CLINICAL STUDIES
Lipoprotein(a) and coronary thrombosis and restenosis after stent placement
Anne Wehinger, MD*,
Adnan Kastrati, MD*,
Shpend Elezi, MD*,
Hannsjörg Baum, MD ,
Siegmund Braun, MD*,
Franz-Josef Neumann, MD* and
Albert Schömig, MD*
* Deutsches Herzzentrum and 1. Medizinische Klinik rechts der Isar, Technische Universität München, Munich, Germany
Institut für Klinische Chemie und Pathochemie, Technische Universität München, Munich, Germany
Manuscript received August 5, 1998;
revised manuscript received October 20, 1998,
accepted December 11, 1998.
Reprint requests and correspondence: Dr. Adnan Kastrati, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany
kastrati{at}dhm.mhn.de
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Abstract
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OBJECTIVES
The objective of this prospective study was to evaluate the relation between high lipoprotein(a) levels and thrombotic and restenotic events after coronary stent implantation.
BACKGROUND
Lipoprotein(a) may promote atherogenesis, coronary thrombosis and restenosis after balloon angioplasty, but the clinical significance remains unclear.
METHODS
The study included 2,223 consecutive patients with successful coronary stent placement. According to the serum level of lipoprotein(a), patients were divided in two groups: 457 patients of the highest quintile formed the high lipoprotein(a) group, and 1,766 patients of the lower four quintiles formed the low lipoprotein(a) group. Primary end points were the incidence of angiographic restenosis at six months and the event-free survival at one year. Secondary end point was the incidence of angiographic stent occlusion.
RESULTS
Early stent occlusion occurred in four of the 457 patients (0.9%) with high and 37 of the 1,766 patients (2.1%) with low lipoprotein(a) levels, odds ratio of 0.41 (95% confidence interval, 0.15 to 1.16). Angiographic restenosis occurred in 173 of the 523 lesions (33.2%) in the high lipoprotein(a) group and 636 of the 1,943 lesions (32.7%) in the low lipoprotein(a) group, odds ratio of 1.02 (0.83 to 1.25). The probability of event-free survival was 73.0% in the high lipoprotein(a) group and 74.8% in the low lipoprotein(a) group (p = 0.45). On the basis of the findings in the low lipoprotein(a) group, the power of this study to detect a 25% increase in the incidence of restenosis and adverse events in the group with elevated lipoprotein(a) was 90% and 75%, respectively.
CONCLUSIONS
Elevated lipoprotein(a) levels did not influence the one-year clinical and angiographic outcome after stent placement. Thrombotic events and measures of restenosis were not adversely affected by the presence of high lipoprotein(a) levels.
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Abbreviations and Acronyms
| | apo(a) | = apolipoprotein(a) | | LDL | = low density lipoprotein | | Lp(a) | = lipoprotein(a) | | MLD | = minimal lumen diameter | | RD | = reference diameter | | TGF-beta | = transforming growth factor-beta |
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Lipoprotein(a) [Lp(a)], an atherogenic macromolecular complex described about 35 years ago (1), contains apolipoprotein(a) [apo(a)], which is a structural homologue of plasminogen and competes with it for binding sites (2–6). It also acts by increasing plasminogen activator inhibitor-1 expression, thus, interfering with endothelial cell and circulating plasmin generation (7). In addition, Lp(a) stimulates proliferation of vascular smooth muscle cells by inhibiting the conversion of latent transforming growth factor-beta (TGF-beta) to active TGF-beta by plasmin (8). Hence, Lp(a) may promote coronary atherogenesis, thrombosis and restenosis (9). However, the clinical significance of the proposed actions of Lp(a) is still unclear (10,11).
Intracoronary stent placement is a widely accepted treatment for coronary artery disease and may provide a better setting for assessing the clinical significance of elevated serum levels of Lp(a) for two reasons. First, despite the efficacy of the antiplatelet drugs currently used as postprocedural therapy (12), the stent remains a thrombogenic device, and second, there are substantial differences in the mechanisms of restenosis between conventional coronary angioplasty and stenting. Whereas arterial remodeling is the main contributor to the lumen renarrowing after percutaneous transluminal coronary angioplasty, myointimal hyperplasia is almost the exclusive mechanism of restenosis after stenting (13). The pathophysiologic processes that lead to the stimulation of smooth muscle cell growth are not well understood, but platelet activation and formation of mural thrombus are thought to play a key role in promoting cell proliferation (14). Thus, coronary stenting is followed by a particularly activated state of those mechanisms responsible for both thrombus and neointima formation, and the clinical response to high levels of Lp(a) may be more readily detectable under these conditions.
