Preprocedural Levels of C-Reactive Protein and Leukocyte Counts Predict 9-Month Mortality After Coronary Angioplasty for the Treatment of Un
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《循环学杂志》
Istituto di Cardiologia, Policlinico S. Orsola, University of Bologna, Bologna, Italy.
Abstract
Background— An accurate preprocedural risk stratification scheme for patients with unprotected left main coronary artery (ULMCA) stenosis who are undergoing coronary stenting is lacking. We examined the predictive value of preprocedural levels of C-reactive protein (CRP), fibrinogen, and leukocyte counts with respect to 9-month clinical outcomes after stenting of the ULMCA stenosis.
Methods and Results— Levels of CRP, fibrinogen, and leukocyte count were prospectively measured in 83 patients undergoing stenting of the ULMCA. A drug-eluting stent was used in 42 patients, and a bare metal stent was used in 41. The end point of the study was death and the combination of death and myocardial infarction (MI). By the 9-month follow-up, there were 11 deaths (13%), 7 MIs (8%), and 16 target lesion revascularizations (19%). Death and death/MI occurred in 19% and 31%, respectively, of 59 patients with high serum levels of CRP (>3 mg/L) but in none of 24 patients with normal CRP levels (for death, P=0.02; for death/MI, P=0.006). In multivariate analysis, the highest tertiles of CRP level (P=0.028) and leukocyte count (P=0.002) were the only independent predictors of death. The highest tertiles of CRP level (P=0.002) and leukocyte count (P=0.002) and acute coronary syndromes (P=0.05) were the only independent predictors of the combined end point death/MI.
Conclusions— Elevated preprocedural levels of CRP indicate an increased risk of death and death/MI after ULMCA stenting. Inflammatory risk assessment in patients with ULMCA stenosis may be useful for selecting patients for percutaneous coronary interventions with very low risk.
Key Words: leukocytes stents angioplasty
Introduction
Surgical revascularization is traditionally considered the treatment of choice for patients with unprotected left main coronary artery (ULMCA) stenosis. With recent improvements in percutaneous techniques, percutaneous coronary intervention (PCI [angioplasty]) has been increasingly applied to ULMCA stenosis with varied long-term success.1–5 Several studies showed excellent short-term results, but follow-up revealed a disappointingly high incidence of mortality and serious morbidity.2,3 Although an aggressive form of restenosis is thought to be the main cause of death in these patients,2,3 the true mechanism by which this event occurs remains elusive.
Editorial p 2226
Risk assessment for PCI has traditionally focused on clinical and anatomic lesion characteristics, but emerging evidence has highlighted the contribution of inflammatory processes to both short- and long-term clinical outcomes. C-reactive protein (CRP), a circulating pentraxin involved in the human immune response, is one of the best-characterized among the available inflammatory biomarkers. Synthesized by hepatocytes in response to proinflammatory cytokines, CRP has emerged as a potential marker of cardiovascular risk.6
Other studies have shown that preprocedural CRP levels predict recurrent coronary events, thrombotic complications, and clinical restenosis after coronary angioplasty.7,8 Therefore, in this study, we prospectively investigated the predictive value of preprocedural CRP levels, leukocyte counts, and fibrinogen levels with respect to 9-month clinical outcomes in a series of patients undergoing coronary stent implantation for treatment of ULMCA stenosis.
Methods
Patients
January 2003 to June 2004, 83 patients underwent coronary stenting for a >50% de novo stenosis of the ULMCA at the Institute of Cardiology, Policlinico S. Orsola, Bologna, Italy. The inclusion criteria were symptomatic ULMCA disease or documented myocardial ischemia.
Exclusion criteria were acute myocardial infarction (MI) with ST-segment elevation, cardiogenic shock, previous coronary artery bypass, previous PCI within 1 year, an intercurrent inflammatory condition, or a history of a neoplastic condition. All patients provided written, informed consent for participation in the study, and the study protocol was approved by the institutional ethics committee.
Laboratory Assay
Fasting blood samples were collected from the antecubital vein with minimal venous stasis or local trauma immediately before the procedure. CRP was measured by the high-sensitivity nephelometric method (Dade Behring). Fibrinogen was measured with the Clauss method9 (Sysmex Corp). Leukocyte count was determined with an automated counter (ADVIA 120, Hematology System).
As previously defined,10 a CRP level 3 mg/L (ie, the 90th percentile of the normal distribution) was considered elevated. Fibrinogen levels >400 mg/dL and leukocyte counts >8500/μL (upper limits of normal values for our laboratory) were considered elevated.
Stenting Procedure
Standard PCI technology was used. Stenting of the distal LMCA was performed with a stent spanning the distal LMCA and the proximal portion of either the left anterior descending coronary artery or the circumflex artery (parent vessel), depending on vessel diameter and the severity of disease. The side branch was then dilated with a conventional balloon or a stent, at the operator’s discretion. During the procedure, patients were given 5000 U of unfractioned heparin as a bolus. Use of a glycoprotein IIb/IIIa inhibitor was at the operator’s discretion.
Hemostasis of the femoral artery was obtained with use of an AngioSeal (St. Jude Medical). After the procedure, all patients received 100 mg aspirin indefinitely and either 250 mg ticlopidine BID or 75 mg/d clopidogrel for 1 month in patients with bare metal stents (BMSs) and for 3 or 6 months in patients with at least 1 drug-eluting stent (DES). Although this was the general strategy adopted, some patients who had acute coronary syndromes or who were considered at high risk underwent prolonged (>6 months) dual antiplatelet therapy regardless of the stent type used.
Samples for determination of total creatine phosphokinase (CPK) and the MB isoenzyme were collected at 6 hours and the morning after PCI from all patients. Among patients with postprocedural CPK elevations, repeated CPK analysis was performed every 6 hours until peak elevation was defined.
