Author + information
- Received July 25, 2002
- Revision received September 18, 2002
- Accepted September 26, 2002
- Published online June 4, 2003.
- Werner Koch, PhD*,* (, )
- Julinda Mehilli, MD*,
- Nicolas von Beckerath, MD*,
- Corinna Böttiger, MD*,
- Albert Schömig, MD* and
- Adnan Kastrati, MD*
- ↵*Reprint requests and correspondence:
Dr. Werner Koch, Deutsches Herzzentrum München, Experimentelle Kardiologie, Lazarettstrasse 36, D-80636, Munich, Germany.
Objectives We tested the hypothesis that patients with the DD genotype of the angiotensin I–converting enzyme (ACE) gene who are treated with ACE inhibitors are at a higher risk of restenosis after coronary stent placement than patients who do not receive ACE inhibitors.
Background Two recent studies with a limited series of patients carrying the DD genotype suggested an unfavorable impact of the use of ACE inhibitors on the restenotic process after implantation of stents in coronary arteries. Because these findings may question the use of ACE inhibitors after coronary stenting, we examined this important issue in a large series of patients.
Methods We determined the ACE gene I/D genotype of 2,222 consecutive patients with symptomatic coronary artery disease who underwent stent implantation. The patients with the DD genotype (n = 612) constituted the study population. The primary end point was in-stent restenosis, which was assessed as angiographic restenosis (≥50% diameter stenosis at six-month follow-up) and clinical restenosis (need for target vessel revascularization due to symptoms or signs of ischemia in the presence of angiographic restenosis over one year after the intervention).
Results Of the 612 patients with the DD genotype, 403 (65.8%) were treated with ACE inhibitors and 209 (34.2%) did not receive ACE inhibitors. The angiographic and clinical restenosis rates were not significantly different between the group treated with ACE inhibitors and the group not receiving ACE inhibitors (p = 0.55). Continuous measures of restenosis, minimal lumen diameter, diameter stenosis, late lumen loss, and loss index were also similar in both groups (p ≥ 0.55). In addition, one-year survival free of myocardial infarction was not significantly different between the two groups (p = 0.27).
Conclusions In contrast to previous reports, our study provides evidence that patients carrying the DD genotype are not exposed to an increased risk of restenosis after stent placement when treated with ACE inhibitors.
Elevated levels of angiotensin II have been implicated in the development of neointimal hyperplasia after vascular injury (1). The DD genotype of the angiotensin I–converting enzyme (ACE) gene is associated with higher angiotensin II levels (2,3), suggesting that carriers of the DD genotype might benefit from treatment with ACE inhibitors after stent placement in coronary arteries. However, the results of recent trials with limited series of patients with the DD genotype unexpectedly indicated an unfavorable impact of ACE inhibition on the restenotic process (4,5). These findings may question the use of ACE inhibitors after coronary stent placement in patients of the DD genotype and leave physicians with a relevant problem, because the DD genotype is common and both stenting and ACE inhibitors are very important therapy options for patients with coronary artery disease. To address this issue, we tested, in a much larger series of patients, for the existence of an association between the use of ACE inhibitors and adverse angiographic and clinical outcomes after coronary stenting in patients carrying the DD genotype.
We determined the I/D genotype of 2,222 consecutive white patients with symptomatic coronary artery disease who underwent coronary stent implantation at Deutsches Herzzentrum München and 1. Medizinische Klinik rechts der Isar der Technischen Universität München. The frequencies of the genotypes DD, ID, and II were 612 (27.5%), 1,144 (51.5%), and 466 (21.0%), respectively. This distribution was not significantly different from the Hardy-Weinberg equilibrium (p = 0.27), a finding which serves as an indication of genetic balance. The 612 patients with the DD genotype constituted the population examined in this study. Stent placement protocols and post-stenting therapy have been previously described (6,7). Post-procedural pharmacologic therapy consisted of aspirin (100 mg twice daily, indefinitely) and ticlopidine (250 mg twice daily for four weeks). Patients who were considered at a higher risk for stent thrombosis received adjunctive therapy with the glycoprotein IIb/IIIa blocker abciximab, which was given as a bolus injection during stent placement and as a 12-h continuous infusion thereafter. Treatment with an ACE inhibitor was at the discretion of the attending physicians, who were unaware of the ACE genotype. The prescribed ACE inhibitors were enalapril (67.4%), captopril (23.9%), ramipril (5.0%), and others (3.7%). All patients were scheduled for angiographic follow-up at six months. They gave written, informed consent for the intervention, follow-up angiography, and genotype determination. The study protocol conformed to the Declaration of Helsinki and was approved by the institutional Ethics Committee.