The objective of this prospective study therefore was to assess the influence of Lp(a) serum levels on the clinical and angiographic outcome after coronary stent placement.
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Methods
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This study was initiated in May 1993 and, until June 1997, enrolled 2,223 consecutive patients who were successfully treated with intracoronary stent placement due to symptomatic coronary artery disease. Only patients who received stenting in the setting of acute myocardial infarction were excluded from the study.
Before the intervention, all patients received heparin (15,000 U) and aspirin (500 mg) as single intravenous bolus. Stent implantation of various slotted-tube stents (44% Palmaz-Schatz stents, Johnson & Johnson) was performed as previously described (12). Short 7-mm or articulated 15-mm stents were hand-crimped on conventional angioplasty balloons and delivered under fluoroscopic guidance. Abciximab was administered in patients who were considered at higher risk for ischemic complications after the procedure. The decision was left at the operator’s discretion. After sheath removal and application of a pressure bandage, all patients received intravenous heparin for 12 h. All patients were given aspirin (100 mg b.i.d. p.o., indefinitely). Subsequent therapy consisted of either oral anticoagulant agents (target International Normalized Ratio 3.5 to 4.5) or ticlopidine (250 mg b.i.d. p.o.) for 4 weeks after stent implantation (12).
Lipoprotein analysis.
Blood samples were drawn from an arm vein before stenting procedure from patients in the fasting state. After centrifugation, the serum was either immediately analyzed or stored at +4°C and analyzed within 24 h from blood withdrawal. Assessment of Lp(a) concentration was performed using a latex-enhanced immunonephelometric assay (Behring Diagnostics GmbH, Marburg, Germany). This method is based on the latex-enhanced particle agglutination technology. The antibody is a rabbit polyclonal antihuman Lp(a) antiserum, which is conjugated to latex and does not cross-react with plasminogen. The method has yielded intra- and interassay coefficients of variation between 2.2% and 7.1% and between 3.4% and 8.6%, respectively and correlated very well (correlation coefficient = 0.93, slope = 0.98 and y-intercept 0.16 mg/dl) with a commonly used immunoenzymometric method (15). The correlation was even closer in patients with triglycerides level under 1,000 mg/dl (15). Another study reported even better data on the validity of the nephelometric method: intraassay and day-to-day coefficients of variation of 2%, and 4.5%, respectively and an excellent correlation with electroimmunodiffusion (correlation coefficient = 0.98) (16).
Angiographic assessment.
Quantitative analysis was performed off-line by operators not involved in the intervention before and immediately after stent placement as well as at repeat angiography at 6 months using the automated edge-detection system CMS (Medis Medical Imaging Systems, Nuenen, The Netherlands). Identical projections of the target lesion were used for all assessed angiograms. Minimal lumen diameter (MLD), reference diameter (RD), diameter stenosis and diameter of the maximally inflated balloon were obtained with this analysis system. Balloon-to-vessel ratio was calculated as diameter of the inflated balloon divided by the RD of the coronary artery and late lumen loss as the difference between the final poststenting MLD and the MLD measured at six-month repeat angiography.
Definitions and study end points.
Patients were divided into quintiles according to their serum Lp(a) levels. The highest quintile was defined as the group with high Lp(a) levels, and the lower four quintiles were combined to form the group with low Lp(a) levels.
The influence of high Lp(a) levels was assessed in terms of both clinical and angiographic outcome. Primary angiographic end point was binary restenosis ( 50% diameter stenosis) at 6-month follow-up. Primary clinical end point of the study was event-free survival at 1 year. All major adverse cardiac events such as cardiac- or procedure-related death, myocardial infarction and target lesion revascularization by angioplasty or aortocoronary bypass surgery were monitored during the entire follow-up period. The assessment was made on the basis of the information provided by hospital readmission records, referring physician or phone contact. For all those patients who revealed cardiac symptoms during phone contact, at least a clinical and electrocardiographic checkup was performed at the outpatient clinic or by the referring physician. Second, angiographically documented stent vessel occlusion during the first 30 days after the procedure was also assessed. Control angiography during the first 30 days was always performed when the patient presented symptoms or signs of ischemia.
Statistical analysis.