Quantitative Coronary Angiography
Coronary angiograms were obtained before the intervention, after stenting, and at follow-up. The projection showing the maximal degree of stenosis was selected at baseline and was used for subsequent analysis. Quantitative coronary angiography was performed with the CAAS II analysis system (Pie Medical). Lesions were classified according to the modified American College of Cardiology/American Heart Association criteria.11
Follow-Up
During follow-up, coronary angiography was performed within 6 months after the intervention or as clinically indicated by symptoms. The 9-month follow-up was performed by a telephone interview.
Definitions and End Points of the Study
An acute coronary syndrome was defined as either unstable angina or non–ST-segment elevation MI. The diagnosis of a non–ST-segment elevation MI was based on the presence of typical symptoms and an increase of either CPK (with the MB isoenzyme >10% of the total value) or troponin I. The diagnosis of a periprocedural MI was based on either the development of new pathological Q waves in at least 2 contiguous ECG leads or an elevation of CPK to >2 times the upper limit of normal.
Poor candidates for surgery were defined as those patients with at least 1 of the following characteristics: age >75 years, severe obstructive pulmonary disease, serum creatinine 2 mg/dL, left ventricular ejection fraction (LVEF) 30%, severe peripheral vascular disease, previous stroke, or a left anterior descending coronary artery not amenable to surgery.
Angiographic success was defined as residual stenosis <30% in the worse of 2 orthogonal views. Procedural success was defined as angiographic success in the absence of death, MI, or the need for further revascularization during hospitalization. Complete revascularization was defined as successful treatment of all stenotic lesions >50% of the reference diameter of the main branches. Angiographic restenosis was defined as a diameter stenosis >50% at follow-up angiography.
Target lesion revascularization (TLR) was defined as repeated PCI of the entire segment involving the implanted stent and the 5-mm distal and proximal borders adjacent to the stent. The end points of the study were death and the combination of death and MI. The combined end point death/MI was assessed as the time to first event, without double counting of clinical events within the same patient.
Statistics
CRP values, fibrinogen levels, and leukocyte counts, which were not normally distributed (Kolmogorov-Smirnov test), were grouped in tertiles for data analysis. Correlations were determined by Spearman’s rank correlation test. Categorical variables were compared by 2 statistics or Fisher’s exact test, as appropriate.
Stepwise logistic regression analysis was performed to determine predictors of death and death/MI at 9-month follow up. Noncorrelated variables with P<0.05 at the univariate analyses were included in the multivariate analysis. Model discrimination was assessed with the c-statistic, and model calibration was assessed with the Hosmer-Lemeshow statistic. Survival and MI-free survival at follow-up were analyzed by a Cox proportional-hazards regression model.
Statistical analyses were performed with SPSS software (SPSS 12.0 for Windows, SPSS Inc). Probability values <0.05 were considered statistically significant.
Results
Baseline Clinical, Angiographic, and Laboratory Characteristics
Clinical characteristics of the patients are listed in Table 1. Patients enrolled in the study had a rather high-risk profile: 68% had an acute coronary syndrome, 46% were older than 75 years, 12% had renal failure (creatinine 2 mg/dL), 5% had a history of stroke, 36% had an abnormal (<50%) LVEF, 6% had LVEF <30%, 42% had a EuroSCORE >512, and 54% were considered poor candidates for surgery. Angiographic findings and the main procedural variables are presented in Table 2. Of note, 52% of patients had concomitant multivessel disease.
In 51% of patients, a DES was deployed in the LMCA. DES diameter was significantly less than BMS diameter (3.3±0.3 versus 4.0±0.3 mm, P<0.001). In the bifurcation treatment, LMCA–parent vessel stenting was performed in 58% of cases with a DES. Side branch treatment consisted of balloon dilatation in 50% of cases, a DES in 35% of cases, and a BMS in 15% of cases.
Preprocedural CRP levels were elevated (>3 mg/L) in 59 patients. Elevated levels of leukocytes and fibrinogen were found in 23 and 43 patients, respectively. CRP levels were weakly correlated with fibrinogen levels (r=0.49, P<0.001). No correlation was found between CRP levels and leukocyte counts, nor between fibrinogen levels and leukocyte counts.
Immediate Results
Angiographic success of the procedure was 100%. Procedural success was 96%. Three patients had a non–Q-wave periprocedural MI. All 3 patients were in the highest tertile of the CRP distribution. No deaths occurred during hospitalization.
Nine-Month Follow-Up: Death and MI
Nine-month follow-up was completed for all patients. Death occurred in 11 patients (13%) and non–ST-segment elevation MI in 4 (5%). Ten patients had sudden deaths and 1 died of cardiogenic shock. Emergent coronary angiography in this last patient showed total occlusion of the LMCA. Two patients died within the first month of the index procedure, 6 between the first and sixth months, and 3 after the sixth month. Three patients who died were on dual antiplatelet therapy, whereas 8 were on single antiplatelet therapy.
The rate of mortality was 15.7% in patients who underwent short dual-antiplatelet therapy (6 months) and 0 in those who underwent prolonged dual-antiplatelet therapy (>6 months, P=0.3). Among the 8 patients who died and were on single-antiplatelet therapy, 6 were in CRP tertile 3, 1 was in tertile 2, and 1 was in tertile 1. Eight patients who died had a BMS in the LMCA, whereas 3 had a DES (P=0.18).
The mortality rate was significantly higher in patients with elevated CRP levels (19% versus 0%, P=0.02). Elevated baseline levels of CRP were also associated with a higher rate of death/MI (31% versus 0%, P=0.006). When examined by CRP tertiles, a progressive increase in death or death/MI was observed. The highest tertile of baseline CRP levels (CRP 10.36 mg/L) was associated with a higher rate of both death (tertile 3 25% versus tertile 1 and 2 7%, P=0.038) and death/MI (Table 3).