Lesion morphology was classified according to the modified American College of Cardiology/American Heart Association grading system as type A, B1, B2, or C (8), and lesion types B2 and C were considered complex lesions. Angiograms were recorded just before and immediately after the intervention and at follow-up. Matched views of the target lesions were selected for quantitative computer-assisted off-line analysis of the angiograms, using the automated edge-detection system CMS (Medis Medical Imaging Systems, Nuenen, Netherlands). The parameters measured were lesion length, reference diameter, minimal lumen diameter (MLD), diameter stenosis, and diameter of the maximally inflated balloon during stent placement. Acute lumen gain was defined as the difference between the final post-stenting MLD and the MLD before the intervention. Late lumen loss was calculated as the difference between the final post-stenting MLD and the MLD measured at the time of follow-up angiography. The loss index was calculated as the ratio of late lumen loss to acute lumen gain. Quantitative analysis of angiograms was performed by operators who were not involved in the stenting procedure and were unaware of the genetic data.
Study end points and definitions
The primary end point of the study was restenosis. Two definitions of restenosis were assessed: the incidence of diameter stenosis ≥50% at six-month follow-up angiography (angiographic restenosis) and the need for target vessel revascularization (TVR) (percutaneous transluminal coronary angiography or aortocoronary bypass grafting) due to symptoms or signs of ischemia in the presence of angiographic restenosis at the stented site over one year after stent placement (clinical restenosis). Other major adverse events evaluated were death from any cause and nonfatal myocardial infarction (MI). The diagnosis of acute MI was based on the criteria applied in the Evaluation of Platelet IIb/IIIa Inhibitor for STENTing (EPISTENT) trial: the presence of new pathologic Q waves or a value of creatine kinase or its MB isoenzyme at least three times greater than the upper limit (9). Creatine kinase levels were determined systematically over 48 h after the stenting procedure. The follow-up protocol included a phone contact or a medical visit at the outpatient clinic at 30 days and between 9 and 15 months after stent placement and a control angiogram at six months. Clinical events were assessed on the basis of the information provided by hospital readmission records, the referring physician, or a phone interview with the patient. For all patients who presented with cardiac symptoms during the interview, at least one clinical and electrocardiographic evaluation was performed at the outpatient clinic or by the referring physician.
Determination of the ACE I/D genotype
Genomic DNA was extracted from peripheral blood leukocytes with a commercially available kit (Qiagen, Hilden, Germany). A portion of intron 16 and a portion of exon 17 of the ACE gene were amplified by polymerase chain reaction, essentially as reported by Rigat et al. (10). The presence (allele I) or absence (allele D) of the 288-base pair (bp) alurepeat sequence was determined by evaluating the size of the DNA products after electrophoretic separation in agarose gels: 479 bp for allele I and 191 bp for allele D. The possibility of mistyping ID heterozygotes as DD homozygotes due to the preferential amplification of the smaller D allele (11)was addressed. All samples typed as DD homozygotes were subjected to a second, independent polymerase chain reaction with a primer pair that permits amplification only in the presence of the I allele but not the D allele; this was done using the method described by Lindpaintner et al. (12). The operators who performed the I/D genotype determination were unaware of the patients’ clinical and angiographic characteristics.
The analyses consisted of comparisons between patients with the DD genotype receiving ACE inhibitors and patients with the DD genotype not treated with ACE inhibitors. The sample size was chosen to provide the analysis with an 80% power, at an alpha level of significance of <0.05, to detect a 40% difference of restenosis rates in patients treated versus patients not treated with ACE inhibitors. Discrete variables are expressed as counts or percentages and compared using the chi-square or Fisher exact test, as appropriate. Continuous variables are expressed as mean value ± SD and compared using the unpaired, two-sided ttest. The Kaplan-Meier method and log-rank test were used to compare one-year event-free survival between the groups. Statistical analyses were performed using S-Plus software (Mathsoft Inc., Seattle, Washington). Correspondence of the I/D genotype distribution with the Hardy-Weinberg equilibrium was tested with the Hardy-Weinberg Diagnostics program, version 1.beta, designed by A. Rogatko and M. Slifker (Fox Chase Cancer Center; http://www.fccc.edu/users/rogatko/hwdiag). A p value of <0.05 was considered statistically significant.
Of the 612 subjects with the DD genotype, 403 (65.8%) were treated with ACE inhibitors and 209 (34.2%) did not receive ACE inhibitors. Baseline, lesion-related, angiographic, and procedural parameters at the time of the intervention were not significantly different between the two groups of patients with the DD genotype (Table 1). Various types of slotted-tube stents were used. Each stent type was equally distributed between the patient groups, with the exception of the Palmaz-Schatz stent (Johnson & Johnson Interventional Systems, Warren, New Jersey), which was implanted in 10.4% of the patients who were treated with ACE inhibitors and in 26.8% of the patients who did not receive ACE inhibitors (p < 0.001). The occurrence of major events during the first 30 days after stent placement was not significantly different between the two groups, but there was a trend in favor of the patients treated with ACE inhibitors (Table 2).