Discrete variables are expressed as counts (%) and compared with chi-square test. Continuous variables are expressed as mean ± SD and compared by means of unpaired, two-sided t test or correlated by means of linear regression analysis. Event-free survival curves for cardiac events were constructed by means of the Kaplan–Meier method. Survival probabilities of the two groups were compared with log-rank test. The effect of Lp(a) levels was also assessed by multivariate methods adjusting for several confounding variables using Cox proportional hazards regression model for the primary clinical end point and logistic regression model for the primary angiographic end point. The confounding variables entered into the models were age, gender, the presence or absence of cardiovascular risk factors, unstable angina, multivessel disease, reduced left ventricular function, complex lesions or chronic occlusions, the vessel where the lesion was located, lesion length, vessel size, MLD before and after the intervention, balloon pressure and balloon-to-vessel ratio, the number of stents implanted as well as the type of postprocedural therapy. All statistical analyses were performed using S-Plus software (Mathsoft, Inc., Seattle, Washington). Statistical significance was assumed for p values <0.05.
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Results
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The median of Lp(a) level for the entire population was 14.4 (interquartile range, 7.2 to 47.2) mg/dl. The cutoff Lp(a) levels that served to define the quintiles were 5.6, 10.4, 23.2 and 56.5 mg/dl. Figure 1 presents median and interquartile range of Lp(a) for patients in each quintile. According to the cutoff value defining the upper quintile (56 mg/dl), 457 patients belonged to the high Lp(a) group and 1,766 patients to the low Lp(a) group. The median (interquartile range) of Lp(a) level was 80.8 mg/dl (68.0 to 100.4 mg/dl) in the high Lp(a) group and 10.4 mg/dl (5.6 to 22.4 mg/dl) in the low Lp(a) group (p < 0.001). Table 1 shows the characteristics of the patients. The only significant differences between the two groups concerned gender distribution and cholesterol levels; in the group with high Lp(a) there were significantly more women (28.2% vs. 21.9%, p = 0.004) and patients with hypercholesterolemia (42.7% vs. 35.4%, p = 0.004). Indeed, patients with high Lp(a) level had a significantly higher total and low density lipoprotein (LDL) cholesterol levels than their counterparts. None of the patients had a triglyceride level above 1,000 mg/dl. There were no significant differences as to the antidiabetic, lipid-lowering and postprocedural antithrombotic treatment received. None of the patients was treated with niacin or neomycin. Table 2 shows no significant differences between the two groups with respect to lesion- and procedure-related characteristics.
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Figure 1 Box plot showing the median and interquartile range of lipoprotein(a) levels for patients belonging to each quintile.
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Angiographic outcome.
High Lp(a) levels were not associated with an increased risk of coronary stent thrombosis. Early stent occlusion occurred in four of the 457 patients (0.9%) with high and 37 of the 1,766 patients (2.1%) with low lipoprotein(a) levels, odds ratio of 0.41 (95% confidence interval, 0.15 to 1.16). Table 3 presents also the occlusion rates for each quintile.
Six-month angiography was performed after 190 ± 74 days in 84% of the patients. Angiographic data at six months (Table 4) did not differ significantly between the two groups. Restenosis occurred in 173 of the 523 lesions (33.2%) in the high lipoprotein(a) group and 636 of the 1,943 lesions (32.7%) in the low lipoprotein(a) group, odds ratio of 1.02 (0.83 to 1.25). The incidence of total occlusions among patients with restenosis was also comparable. Table 3 also presents the restenosis rates for each quintile. In addition, the actual levels of Lp(a) correlated neither with MLD (R = 0.01, p = 0.60) nor with late lumen loss (R = 0.01, p = 0.57) at follow-up. As shown by the overlapping curves in Figure 2, diameter stenosis did not differ between the two groups either before and immediately after stent placement or at 6-month angiography. Moreover, no influence of high Lp(a) on restenosis could be detected when patients on antidiabetic or statin therapy and those who periprocedurally received abciximab or anticoagulant agents were excluded from the analysis (Table 5, left side). Even after adjusting for the potential influence of other patient- and lesion-related factors (see Methods) there was no link between the presence of high Lp(a) levels and angiographic restenosis (odds ratio of 1.03 [95% confidence interval, 0.83 to 1.28]). The multivariate analysis was also done using total and LDL cholesterol levels as continuous variables in separate models. These analyses yielded similar results as above, and no interaction effect on restenosis was observed between Lp(a) and either total or LDL cholesterol.
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Figure 2 Plot of the cumulative distribution of diameter stenosis before the procedure, immediately after stent implantation and at 6-month angiographic follow-up. Lp(a) = lipoprotein(a).
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Table 5 Primary Angiographic and Clinical End Point Analysis After Controlling for the Effect of Concomitant Therapy*
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Clinical outcome.