Death and death/MI were also significantly increased in patients with an elevated leukocyte count and in those with an elevated fibrinogen level. The highest tertiles of baseline leukocyte count (leukocytes 8224/μL) and fibrinogen level (fibrinogen 447 mg/dL) were associated with a higher rate of both death (for leukocyte counts, tertile 3 32% versus tertile 1 and 2 4%, P<0.001; for fibrinogen levels, tertile 3 25% versus tertile 1 and 2 7%, P=0.038) and death/MI (Table 3). Furthermore, death and death/MI were higher in patients who were considered poor candidates for surgery compared with good candidates (for death, 17.7% versus 7.8, respectively, P=0.3; for death/MI, 33% versus 7.8%, P=0.01) (Table 3).
Nine-Month Follow-Up: Restenosis and TLR
Follow-up angiography at a median of 110 days (25th and 75th percentiles, 79 and 150 days, respectively) was performed in 51 patients. Angiography was not performed in 32 patients because of death before the scheduled angiography (8 patients), patient refusal (12 patients), age 85 (9 patients), or serious comorbidities (3 patients) in the absence of clinical symptoms of cardiac ischemia.
Restenosis occurred in 16 of the 51 patients studied (19%). Restenosis occurred in 1 of 10 patients with ostial or midshaft LMCA stenosis (10%) and in 15 of 41 patients with bifurcation involvement (37%, P=0.14). In patients with bifurcation involvement, restenosis occurred in 3 cases in the LMCA–parent vessel only, in 7 cases in the side branch, and in 5 cases in both vessels.
Fourteen patients underwent a second PCI (4 with brachytherapy), 1 was referred to cardiac surgery, and 1, who was asymptomatic and had 55% restenosis of a DES at the ostium of the circumflex artery, was treated with medical therapy. TLR was performed in 16 patients: in 15 cases for restenosis and in 1 case because of dissection at the ostium of the LMCA found at the 2-month follow-up angiography.
Patients with a DES in the LMCA had a lower rate of restenosis compared with patients with a BMS (8% versus 27%, P=0.14). When the side branch in the bifurcation lesion was also considered, TLR was 20% in patients with a DES and 42% in those with a BMS (P=0.1). For the combination of death, MI, and TLR, patients with a DES had significantly fewer events than those with BMS (DES 24% versus BMS 49%, P=0.03)
Multivariate Analysis
Independent predictors of death and death/MI at 9-month follow-up are shown in Table 5. In univariate analysis, tertiles of CRP, fibrinogen, and leukocyte count; LVEF <30%; and a EuroSCORE >5 were associated with an increased risk of death.
However, in the logistic regression analysis, CRP tertiles (tertile 3 versus tertiles 1 and 2: odds ratio [OR]=5.4, 95% confidence interval [CI]=1.2 to 24.2, P=0.028) and leukocyte tertiles (tertile 3 versus tertiles 1 and 2: OR=14.7, 95% CI=2.7 to 80.7, P=0.002) were the only independent predictors of death (2 model=17.8, df=2, P<0.001). Interestingly, the presence of an acute coronary syndrome, which was associated with higher CRP levels, did not reach statistical significance (P=0.09). The risk predicted by the model was well correlated with the observed events (89.2% of correct classification, c-statistic=0.84, Hosmer-Lemeshow goodness-of-fit P=0.748).
In the univariate analysis, tertiles of CRP, fibrinogen, and leukocyte count; EuroSCORE >5; LVEF <30%; acute coronary syndrome; diabetes; age >75 years; and poor candidate for surgery were associated with an increased risk of death/MI (Table 3).
However, in the logistic regression analysis, CRP tertiles (tertile 3 versus tertiles 1 and 2: OR=11.5, 95% CI=2.5 to 52.0, P=0.002), leukocyte tertiles (tertile 3 versus tertiles 1 and 2: OR=10.9, 95% CI=2.4 to 49.7, P=0.002), and acute coronary syndrome (OR=9.5, 95% CI=1.0 to 92.6, P=0.05) were the only independent predictors of death/MI (2 model=32.8, df=3, P<0.001). The risk predicted by the model was well correlated with the observed events (89.2% of correct classification, c-statistic=0.86, Hosmer-Lemeshow goodness-of-fit P=0.693)
A Cox proportional-hazards model was used to evaluate the timing of adverse events at follow-up. Among all of the variables tested, CRP and leukocyte tertile distributions remained the only independent predictors of death (Figure). Similar results were found when we considered the combined end point of death/MI (for CRP tertile 3 versus tertiles 1 and 2: hazard ratio [HR]=5.8, 95% CI=2.0 to 16.6, P=0.001; for leukocyte counts, tertile 3 versus tertiles 1 and 2: HR=5.0, 95% CI=1.9 to 13.7, P=0.002).
Survival at 9-month follow-up by preprocedural levels of CRP (A) and leukocyte counts (B) (multivariate Cox regression analysis). Among all clinical, angiographic, and procedural variables, CRP tertiles (tertile 3 vs tertiles 1 and 2: HR=5.6, 95% CI=1.6 to 19.7, P=0.007) and leukocyte tertiles (tertile 3 versus tertiles 1 and 2: HR=13.7, 95% CI=2.9 to 64.2, P=0.001) were the only independent predictors of death.
