Impact of Periprocedural Creatine Kinase-MB Isoenzyme Release
on Long-Term Mortality in Contemporary Percutaneous Coronary
Int

Elevation of biochemical markers of myocardial damage following percutaneous coronary intervention (PCI) is frequently observed,^1–4 however, its significance remains controversial.^5,6 Multiple reports have demonstrated a linear relationship between the extent of myocardial necrosis as measured by peak creatine kinase-MB (CK-MB) and the long-term outcome,^1–4,7 with higher late mortality associated with even minor elevation in postprocedure CK-MB,^8–10 whereas others suggested that increased risk may become apparent only for large non-Q-wave (CK-MB > 5 to 8 times the upper limit of normal [ULN]) and Q-wave myocardial infarctions (MI).^11–15 Furthermore, several authors have shown no association between CK-MB elevation after PCI and any adverse clinical consequences.^16–18 It is important, however, to highlight that a large number of PCI procedures in these studies were performed over a decade ago, and many of them used exclusively balloon angioplasty or directional atherectomy. There have been substantial advances in PCI technology and adjunctive pharmacotherapy over the last few years, with emerging evidence for high loading doses of clopidogrel¹⁹ and statins before coronary intervention being associated with reduced periprocedural myonecrosis and death.^20–23
The objective of our study was to evaluate the incidence and long-term impact of periprocedural CK-MB elevation on mortality in a large cohort of patients undergoing coronary stenting in the current PCI era.

Methods
Patient population. We performed a retrospective analysis and data review of all patients undergoing PCI at our tertiary center between January 1, 2003 and December 31, 2005. Baseline demographics and procedural characteristics were recorded prospectively by the operating cardiologists on all patients.

A total of 4,958 patients underwent PCI with deployment of at least 1 stent during the study period. The procedural success rate was 98%. Patients with acute ST-elevation MI or cardiogenic shock (n = 617), as well as patients with no available CK-MB levels (n = 477) were excluded. A total of 3,864 patients were available for analysis (Figure 1 illustrates the study profile).
Routine hospital procedure involves loading patients with 600 mg of aspirin and 600 mg of clopidogrel between 2–24 hours prior to undergoing PCI, and all patients received standard unfractionated heparin at the time of the procedure to achieve an activated clotting time > 200 seconds with glycoprotein (GP) IIb/IIIa agents and > 280 seconds with heparin alone. The dual antiplatelet therapy was continued for a period of 1 year, and aspirin indefinitely following stent implantation.
CK-MB measurement. Blood samples for CK-MB levels were routinely collected 18–24 hours after PCI. The analysis was performed using the biotinylated monoclonal anti-CKMB immunoassay, Elecsys Analyzer (Roche Diagnostics, Basel, Switzerland). The ULN for the assay is 4 ug/l.
Outcome. The primary outcome measure of the study was death (from any cause) and was obtained from the National Strategic Tracing Service (NSTS), which records all deaths in the United Kingdom. To establish current vital status as of June 30, 2006, patients were matched to the NSTS based on patient name, National Health Service number, date of birth, gender and postcode. The mean follow-up period was 22 months, and the median was 21 months (range 6–42 months and interquartile range 16.6 months). Follow up was 100% complete.

Statistical analysis. Continuous data are shown as mean values ± standard deviation. Due to nonnormality of some data (Shapiro-Wilk), these are expressed as median values. Categorical data are shown as percentages with absolute numbers. Cox proportional hazards analysis with forward stepwise selection was performed to examine the association between CK-MB level post PCI (as a continuous variable) and follow-up mortality. Potential confounding risk factors included in the analysis are listed in Table 1. Ejection fraction and renal failure (measured by serum creatine) were dichotomized at 50% and 200 umol/l, respectively, during data collection. To further examine the relationship between CK-MB levels and mortality, we applied strata of CK-MB (normal [as the reference group], 1–3 ULN, 3–5 ULN, and > 5 ULN), which has been adopted by previous investigators, to the Cox proportional hazards model. To account for potential bias from urgent cases, e.g., acute coronary syndromes, we repeated the multivariate analysis only on elective patients. A multivariate logistic regression analysis was carried out to assess risk factors for CK-MB elevation above the ULN. Kaplan-Meier curves were plotted to show the occurrence of death over time. A p-value < 0.05 was considered statistically significant. All analysis was performed using SAS for Windows, version 8.2 (SAS Institute, Cary, North Carolina).

