the composite endpoint. In patients withan initially successful intervention, there was a 26%reduction in target vessel revascularization. There was nodifference in death between groups at 6 months and therewas no difference in MI between groups except during theinitial 48 hr [16]. Recently, a report of 3-year follow-updata from the EPIC trial demonstrated a persistentreduction in major ischemic events in patients whoreceived the original index procedure utilizing abciximab[17]. At 1 year, there was a 19% reduction of thecomposite endpoint for the abciximab bolus and infusionas compared with placebo, with little effect of the bolusonly. The effect persisted at 3 years with a 13% reductionof the composite endpoint. The benefit of mortalityreduction (12.7% vs. 5.1% mortality, a 60% reduction)was confined to the subgroup of patients categorized asthe highest-risk group, consisting of patients with evolv-ing MI or unstable angina. The relationship betweenperiprocedural myocardial infarction and long-term sur-vival for the entire study group was presented via survivalcurves. Risk ratios for death were 1.47 for CK greaterthan or equal to one time normal, 1.65 for CK greater thanor equal to time times normal, 1.94 for CK greater than orequal to three times normal. The ratios for survivors from30 days after the procedure were 0.95, 0.99, and 1.24,respectively. The risk ratios from 30 days for survivorsdid not reach statistical significance. This study is felt tostrengthen the inverse relationship between periproce-dural myocardial infarction and long-term survival asthere was a significant increase in the mortality of thoseindividuals with a postprocedural creatine kinase eleva-tion [18]. Revascularization was less frequent in treatedgroups at 3-year follow-up, 40.1% for the placebo group,38.6% for the bolus only group, and 34.8% for the bolusplus infusion group.

As noted previously, only the highest-risk group receiv-ing abciximab demonstrated a reduction in mortalityassociated with this therapy. Other studies have demon-strated periprocedural therapies resulting in a decrease insubsequent clinical events and/or periprocedural myocar-dial infarction with no difference in mortality on long-term follow-up. The CAPTURE trial [19] recruitedpatients with refractory unstable angina under therapywith medical treatment including heparin and nitrates andtreated them with abciximab or placebo 18 to 24 hr beforeangioplasty and for 1 hr after completion of revasculariza-tion. The primary endpoint was defined as it was duringthe EPIC trial noted above. The primary endpoint oc-curred in 15.9% of patients in the placebo group and

11.3% in the abciximab group (P 5 0.002). The differ-ence was mainly due to the difference in the proportion ofpatients with MI 8.2% vs. 4.1%, respectively (P 50.002). The composite endpoint was lower at 6 months inthe treated group but did not meet significance and therewas no difference in death at 30 days or 6 months. TheEPILOG investigators randomly assigned patients under-going percutaneous revascularization (in contrast to theabove studies, patients with acute myocardial infarctionor unstable angina associated with EKG findings withinthe previous 24 hr were excluded) to receive one of threetherapy combinations. In combination with angioplasty,patients received either abciximab with standard-dose,weight-adjusted heparin (initial bolus 100 U per kg bodyweight); abciximab with low-dose weight-adjusted hepa-rin (initial bolus 70 U per kg body weight); or placebowith standard-dose weight-adjusted heparin [20]. Theprimary endpoint was death from any cause, myocardialinfarction, or urgent revascularization. The primary end-point at 30 days occurred in 11.7% of the placebo group,5.2% in the group assigned to abciximab with low-doseheparin, and 5.4% in the group assigned to abciximab andstandard-dose heparin. There was a nonsignificant trendtoward a decreased incidence of death at 30 day and 6months. This study demonstrated that the benefits ofabciximab in reduction of periprocedural events extendsbeyond those with acute ischemic syndromes and that theincrease in bleeding complications seen in EPIC is notseen when abciximab is used with low-dose heparin.Serruys et al. [21] compared use of hirudin with heparinin the prevention of restenosis after coronary angioplastyin a population of patients with unstable angina. Thepatients received one of three treatments, heparin, hirudinIV for 24 hr, or hirudin IV for 24 hr plus subcutaneoushirudin twice daily for three consecutive days. There wasa reduction in early events (composite of death , MI,CABG, bailout procedure, second angioplasty) in pa-tients receiving IV hirudin (7.9%) and IV hirudin plussubcutaneous hirudin for 3 days (5.6%) as compared toheparin at 96 hr after the procedure. These differenceswere no longer present at 30 weeks of follow-up. Therewas no significant mortality advantage at 96 hr or 30weeks.