Discussion
Although procedural success and short-term outcome after PCI of the ULMCA are favorable, several studies have shown a rather high long-term mortality rate. Depending on the risk profile of the patient, long-term mortality varies from 3.4% in those at low risk to 24.2% in those at high risk.1–5 In our study, the mortality rate was relatively high, but we must emphasize that patients enrolled in our study had a rather high-risk profile initially. On the other hand, the mortality rate in patients who were good candidates for surgery was 7.8%, which is similar to the surgical mortality rate reported in the French Registry, in which good candidates for surgery were defined in the same way as in our study.13 Considering the uncertainty of the clinical outcome after PCI, in the ACC/AHA guidelines for PCI, surgery is the recommended therapy for treatment of ULMCA stenosis, although there is general agreement that PCI is not recommended (class III indication).11
Judicious patient selection, therefore, remains critical for the interventionalist, and accurate stratification is needed to identify who, among these patients, is most likely to benefit from PCI. Age, LVEF, renal function, reference diameter, mitral regurgitation, and the presence of multivessel disease have been traditionally identified as predictors of outcome after PCI of the ULMCA,2–5 but an accurate stratification scheme is still lacking.
Besides traditional clinical and anatomic risk factors, inflammatory markers are now emerging as prognostic factors among patients undergoing PCI. Although several studies have demonstrated an association between preprocedural CRP levels and the risk of death or MI after PCI of the remote coronary tree,8,14 no data are available on long-term clinical outcomes after PCI of the ULMCA.
To our knowledge, this prospective study is the first to provide evidence that elevated pretreatment levels of CRP or of leukocyte count are closely associated with the risk of death and death/MI after PCI of the ULMCA. Assessment of the inflammatory status of patients undergoing PCI of the ULMCA, therefore, provides incremental prognostic information beyond that defined by traditional factors and may be an important element in selecting patients at low risk who may be referred to PCI. In our study, patients with CRP levels <3 mg/L had extremely favorable short- and long-term outcomes, with no major events during the follow-up period. On the other hand, a progressive increase in death or death/MI was observed in relation to CRP tertiles. In the multivariate analysis, patients in tertile 3 (CRP 10.36 mg/L) had an OR of death=5.4 (P=0.028) compared with patients in tertiles 1 and 2. Besides CRP levels, tertiles of leukocyte count showed an even stronger association with death (tertile 3 versus tertiles 1 and 2: OR=14.7, P=0.002).
The association between leukocytosis and the risk of mortality and morbidity in patients with coronary heart disease has been reported in a large number of studies.15 Although generally considered a nonspecific marker of inflammatory processes, leukocytosis is now emerging as a potential factor that may directly contribute to vascular disease. Leukocytes, in fact, may have prothrombotic effects, producing tissue factor,16,17 providing a catalytic surface for thrombin generation, and forming platelet-leukocyte aggregates.18 They may also exert vascular effects by compromising the microvasculature by adhesion, aggregation, and platelet recruitment19; releasing proinflammatory and vasculotoxic factors20; and contributing to intimal hyperplasia after vascular injury.21 Of note, in our study, CRP levels and leukocyte counts were more important determinants of outcome than clinical instability.
Inflammatory risk stratification in patients with ULMCA stenosis is therefore extremely useful and may identify those patients who are most likely to benefit from PCI or those who should undergo close angiographic follow-up if treated with PCI. The link between inflammation and death after PCI of the ULMCA remains to be elucidated. Furthermore, it is not clear whether CRP itself portends an adverse prognosis in patients with ULMCA stenosis, independent of the treatment used, or whether our results apply only to PCI. This issue therefore deserves further investigation.
Several studies have shown that most deaths after PCI of the ULMCA occur within 6 months of the intervention,2,3 and thus it seems reasonable to assume that the main mechanism leading to death after PCI of the ULMCA involves an aggressive form of restenosis, which may manifest as sudden death. In the context of in-stent restenosis, the role of CRP levels is controversial. Some studies have demonstrated that preprocedural levels of CRP predict both clinical7 and angiographic22 restenosis, whereas others have failed to demonstrate this association.23 Therefore, given the inconsistency of the association between CRP and restenosis, it is possible that other mechanisms, such as stent thrombosis, are responsible for abrupt occlusion of the LMCA and consequent sudden death. The hypothesis of stent thrombosis as the leading cause of death in these patients is concordant with previous findings that have shown an association between CRP and death and MI, but not with restenosis,14 and with an experimental animal study that showed increased thrombosis after arterial injury in transgenic mice producing human CRP.24 In that study, transluminal wire injury caused thrombotic occlusion of the femoral artery in 75% of CRP-transgenic mice compared with only 17% in wild-type mice (P<0.05). This hypothesis is also consistent with our findings that among the 11 patients who died, only 3 were still on dual-antiplatelet therapy, whereas 8 had suspended this treatment. This finding raises the possibility that prolonged (1-year) dual-antiplatelet therapy may be beneficial in these patients, but further investigations are needed to confirm these data. On the other hand, we cannot exclude alternative explanations, such as recurrent ischemia due to progression of coronary artery disease25 or primary arrhythmic death.26
Another emerging issue in the treatment of LMCA stenosis is the use of DESs. In our study, among the 42 patients with DESs, 3 patients died (1 after discontinuing antiplatelet therapy 60 days after the procedure). Although not statistically significant, patients with DESs had a 65% relative reduction in mortality compared with patients with BMSs (P=0.18). When considering the combination of death, MI, and TLR, patients with DESs had a significantly lower incidence of events compared with those with BMSs (DES 24% versus BMS 49%, P=0.03). Recent studies in which DESs have been compared with BMSs for the treatment of ULMCA stenoses are consistent with our findings.27,28 More widespread use of DESs in the treatment of ULMCA stenosis might provide significant improvements in the prognosis of patients treated with PCI.
Study Limitations
A limitation of the study is represented by the limited angiographic follow-up (62%). This limitation does not allow us to determine the true angiographic restenosis rate in patients with ULMCA stenosis and its possible relation to inflammatory markers. However, the primary end point of the study was death or death/MI and its relation with inflammatory markers. Even though the 65% relative reduction in mortality found in patients with DESs seems a very appealing result, we must emphasize that the study was not sufficiently powered to assess this issue, and therefore, no definitive conclusions can be drawn.