There was no significant difference in 1-year survival between the groups (Fig. 3). The probability of event-free survival was 73.0% for the group with high and 74.8% for the group with low Lp(a) levels (p = 0.45, Fig. 3A). The probability of 1-year survival free of myocardial infarction was 96.5% for patients with high Lp(a) levels and 96.8% for patients with low Lp(a) levels (p = 0.74, Fig. 3B). Death due to noncardiac causes occurred in 0.9% of the patients with high Lp(a) levels and 0.6% of those with low Lp(a) levels (p = 0.75). Repeat angioplasty at the target lesion was performed in 22.8% of the patients in the high Lp(a) group and 22.4% of those in the low Lp(a) group (p = 0.89), odds ratio of 1.02 (0.80 to 1.30). More specifically, it was performed in 21.6, 20.3, 23.8, 23.8 and 22.8% in the first, second, third, fourth and fifth quintile, respectively (p = 0.70). Angioplasty in nontarget lesions was carried out in 9.2% of the patients with high Lp(a) levels and 9.6% of those with low Lp(a) levels (p = 0.78). Moreover, no influence of high Lp(a) on event-free survival could be detected when patients on antidiabetic or statin therapy, and those who periprocedurally received abciximab or anticoagulant agents were excluded from the analysis (Table 5, right side). Even after adjusting for the potential influence of other patient- and lesion-related factors (see Methods) by means of Cox analysis there was no link between the presence of high Lp(a) levels and an adverse clinical outcome at one year (hazard ratio of 1.04 [95% confidence interval, 0.85 to 1.28]). Cox analysis was also done using total and LDL cholesterol levels as continuous variables in separate models. These analyses yielded similar results as above, and no interaction effect on 1-year outcome was observed between Lp(a) and either total or LDL cholesterol.
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Figure 3 Kaplan–Meier curves of 1-year survival free of any cardiac event (A) and free of myocardial infarction (B) for patients with high and low lipoprotein(a) [Lp(a)] levels.
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Discussion
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This study assessed the clinical significance of elevated Lp(a) serum levels after coronary stent placement. Our hypothesis was that vessel wall injury during the procedure and the presence of the stent would be accompanied by a greater tendency to thrombosis and smooth muscle cell growth in patients with increased Lp(a) concentrations in blood. We tested this hypothesis prospectively in a large cohort of 2,223 consecutive patients with a high rate of reangiography. Early stent thrombosis, late restenosis and the incidence of major adverse cardiac events were used as outcome measures to reflect the potential prothrombotic and prorestenotic actions of Lp(a). This study demonstrated strikingly similar and consistent results in the two groups with high and low Lp(a) levels for all study end points, suggesting that elevated levels of this lipoprotein particle exert no significant clinical influence after the intervention. Based on a one-year cardiac event rate of 25% and restenosis rate of 33% in the group with low Lp(a), the power of this study to detect a 25% increase in the incidence of these outcomes in the group with elevated Lp(a) is 75% and 90%, respectively.
Baseline characteristics.
The median value of Lp(a) concentration for the entire population in this study was 14.4 mg/dl. The Lp(a) levels found here are similar to those reported by the Quebec Cardiovascular Study in French Canadian men (17). Other studies encompassing Caucasian populations have reported a median value of 10 mg/dl in subjects free of cardiovascular disease (18,19) and of 7 to 29 mg/dl in patients with coronary artery disease (20–23). Both the median and the cutoff value for the upper quintile in our study correspond very well to the respective values reported recently (23).
Except for the proportion of women and the incidence of hypercholesterolemia, all other baseline characteristics, including angiographic and procedural data, were comparable between the two groups. Women contributed with a higher number to the group with increased Lp(a) levels. Although it is known that postmenopausal women have higher Lp(a) concentrations (18), it would not be expected that their major presence would have minimized the risk in the group of patients with high Lp(a) levels. The difference in cholesterol levels reflects only a major contribution of elevated Lp(a) concentration. Nevertheless, even after adjusting for the potential influence of baseline characteristics, the multivariate analysis did not show any association between Lp(a) concentration and outcome after stenting.
Lipoprotein(a) and the risk of stent thrombosis.
Patients with high Lp(a) levels did not show any greater risk for stent vessel occlusion during the first 30 days after the procedure as compared with patients with low Lp(a). There are no previous data on the relation between Lp(a) levels and the risk of thrombotic occlusion after coronary interventions. The suggested prothrombotic role of Lp(a) has prompted several investigators to analyze the relation between its plasma concentration and the risk of myocardial infarction. The conflicting results reported by these studies (19,23) are difficult to interpret. This issue is further complicated by the finding of transient increases of Lp(a) levels during the acute phase of myocardial infarction (24), which does not enable reaching a conclusion about a causative role of Lp(a). To avoid this bias, we excluded patients who underwent stenting in the setting of acute myocardial infarction. The reason why we could not detect any significant clinical prothrombotic influence of high Lp(a) levels after stenting is unclear. Previous work from our institution has demonstrated the pivotal role of platelet activation in the coagulation cascade triggered by stent implantation (25). Most of our patients were treated with a combined antiplatelet therapy that has been shown to reduce the thrombotic events after stent implantation (12).