The fact that the above studies failed to show amortality benefit utilizing IIb/IIIa inhibitors and hirudineven though periprocedural events were decreased, espe-cially MI in the case of IIb/IIIa inhibitors, seems tocontradict the thesis that postprocedural CK MB releaseresults in increased mortality. The contradiction may bedue to the fact that the difference in the number ofmyocardial infarctions in the treatment population ascompared to the control population is not great enough todemonstrate the small differences in mortality between

298 Kelly and Arora

those with vs. those without CK MB elevations, whichhave been suggested by the previous studies. A similarcontradiction exists in the study of patients survivingtransient vessel closure by Abdelmeguid et al. [6].Elevations of CK and CK MB periprocedurally correlatedwith increased mortality when the whole study popula-tion was analyzed. Nonetheless, survival curves plotted inthis study show no difference in mortality in those whohave experienced uncomplicated transient vessel closurevs. controls, even though 50% of those with transientuncomplicated vessel closure had elevated CK as op-posed to 12% of the controls and CK MB was signifi-cantly higher in the group that underwent transient vesselclosure (55.3 IU/L vs 7.7 IU/L,P 5 0.004).

Use of Other Markers in Evaluating MyocardialInjury After Percutaneous Interventions

The role of the troponins and CK MB mass assays inpercutaneous interventions have not been defined; how-ever, several preliminary studies have been done [22–25].The long-term prognostic value of postprocedural eleva-tions in these markers has not yet been determined.

Significance of CK MB Elevations

Patients with elevation of CK MB postprocedurallyhave not formally been studied via echocardiography,perfusion scintigraphy, or infarct avid scintigraphy toverify the presence of new infarction. There is datasuggesting that CK MB can become elevated in theabsence of cell death. Study of cell cultures have demon-strated gradual release of cytosolic enzymes from revers-ibly injured myocytes [26] and short periods of coronaryartery occlusion in baboons has been shown to causerelease of enzymes in the absence of demonstrableregional myocardial dysfunction [27]. However, minorincreases of CK MB, even in the absence of total CKelevation, have been shown to indicate myocardial necro-sis in humans [28].

As demonstrated in the above studies, correlates ofenzyme elevation include directional atherectomy, proce-dures performed on saphenous venous grafts, multivesselprocedures, higher residual stenoses, severe initial steno-ses, and complex lesions. Many mechanisms of enzymeelevation after coronary intervention have been postu-lated, including ischemia resulting from balloon inflationwithout anterograde perfusion [29]; procedural complica-tions such as transient coronary occlusion [6], distalparticulate embolization [5], side-branch occlusion [1,3],and large dissections; arterial injury, which may act as anidus for platelet aggregation; thrombus formation; andperiprocedural hypotension [30]. In approximately 30%of the cases where enzyme elevation occurs, there is noclear cause [31].

Several potential mechanisms for adverse outcomeassociated with CK MB elevations postprocedurally havebeen described. One mechanism involves the possibilityof microinfarcts providing a nidus for ventricular arrhyth-mia and sudden death [8]. As noted by Abdelmeguid et al.[8], this phenomena could result from slow conductionoccurring in microscopic zones of necrosis, which mayincrease susceptibility to ventricular arrythmias via mi-croreentrant circuits [32–34] or this could be a result of afocal mechanism [35]. Another mechanism involves thepossibility of microemboli compromising coronary collat-erals resulting in larger infarcts should future coronaryocclusions occur [8]. It is possible that the presence ofelevated CK MB after revascularization is a marker ofdisease severity or susceptibility to ischemia and that theelevations and likely associated necrosis per se do notpredispose patients to future adverse outcomes [31]. CKMB elevation, particularly as a predictor of combinedendpoints, is more likely to reflect disease severity andless likely to reflect a particular mechanism of adverseoutcome as a consequence of an interventional procedure.The mechanisms of restenosis, myocardial infarction, andsudden death in patients who have undergone percutane-ous revascularization are likely different.

DISCUSSION

A number of the studies considered herein suggest thatmild to moderate periprocedural elevations in CK withconcurrent CK MB elevation result in increased subse-quent myocardial infarction and mortality. The limita-tions of these studies have been noted above, as haveexamples in the literature where reductions in periproce-dural enzyme elevations by IIb/IIIa inhibitors have notresulted in decreased mortality. One of the greatestlimitations of the retrospective studies considered hereinis the lack of a control population of patients who did notundergo intervention. Studies that have compared PTCAto medical management, though few in number, have notdemonstrated an increase in mortality in patients undergo-ing interventional procedures [36,37]. Studies of patientseligible for participation in trials of angioplasty vs.CABG have not demonstrated increased mortality inthose assigned to angioplasty as opposed to CABG[38–41] with the exception of diabetic patients [42]. Thepotential risks that percutaneous revascularization inter-ventions pose must be evaluated in light of the risks ofalternative procedures and the risks of continued medicalmanagement. Prospective clinical trials examining therelationship of periprocedural enzyme elevations to long-term prognosis will need to address this issue.