Acknowledgments
This research was supported by funding from Fondazione Fanti Melloni, Bologna, Italy. We are indebted to Dr Barry S. Coller for his invaluable contribution to the discussion of the study.
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Abstract
Background— An accurate preprocedural risk stratification scheme for patients with unprotected left main coronary artery (ULMCA) stenosis who are undergoing coronary stenting is lacking. We examined the predictive value of preprocedural levels of C-reactive protein (CRP), fibrinogen, and leukocyte counts with respect to 9-month clinical outcomes after stenting of the ULMCA stenosis.
Methods and Results— Levels of CRP, fibrinogen, and leukocyte count were prospectively measured in 83 patients undergoing stenting of the ULMCA. A drug-eluting stent was used in 42 patients, and a bare metal stent was used in 41. The end point of the study was death and the combination of death and myocardial infarction (MI). By the 9-month follow-up, there were 11 deaths (13%), 7 MIs (8%), and 16 target lesion revascularizations (19%). Death and death/MI occurred in 19% and 31%, respectively, of 59 patients with high serum levels of CRP (>3 mg/L) but in none of 24 patients with normal CRP levels (for death, P=0.02; for death/MI, P=0.006). In multivariate analysis, the highest tertiles of CRP level (P=0.028) and leukocyte count (P=0.002) were the only independent predictors of death. The highest tertiles of CRP level (P=0.002) and leukocyte count (P=0.002) and acute coronary syndromes (P=0.05) were the only independent predictors of the combined end point death/MI.
Conclusions— Elevated preprocedural levels of CRP indicate an increased risk of death and death/MI after ULMCA stenting. Inflammatory risk assessment in patients with ULMCA stenosis may be useful for selecting patients for percutaneous coronary interventions with very low risk.
Key Words: leukocytes stents angioplasty
Introduction
Surgical revascularization is traditionally considered the treatment of choice for patients with unprotected left main coronary artery (ULMCA) stenosis. With recent improvements in percutaneous techniques, percutaneous coronary intervention (PCI [angioplasty]) has been increasingly applied to ULMCA stenosis with varied long-term success.1–5 Several studies showed excellent short-term results, but follow-up revealed a disappointingly high incidence of mortality and serious morbidity.2,3 Although an aggressive form of restenosis is thought to be the main cause of death in these patients,2,3 the true mechanism by which this event occurs remains elusive.
Editorial p 2226
Risk assessment for PCI has traditionally focused on clinical and anatomic lesion characteristics, but emerging evidence has highlighted the contribution of inflammatory processes to both short- and long-term clinical outcomes. C-reactive protein (CRP), a circulating pentraxin involved in the human immune response, is one of the best-characterized among the available inflammatory biomarkers. Synthesized by hepatocytes in response to proinflammatory cytokines, CRP has emerged as a potential marker of cardiovascular risk.6
Other studies have shown that preprocedural CRP levels predict recurrent coronary events, thrombotic complications, and clinical restenosis after coronary angioplasty.7,8 Therefore, in this study, we prospectively investigated the predictive value of preprocedural CRP levels, leukocyte counts, and fibrinogen levels with respect to 9-month clinical outcomes in a series of patients undergoing coronary stent implantation for treatment of ULMCA stenosis.
Methods
Patients
January 2003 to June 2004, 83 patients underwent coronary stenting for a >50% de novo stenosis of the ULMCA at the Institute of Cardiology, Policlinico S. Orsola, Bologna, Italy. The inclusion criteria were symptomatic ULMCA disease or documented myocardial ischemia.
Exclusion criteria were acute myocardial infarction (MI) with ST-segment elevation, cardiogenic shock, previous coronary artery bypass, previous PCI within 1 year, an intercurrent inflammatory condition, or a history of a neoplastic condition. All patients provided written, informed consent for participation in the study, and the study protocol was approved by the institutional ethics committee.
Laboratory Assay
Fasting blood samples were collected from the antecubital vein with minimal venous stasis or local trauma immediately before the procedure. CRP was measured by the high-sensitivity nephelometric method (Dade Behring). Fibrinogen was measured with the Clauss method9 (Sysmex Corp). Leukocyte count was determined with an automated counter (ADVIA 120, Hematology System).
As previously defined,10 a CRP level 3 mg/L (ie, the 90th percentile of the normal distribution) was considered elevated. Fibrinogen levels >400 mg/dL and leukocyte counts >8500/μL (upper limits of normal values for our laboratory) were considered elevated.
Stenting Procedure
Standard PCI technology was used. Stenting of the distal LMCA was performed with a stent spanning the distal LMCA and the proximal portion of either the left anterior descending coronary artery or the circumflex artery (parent vessel), depending on vessel diameter and the severity of disease. The side branch was then dilated with a conventional balloon or a stent, at the operator’s discretion. During the procedure, patients were given 5000 U of unfractioned heparin as a bolus. Use of a glycoprotein IIb/IIIa inhibitor was at the operator’s discretion.
Hemostasis of the femoral artery was obtained with use of an AngioSeal (St. Jude Medical). After the procedure, all patients received 100 mg aspirin indefinitely and either 250 mg ticlopidine BID or 75 mg/d clopidogrel for 1 month in patients with bare metal stents (BMSs) and for 3 or 6 months in patients with at least 1 drug-eluting stent (DES). Although this was the general strategy adopted, some patients who had acute coronary syndromes or who were considered at high risk underwent prolonged (>6 months) dual antiplatelet therapy regardless of the stent type used.
Samples for determination of total creatine phosphokinase (CPK) and the MB isoenzyme were collected at 6 hours and the morning after PCI from all patients. Among patients with postprocedural CPK elevations, repeated CPK analysis was performed every 6 hours until peak elevation was defined.