Lipoprotein(a) and the risk of restenosis.
Patients with high Lp(a) levels did not present a major risk for restenosis after coronary stent placement. The restenosis rate was almost identical. Consistent with this, the 1-year clinical outcome was almost identical, with a probability of event-free survival of 73.0% and 74.8% in the group with high and low Lp(a), respectively. The similar restenosis rates also explain the comparable need for repeat angioplasty at the target lesion. Multivariate analysis showed neither an independent effect nor any interaction between Lp(a) and other lipids with respect to restenosis and clinical outcome in general. Studies with conventional balloon angioplasty on this subject did not lead to concordant results. Lipoprotein(a) was associated with higher restenosis rate in some (20,22) but not in other studies (21,26). The limited number of patients (ranging from 62 to 240) is a major drawback of these studies. On the other hand, most of the published data support the proatherogenic role of Lp(a) by demonstrating a higher risk of coronary artery disease in cohorts with elevated Lp(a) concentrations (21,27–33). Even when no independent role as a risk factor was found, Lp(a) seemed to increase the risk associated with other lipid risk factors (17). The lack of association of Lp(a) levels with restenosis after stenting in our study is an additional example of the differences existing between this process and atherosclerosis (34). It may not be considered as in contradiction with the proatherogenic role of Lp(a). Restenosis after coronary catheter-based interventions is a time-limited phenomenon that is generally completed within the first six months after the intervention (35,36). The one-year follow-up of this study is sufficiently long to assess influences on restenosis. Longer periods would have been necessary to investigate the potential role of Lp(a) on the progression of atherosclerosis.
Limitations of the study.
The limitation that our study shares with many previous studies on the role of Lp(a) is the lack of standardized assays for Lp(a) level determination due mainly to apo(a) polymorphism (37). In addition, important ethnic variations in Lp(a) levels have been recognized (5). Both these considerations render very difficult the assignment of robust cutoff points for defining the group with high Lp(a) levels. In an attempt to circumvent these difficulties, all outcome measures in the present study were analyzed after dividing the population into five subgroups on the basis of Lp(a) levels defining the quintiles, and particular attention was paid to the 20% of the population with the highest Lp(a) values.
It has recently been suggested that the size of apo(a) may also play a role in the risk for developing coronary artery disease (32). We have no data on this subject, and further studies are warranted to assess whether the risk for thrombotic or restenotic complications is associated with certain apo(a) isoforms rather than total serum level of Lp(a).
Another limitation may arise from the antithrombotic therapy that is an integral part of the postprocedural care for patients undergoing percutaneous coronary interventions. This may have blunted the potential negative influence of high Lp(a), especially for our secondary end point of stent thrombosis. The potential bias introduced by concomitant antithrombotic therapy is unlikely to be significant for our primary end points for two reasons. First, the antithrombotic agents were evenly distributed between the subgroups with different Lp(a) levels, and no difference in outcome between high and low Lp(a) patients could be detected irrespective of the type of antithrombotic therapy. Second, most of our patients were treated with aspirin and ticlopidine, for which there is no clinical evidence of an influence on restenosis.
Conclusions.
Elevated Lp(a) levels were not associated with an adverse one-year clinical and angiographic outcome after stent placement. Both thrombotic events and all measures of restenosis were not influenced by the presence of high serum Lp(a) concentration. These results suggest that Lp(a) may have limited clinical relevance in patients who receive intracoronary stents and are routinely treated with antithrombotic therapy after the procedure.
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M. N. Zairis, J. A. Ambrose, S. J. Manousakis, A. S. Stefanidis, O. A. Papadaki, H. I. Bilianou, M. C. DeVoe, C. N. Fakiolas, E. G. Pissimissis, C. D. Olympios, et al.
The impact of plasma levels of C-reactive protein, lipoprotein (a) and homocysteine on the long-term prognosis after successful coronary stenting: The global evaluation of new events and restenosis after stent implantation study
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[Abstract]
[Full Text]
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P.J. de Feyter
Editorials: Lipids and coronary restenosis: an elusive link
Eur. Heart J.,
October 1, 1999;
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