Recommendations

In view of the above findings, it has been recom-mended that cardiac enzymes be routinely monitoredafter percutaneous interventions [30,31]. Cardiac en-zymes should be monitored in prospective clinical trialsinvolving percutaneous interventions to answer the ques-tion of whether enzyme elevations are a cause of deathand to improve our understanding of the causes ofincreased cardiac enzymes [30].

Until more data are available, strategies to avoidenzyme elevations should include avoidance of tech-niques known to be associated with increased frequencyof enzyme elevations, such as directional coronary ather-ectomy, except in patients who cannot otherwise betreated [31]. Other strategies include a standard ofpractice to avoid sacrifice of side branches, to reversequickly in laboratory coronary artery closure, and toprevent coronary embolism as well as slow flow [30]. Ithas been recommended that potent IIb/IIIa inhibitors suchas abciximab be given to patients undergoing percutane-ous intervention, especially those patients at high risk,such as those with target lesions involving previous veingrafts [31]. Postprocedure recommendations include closemonitoring of patients with enzyme elevations greaterthan 1.5 times normal who also had a procedural compli-cation (abrupt vessel closure, distal embolization) for 2–3days after the procedure in a manner similar to that fornon–Q-wave MI; use of a beta-blocker, nitrates, andaspirin in these patients; and monitoring of those whohave enzyme elevations greater than 1.5 times normal inthe absence of in laboratory complications for 1–2 daysafter the procedure [31]. Regarding the latter group,future studies need to address whether careful monitoringof these patients in the first few years after the procedurecan alter long-term prognosis [31]. These recommenda-tions are summarized in Table III.

Most of the studies analyzing enzyme release afterpercutaneous coronary interventions have utilized CKand CK MB and have demonstrated the frequency ofenzyme elevations to be in the range of 5%–20% [1–15].Early studies addressing the significance of CK MBelevations in the context of successful percutaneouscoronary interventions found enzyme elevation to be oflittle consequence [1,2]. Subsequent studies suggestedthat large elevations of CK MB (.5 times normal)correlate with increased mortality [3,4]. More recentstudies have suggested that elevations of CK in the rangeof 1.5 or 2 to 5 times normal with concomitant CK MBelevation [5–7,9,10] and even elevations of CK less thanor equal to twice normal with concomitant CK MBelevation [8], to correlate with adverse outcome. Further

study on the impact of postprocedural enzyme elevationson subsequent outcomes in a prospective manner isnecessary to validate the results of the studies consideredin this review, which show a correlation between postpro-cedural CK MB elevation and adverse outcome. This typeof study would be enhanced by use of technitium 99-msestamibi scanning, or, alternatively, infarct avid imagingutilizing antimyosin antibody or newer infarct avidimaging agents such as technitium 99-m glucoronic acidto detect new periprocedural infarcts. Such studies wouldclarify the meaning and prognostic significance of peripro-cedural enzyme elevations. Standards of practice to avoidtechniques more strongly associated with CK MB eleva-tions and to monitor those patients with enzyme eleva-tions should be followed.

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TABLE III. Re commendations

ProceduralRoutine monitoring of cardiac enzymes after percutaneous interven-

tionsStandards of practice to avoid techniques associated with frequent

enzyme elevationsStandards of practice to avoid sacrifice of side branches, to reverse

quickly in-laboratory coronary artery closure, to prevent coronaryembolization, and to avoid slow flow

Use of IIb/IIIa inhibitors during percutaneous interventions, espe-cially those at high risk and those with target lesions involvingvenous grafts

PostproceduralClose monitoring of patients with enzyme elevations greater than 1.5

times normal who also had a procedural complication for 2–3 daysin a manner similar to that for non–Q-wave MI

Use of beta-blockers, nitrates, and aspirin in the groups of patientsdescribed above

Close monitoring of those with enzyme elevations 1.5 times normalwithout procedural complications for 1–2 days

Future studies need to address whether careful monitoring of patientswith postprocedural enzyme elevations during the first few yearsafter the procedure can alter long-term prognosis

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Prognostic significance of myocardial enzyme release after coronary interventions