Quantitative Coronary Angiography
Coronary angiograms were obtained before the intervention, after stenting, and at follow-up. The projection showing the maximal degree of stenosis was selected at baseline and was used for subsequent analysis. Quantitative coronary angiography was performed with the CAAS II analysis system (Pie Medical). Lesions were classified according to the modified American College of Cardiology/American Heart Association criteria.11
Follow-Up
During follow-up, coronary angiography was performed within 6 months after the intervention or as clinically indicated by symptoms. The 9-month follow-up was performed by a telephone interview.
Definitions and End Points of the Study
An acute coronary syndrome was defined as either unstable angina or non–ST-segment elevation MI. The diagnosis of a non–ST-segment elevation MI was based on the presence of typical symptoms and an increase of either CPK (with the MB isoenzyme >10% of the total value) or troponin I. The diagnosis of a periprocedural MI was based on either the development of new pathological Q waves in at least 2 contiguous ECG leads or an elevation of CPK to >2 times the upper limit of normal.
Poor candidates for surgery were defined as those patients with at least 1 of the following characteristics: age >75 years, severe obstructive pulmonary disease, serum creatinine 2 mg/dL, left ventricular ejection fraction (LVEF) 30%, severe peripheral vascular disease, previous stroke, or a left anterior descending coronary artery not amenable to surgery.
Angiographic success was defined as residual stenosis <30% in the worse of 2 orthogonal views. Procedural success was defined as angiographic success in the absence of death, MI, or the need for further revascularization during hospitalization. Complete revascularization was defined as successful treatment of all stenotic lesions >50% of the reference diameter of the main branches. Angiographic restenosis was defined as a diameter stenosis >50% at follow-up angiography.
Target lesion revascularization (TLR) was defined as repeated PCI of the entire segment involving the implanted stent and the 5-mm distal and proximal borders adjacent to the stent. The end points of the study were death and the combination of death and MI. The combined end point death/MI was assessed as the time to first event, without double counting of clinical events within the same patient.
Statistics
CRP values, fibrinogen levels, and leukocyte counts, which were not normally distributed (Kolmogorov-Smirnov test), were grouped in tertiles for data analysis. Correlations were determined by Spearman’s rank correlation test. Categorical variables were compared by 2 statistics or Fisher’s exact test, as appropriate.
Stepwise logistic regression analysis was performed to determine predictors of death and death/MI at 9-month follow up. Noncorrelated variables with P<0.05 at the univariate analyses were included in the multivariate analysis. Model discrimination was assessed with the c-statistic, and model calibration was assessed with the Hosmer-Lemeshow statistic. Survival and MI-free survival at follow-up were analyzed by a Cox proportional-hazards regression model.
Statistical analyses were performed with SPSS software (SPSS 12.0 for Windows, SPSS Inc). Probability values <0.05 were considered statistically significant.
Results
Baseline Clinical, Angiographic, and Laboratory Characteristics
Clinical characteristics of the patients are listed in Table 1. Patients enrolled in the study had a rather high-risk profile: 68% had an acute coronary syndrome, 46% were older than 75 years, 12% had renal failure (creatinine 2 mg/dL), 5% had a history of stroke, 36% had an abnormal (<50%) LVEF, 6% had LVEF <30%, 42% had a EuroSCORE >512, and 54% were considered poor candidates for surgery. Angiographic findings and the main procedural variables are presented in Table 2. Of note, 52% of patients had concomitant multivessel disease.
In 51% of patients, a DES was deployed in the LMCA. DES diameter was significantly less than BMS diameter (3.3±0.3 versus 4.0±0.3 mm, P<0.001). In the bifurcation treatment, LMCA–parent vessel stenting was performed in 58% of cases with a DES. Side branch treatment consisted of balloon dilatation in 50% of cases, a DES in 35% of cases, and a BMS in 15% of cases.
Preprocedural CRP levels were elevated (>3 mg/L) in 59 patients. Elevated levels of leukocytes and fibrinogen were found in 23 and 43 patients, respectively. CRP levels were weakly correlated with fibrinogen levels (r=0.49, P<0.001). No correlation was found between CRP levels and leukocyte counts, nor between fibrinogen levels and leukocyte counts.
Immediate Results
Angiographic success of the procedure was 100%. Procedural success was 96%. Three patients had a non–Q-wave periprocedural MI. All 3 patients were in the highest tertile of the CRP distribution. No deaths occurred during hospitalization.
Nine-Month Follow-Up: Death and MI
Nine-month follow-up was completed for all patients. Death occurred in 11 patients (13%) and non–ST-segment elevation MI in 4 (5%). Ten patients had sudden deaths and 1 died of cardiogenic shock. Emergent coronary angiography in this last patient showed total occlusion of the LMCA. Two patients died within the first month of the index procedure, 6 between the first and sixth months, and 3 after the sixth month. Three patients who died were on dual antiplatelet therapy, whereas 8 were on single antiplatelet therapy.
The rate of mortality was 15.7% in patients who underwent short dual-antiplatelet therapy (6 months) and 0 in those who underwent prolonged dual-antiplatelet therapy (>6 months, P=0.3). Among the 8 patients who died and were on single-antiplatelet therapy, 6 were in CRP tertile 3, 1 was in tertile 2, and 1 was in tertile 1. Eight patients who died had a BMS in the LMCA, whereas 3 had a DES (P=0.18).
The mortality rate was significantly higher in patients with elevated CRP levels (19% versus 0%, P=0.02). Elevated baseline levels of CRP were also associated with a higher rate of death/MI (31% versus 0%, P=0.006). When examined by CRP tertiles, a progressive increase in death or death/MI was observed. The highest tertile of baseline CRP levels (CRP 10.36 mg/L) was associated with a higher rate of both death (tertile 3 25% versus tertile 1 and 2 7%, P=0.038) and death/MI (Table 3).