Results
Baseline characteristic. The clinical, angiographic and procedural characteristics of the 3,864 patients included in the analysis are shown in Table 1. This is a “real-world” cohort of patients who were referred to our regional cardiothoracic center, with about 30% of patients treated for non- ST-elevation acute coronary syndromes and a high prevalence (54.5%) of complex (type C) lesions.

CK-MB elevation and mortality. Table 2 describes the incidence of CK-MB elevation and the unadjusted mortality during the follow-up period. CK-MB elevation above the ULN was detected in 1,135 (29.4%) patients. The mortality rate was 2.4% (64/2,729) in patients with normal CK-MB levels. Patients with no available CK-MB levels had an unadjusted mortality rate of 2.9% (14/477), which was not significantly different from those with normal CK-MB levels (chi-square, p = 0.44).
Increasing age, increasing number of lesions treated, urgent PCI, 2- and 3-vessel disease, AHA C-type lesions, GP inhibitor use, renal dysfunction, hypertension and left main stem lesions were found to be predictors of CK-MB elevation above the ULN. (Table 3 shows factors associated with CK-MB elevation > ULN with adjusted odds ratios).
Multivariate analysis shows that an elevation of periprocedural CK-MB was independently associated with an increased risk of death (adjusted hazard ratio for every 10 units: 1.09; 95% CI: 1.05–1.12; p < 0.001). Other independent predictors of mortality were increasing age, renal dysfunction, peripheral vascular disease, New York Heart Association Class > 2, urgent PCI, current smoker and 3- vessel disease (Table 4).

When we applied strata of CK-MB to the Cox proportional hazards model, as demonstrated in Figure 2, the adjusted hazard ratio for mortality increased with more substantial CK-MB release (adjusted HR 1.30, 1.76 and 2.26 for CK-MB levels of 1–3 ULN, 3–5 ULN and > 5 ULN, respectively). Figure 3 shows the cumulative risk of death over time (event curve) depending on a normal or abnormal CK-MB elevation (i.e., CK-MB above the ULN).
We also explored the impact of CK-MB release after stenting excluding non-ST-elevation acute coronary syndrome patients, as their subsequent mortality may be related to their clinical presentation rather than the direct effect of periprocedural CK-MB elevation. Again, the CK-MB level postelective PCI and stenting was found to be independently associated with follow-up mortality (adjusted hazard ratio of 1.08; 95% CI: 1.03–1.13; p = 0.001), as shown in Table 5.