Death and death/MI were also significantly increased in patients with an elevated leukocyte count and in those with an elevated fibrinogen level. The highest tertiles of baseline leukocyte count (leukocytes 8224/μL) and fibrinogen level (fibrinogen 447 mg/dL) were associated with a higher rate of both death (for leukocyte counts, tertile 3 32% versus tertile 1 and 2 4%, P<0.001; for fibrinogen levels, tertile 3 25% versus tertile 1 and 2 7%, P=0.038) and death/MI (Table 3). Furthermore, death and death/MI were higher in patients who were considered poor candidates for surgery compared with good candidates (for death, 17.7% versus 7.8, respectively, P=0.3; for death/MI, 33% versus 7.8%, P=0.01) (Table 3).
Nine-Month Follow-Up: Restenosis and TLR
Follow-up angiography at a median of 110 days (25th and 75th percentiles, 79 and 150 days, respectively) was performed in 51 patients. Angiography was not performed in 32 patients because of death before the scheduled angiography (8 patients), patient refusal (12 patients), age 85 (9 patients), or serious comorbidities (3 patients) in the absence of clinical symptoms of cardiac ischemia.
Restenosis occurred in 16 of the 51 patients studied (19%). Restenosis occurred in 1 of 10 patients with ostial or midshaft LMCA stenosis (10%) and in 15 of 41 patients with bifurcation involvement (37%, P=0.14). In patients with bifurcation involvement, restenosis occurred in 3 cases in the LMCA–parent vessel only, in 7 cases in the side branch, and in 5 cases in both vessels.
Fourteen patients underwent a second PCI (4 with brachytherapy), 1 was referred to cardiac surgery, and 1, who was asymptomatic and had 55% restenosis of a DES at the ostium of the circumflex artery, was treated with medical therapy. TLR was performed in 16 patients: in 15 cases for restenosis and in 1 case because of dissection at the ostium of the LMCA found at the 2-month follow-up angiography.
Patients with a DES in the LMCA had a lower rate of restenosis compared with patients with a BMS (8% versus 27%, P=0.14). When the side branch in the bifurcation lesion was also considered, TLR was 20% in patients with a DES and 42% in those with a BMS (P=0.1). For the combination of death, MI, and TLR, patients with a DES had significantly fewer events than those with BMS (DES 24% versus BMS 49%, P=0.03)
Multivariate Analysis
Independent predictors of death and death/MI at 9-month follow-up are shown in Table 5. In univariate analysis, tertiles of CRP, fibrinogen, and leukocyte count; LVEF <30%; and a EuroSCORE >5 were associated with an increased risk of death.
However, in the logistic regression analysis, CRP tertiles (tertile 3 versus tertiles 1 and 2: odds ratio [OR]=5.4, 95% confidence interval [CI]=1.2 to 24.2, P=0.028) and leukocyte tertiles (tertile 3 versus tertiles 1 and 2: OR=14.7, 95% CI=2.7 to 80.7, P=0.002) were the only independent predictors of death (2 model=17.8, df=2, P<0.001). Interestingly, the presence of an acute coronary syndrome, which was associated with higher CRP levels, did not reach statistical significance (P=0.09). The risk predicted by the model was well correlated with the observed events (89.2% of correct classification, c-statistic=0.84, Hosmer-Lemeshow goodness-of-fit P=0.748).
In the univariate analysis, tertiles of CRP, fibrinogen, and leukocyte count; EuroSCORE >5; LVEF <30%; acute coronary syndrome; diabetes; age >75 years; and poor candidate for surgery were associated with an increased risk of death/MI (Table 3).
However, in the logistic regression analysis, CRP tertiles (tertile 3 versus tertiles 1 and 2: OR=11.5, 95% CI=2.5 to 52.0, P=0.002), leukocyte tertiles (tertile 3 versus tertiles 1 and 2: OR=10.9, 95% CI=2.4 to 49.7, P=0.002), and acute coronary syndrome (OR=9.5, 95% CI=1.0 to 92.6, P=0.05) were the only independent predictors of death/MI (2 model=32.8, df=3, P<0.001). The risk predicted by the model was well correlated with the observed events (89.2% of correct classification, c-statistic=0.86, Hosmer-Lemeshow goodness-of-fit P=0.693)
A Cox proportional-hazards model was used to evaluate the timing of adverse events at follow-up. Among all of the variables tested, CRP and leukocyte tertile distributions remained the only independent predictors of death (Figure). Similar results were found when we considered the combined end point of death/MI (for CRP tertile 3 versus tertiles 1 and 2: hazard ratio [HR]=5.8, 95% CI=2.0 to 16.6, P=0.001; for leukocyte counts, tertile 3 versus tertiles 1 and 2: HR=5.0, 95% CI=1.9 to 13.7, P=0.002).
Survival at 9-month follow-up by preprocedural levels of CRP (A) and leukocyte counts (B) (multivariate Cox regression analysis). Among all clinical, angiographic, and procedural variables, CRP tertiles (tertile 3 vs tertiles 1 and 2: HR=5.6, 95% CI=1.6 to 19.7, P=0.007) and leukocyte tertiles (tertile 3 versus tertiles 1 and 2: HR=13.7, 95% CI=2.9 to 64.2, P=0.001) were the only independent predictors of death.
Discussion
Although procedural success and short-term outcome after PCI of the ULMCA are favorable, several studies have shown a rather high long-term mortality rate. Depending on the risk profile of the patient, long-term mortality varies from 3.4% in those at low risk to 24.2% in those at high risk.1–5 In our study, the mortality rate was relatively high, but we must emphasize that patients enrolled in our study had a rather high-risk profile initially. On the other hand, the mortality rate in patients who were good candidates for surgery was 7.8%, which is similar to the surgical mortality rate reported in the French Registry, in which good candidates for surgery were defined in the same way as in our study.13 Considering the uncertainty of the clinical outcome after PCI, in the ACC/AHA guidelines for PCI, surgery is the recommended therapy for treatment of ULMCA stenosis, although there is general agreement that PCI is not recommended (class III indication).11
Judicious patient selection, therefore, remains critical for the interventionalist, and accurate stratification is needed to identify who, among these patients, is most likely to benefit from PCI. Age, LVEF, renal function, reference diameter, mitral regurgitation, and the presence of multivessel disease have been traditionally identified as predictors of outcome after PCI of the ULMCA,2–5 but an accurate stratification scheme is still lacking.
Besides traditional clinical and anatomic risk factors, inflammatory markers are now emerging as prognostic factors among patients undergoing PCI. Although several studies have demonstrated an association between preprocedural CRP levels and the risk of death or MI after PCI of the remote coronary tree,8,14 no data are available on long-term clinical outcomes after PCI of the ULMCA.
To our knowledge, this prospective study is the first to provide evidence that elevated pretreatment levels of CRP or of leukocyte count are closely associated with the risk of death and death/MI after PCI of the ULMCA. Assessment of the inflammatory status of patients undergoing PCI of the ULMCA, therefore, provides incremental prognostic information beyond that defined by traditional factors and may be an important element in selecting patients at low risk who may be referred to PCI. In our study, patients with CRP levels <3 mg/L had extremely favorable short- and long-term outcomes, with no major events during the follow-up period. On the other hand, a progressive increase in death or death/MI was observed in relation to CRP tertiles. In the multivariate analysis, patients in tertile 3 (CRP 10.36 mg/L) had an OR of death=5.4 (P=0.028) compared with patients in tertiles 1 and 2. Besides CRP levels, tertiles of leukocyte count showed an even stronger association with death (tertile 3 versus tertiles 1 and 2: OR=14.7, P=0.002).
The association between leukocytosis and the risk of mortality and morbidity in patients with coronary heart disease has been reported in a large number of studies.15 Although generally considered a nonspecific marker of inflammatory processes, leukocytosis is now emerging as a potential factor that may directly contribute to vascular disease. Leukocytes, in fact, may have prothrombotic effects, producing tissue factor,16,17 providing a catalytic surface for thrombin generation, and forming platelet-leukocyte aggregates.18 They may also exert vascular effects by compromising the microvasculature by adhesion, aggregation, and platelet recruitment19; releasing proinflammatory and vasculotoxic factors20; and contributing to intimal hyperplasia after vascular injury.21 Of note, in our study, CRP levels and leukocyte counts were more important determinants of outcome than clinical instability.
Inflammatory risk stratification in patients with ULMCA stenosis is therefore extremely useful and may identify those patients who are most likely to benefit from PCI or those who should undergo close angiographic follow-up if treated with PCI. The link between inflammation and death after PCI of the ULMCA remains to be elucidated. Furthermore, it is not clear whether CRP itself portends an adverse prognosis in patients with ULMCA stenosis, independent of the treatment used, or whether our results apply only to PCI. This issue therefore deserves further investigation.
Several studies have shown that most deaths after PCI of the ULMCA occur within 6 months of the intervention,2,3 and thus it seems reasonable to assume that the main mechanism leading to death after PCI of the ULMCA involves an aggressive form of restenosis, which may manifest as sudden death. In the context of in-stent restenosis, the role of CRP levels is controversial. Some studies have demonstrated that preprocedural levels of CRP predict both clinical7 and angiographic22 restenosis, whereas others have failed to demonstrate this association.23 Therefore, given the inconsistency of the association between CRP and restenosis, it is possible that other mechanisms, such as stent thrombosis, are responsible for abrupt occlusion of the LMCA and consequent sudden death. The hypothesis of stent thrombosis as the leading cause of death in these patients is concordant with previous findings that have shown an association between CRP and death and MI, but not with restenosis,14 and with an experimental animal study that showed increased thrombosis after arterial injury in transgenic mice producing human CRP.24 In that study, transluminal wire injury caused thrombotic occlusion of the femoral artery in 75% of CRP-transgenic mice compared with only 17% in wild-type mice (P<0.05). This hypothesis is also consistent with our findings that among the 11 patients who died, only 3 were still on dual-antiplatelet therapy, whereas 8 had suspended this treatment. This finding raises the possibility that prolonged (1-year) dual-antiplatelet therapy may be beneficial in these patients, but further investigations are needed to confirm these data. On the other hand, we cannot exclude alternative explanations, such as recurrent ischemia due to progression of coronary artery disease25 or primary arrhythmic death.26
Another emerging issue in the treatment of LMCA stenosis is the use of DESs. In our study, among the 42 patients with DESs, 3 patients died (1 after discontinuing antiplatelet therapy 60 days after the procedure). Although not statistically significant, patients with DESs had a 65% relative reduction in mortality compared with patients with BMSs (P=0.18). When considering the combination of death, MI, and TLR, patients with DESs had a significantly lower incidence of events compared with those with BMSs (DES 24% versus BMS 49%, P=0.03). Recent studies in which DESs have been compared with BMSs for the treatment of ULMCA stenoses are consistent with our findings.27,28 More widespread use of DESs in the treatment of ULMCA stenosis might provide significant improvements in the prognosis of patients treated with PCI.
Study Limitations
A limitation of the study is represented by the limited angiographic follow-up (62%). This limitation does not allow us to determine the true angiographic restenosis rate in patients with ULMCA stenosis and its possible relation to inflammatory markers. However, the primary end point of the study was death or death/MI and its relation with inflammatory markers. Even though the 65% relative reduction in mortality found in patients with DESs seems a very appealing result, we must emphasize that the study was not sufficiently powered to assess this issue, and therefore, no definitive conclusions can be drawn.
Acknowledgments
This research was supported by funding from Fondazione Fanti Melloni, Bologna, Italy. We are indebted to Dr Barry S. Coller for his invaluable contribution to the discussion of the study.
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