Discussion
The incidence of postprocedure CK-MB elevation is high (29.4%) in this contemporary series of PCI and is associated with a subsequent increased risk of death during follow up. Even modest a elevation of CK-MB is clinically important, with a 30% increase in mortality for one- to three-fold CK-MB levels. This risk increases progressively and is more than doubled with over five-fold CK-MB elevations.
The routine use of high loading doses of aspirin and clopidogrel and vigorous treatment with a statin might have been expected to lower the incidence of CK-MB leaks post PCI.^19–23 However, this was not the case, as almost 1 in 3 subjects undergoing PCI in our cohort had a degree of CK-MB elevation postprocedure. Stents, through the “cheese grater effect”, can create some degree of embolization from atheromatous plaques,^24,25 and the trend by cardiologists to implant stents at high pressure and routinely apply postdilatation strategies to achieve a stent-to-vessel ratio ≥ 1 (stent overexpansion) has been shown to result in increased rates of CKMB elevation.²⁶ This effect is amplified in lesions containing thrombus, such as in acute coronary syndromes, which compromises 30% of our cohort.
Comparison with other studies. Previous analyses on the relationship between CK-MB elevation post PCI and mortality have produced a spectrum of results. In general, most agree that large elevations are associated with less favorable outcomes. However, the debate focuses on whether smaller elevations actually can affect survival. Saucedo et al¹⁵ evaluated the impact of periprocedural CK-MB levels on late clinical outcomes in 900 consecutive patients who underwent coronary stent implantation between January 1994 and December 1995. They found that only patients with a high CK-MB elevation (> 5 times [x] the ULN) had a higher mortality rate at 1-year follow up. Brener et al²⁷ examined 3,478 patients who underwent coronary stenting between 1992 and 2000, and divided them into 5 strata according to peak CK-MB: normal, 1–3 x, 3–5 x, 5–10 x, > 10 x the ULN. They showed that CK-MB elevation above the ULN occurred in 24% of patients, and 5.3% of patients had a level > 5 x the ULN. The excess risk of mortality was concentrated mainly in the highest stratum of CK-MB elevation. More recently, Jeremias et al²⁸ examined the relationship between periprocedural CKMB and 1-year mortality in 5,850 patients enrolled in 6 clinical trials of native coronary artery stenting and found no effect of periprocedural MI on 1-year mortality, if unsuccessful procedures are excluded.
Our results agree with a meta-analysis performed by Ioannidis et al⁹ of 7 studies with CK-MB measurements and survival outcomes, which included 23,230 subjects who underwent PCI with a variety of revascularization procedures (primarily PTCA and directional coronary atherectomy), and found that any increase in CK-MB after PCI is associated with a small, but statistically and clinically significant, increase in the subsequent risk of death. In a recent multicenter prospective study, Cavallini et al⁷ evaluated the effect of periprocedural CK-MB elevation on 2-year mortality in 3,494 patients who underwent PCI between February 2000 and October 2000 and demonstrated that the risk of death increases linearly with any elevation of the marker (odds ratio per unit: 1.04; 95% CI: 1.01–1.07; p = 0.009). The stent use in this study was 82.6%, and 77.1% for patients with and without CK-MB elevation, respectively.
It is difficult to explain why some of the large studies found an association between any level of CK-MB elevation and mortality, while others found that such a relationship existed only for higher levels of CK-MB. It is possible that the lack of association between smaller CK-MB elevations and mortality in some of these studies is related to the relatively short follow-up periods or small number of events, and that the mortality hazard from smaller CK-MB elevations will only become apparent after longer-term follow up or in a larger sample size.
Mechanisms for late mortality. The mechanism responsible for the association between CK-MB elevation and risk of death is not clear. Previous explanations for this relationship came from animal studies which showed that, in the presence of angiographically normal epicardial coronary arteries, microembolizations can cause numerous small infarcts which in turn can create zones of slow conduction and serve as a nidus for ventricular arrhythmias via reentrant circuits.^29,30 The advent of sophisticated imaging modalities such as contrast-enhanced magnetic resonance imaging,^31,32 has provided evidence that even a minor elevation of cardiac enzymes post PCI is the result of discrete areas of microinfarction. These microinfarctions can impair left ventricular function and cause electrical instability, and subsequently increase mortality. CK-MB elevation post PCI, however, may simply be a surrogate for more extensive atherosclerotic disease and a marker for high-risk patients.
Study limitations. This is a retrospective analysis with all the inherent limitations of this type of study. Although in our analysis we have accounted for mortality risk factors, we cannot exclude factors that are not included in the Cox proportional hazards model such as the amount of atheroma burden and arterial inflammation, which could be the real causative agents of increased long-term mortality.³³ Furthermore, there were no strict guidelines of CK-MB collection, allowing the possibility that the actual peak value might have been missed, thus leading to incorrect categorization of the degree of myocardial necrosis. Additionally, we do not have information about the causes of death, thus, the contribution of coronary disease and PCI to outcomes may have been overstated. Finally, we did not have CK-MB values pre-PCI for all of our patients, and this is particularly relevant for acute coronary syndrome patients. To overcome this, we performed the same analysis in elective cases and showed similar results, with CK-MB being associated with increased mortality.

Conclusion
Our study shows that in the contemporary era of stenting and advanced pharmacotherapy, periprocedural CK-MB elevation is a common occurrence. Furthermore, elevation in CK-MB post PCI appears important and is associated with long-term mortality with the risk increasing as CK-MB levels rise. Routine measurement of CK-MB or other biochemical markers of myocardial damage after PCI will identify patients who may benefit from additional secondary preventive medication and care following MI. Provision of feedback to operators about enzyme release events has, in our center, raised awareness of procedural and drug treatment issues associated with these cases, and preliminary data suggest that the incidence has fallen over the period of this initiative.

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