Restenosis after stenting
Follow-up angiography of coronary arteries was done in 495 of the patients (80.9%) with the DD genotype, 326 of whom belonged to the group treated with ACE inhibitors and 169 to the group not treated with ACE inhibitors. Among these patients, the angiographic restenosis rate was 34.0% in the group treated with ACE inhibitors and 31.4% in the group not receiving ACE inhibitors (p = 0.55) (Table 3, Fig. 1). Continuous measures of restenosis, MLD, diameter stenosis, late lumen loss, and loss index were also similar in both groups (p ≥ 0.55) (Table 3). Among the 612 patients with the DD genotype, the need for TVR due to symptoms or signs of ischemia in the presence of angiographic restenosis at the stented site (clinical restenosis) was 18.1% in the group treated with ACE inhibitors and 20.1% in the group without ACE inhibitors over one year after stent placement (p = 0.55) (Fig. 1).
For comparison, we report here the incidence of angiographic restenosis observed among patients with ACE genotypes other than DD who were not included in this analysis: in the group with genotype ID, the rate was 35.4% in patients who received ACE inhibitors and 34.6% in patients who did not receive ACE inhibitors. In the group with genotype II, the rate was 32.9% in patients who were treated with ACE inhibitors and 34.2% in patients who were not treated with ACE inhibitors.
Analysis of secondary end points
Complete clinical follow-up data were available for all patients with the DD genotype, irrespective of the presence or absence of follow-up angiography. Event-free survival one year after stent placement (survival free of MI and TVR) was 76.7% in patients with ACE inhibitor and 71.8% in patients without ACE inhibitor (p = 0.18). One-year survival free of MI was 95.8% in the group treated with ACE inhibitors and 93.8% in the group without ACE inhibitors (p = 0.27). Overall survival one year after stenting was 98.3% in patients treated with ACE inhibitors and 97.6% in patients not treated with ACE inhibitors (p = 0.58).
Neointimal hyperplasia, rather than lumen renarrowing by arterial remodeling, is prevailing in the restenotic process after placement of stents in coronary arteries (13). The renin-angiotensin-aldosterone system has been implicated in the pathogenesis of neointimal hyperplasia, and a role for angiotensin II in the migration and proliferation of vascular smooth muscle cells in restenotic lesions has been proposed (1). Subjects with the DD genotype of the ACE gene exhibit significantly higher angiotensin II levels and ACE activities as compared with individuals with the II or ID genotype (2,3), suggesting a higher risk of restenosis for carriers of the DD genotype. The potential influence of the I/D genotype on restenosis after percutaneous coronary interventions has been the focus of several association studies (5,14–16). Initial reports suggested an augmented risk of in-stent restenosis among carriers of the DD genotype (14,15), a finding that could not be confirmed in subsequent studies (5,16). Based on these observations, one might propose that the use of ACE inhibitors has a beneficial effect on the development of in-stent restenosis in patients with the DD genotype. However, an unexpected impact of ACE inhibitors on restenosis has been observed in groups of these patients (4,5). Performing a placebo-controlled trial, Meurice et al. (4)found an unfavorable effect of the ACE inhibitor quinapril on the restenotic process after coronary stent implantation in patients with the DD genotype, as indicated by a significantly higher late loss of the lumen diameter and a higher loss index, although the diameter stenosis and incidence of restenosis were not significantly different. In a post hoc analysis of patients with the DD genotype who were treated or not treated with ACE inhibitors or angiotensin II receptor antagonists, Jørgensen et al. (5)found that the in-stent restenosis rate and continuous parameters of restenosis were elevated in the group of treated subjects. In contrast to the results of these studies (4,5), we observed that patients with the DD genotype of the ACE gene who received ACE inhibitors were not at a higher risk of restenosis after stenting of coronary arteries than patients who were not treated with ACE inhibitors. Our two patient groups were well balanced in their baseline, lesion-related, angiographic, and procedural characteristics at the time of the intervention. We do not know the reasons for the divergent findings between our study and the previous trials (4,5), although differences in patients’ baseline parameters and population sizes offer possible explanations. Our analysis included complete angiographic data of relatively high numbers of patients with the DD genotype who were treated (n = 326) and not treated (n = 169) with ACE inhibitors, whereas the findings of Meurice et al. (4)and Jørgensen et al. (5)were based on much lower numbers of treated (n = 38 and n = 15, respectively) and untreated patients (n = 41 and n = 89, respectively) with the DD genotype. In addition, we included a consecutive series of patients with stent implants, thereby avoiding the exclusion criteria used in the previous studies (4,5).
We must acknowledge two limitations of the study. First, although this retrospective analysis involved a large number of patients who carried the DD genotype and underwent coronary stenting, the treatment and control groups were not the product of a randomized study design. However, because of the frequent use of ACE inhibitors among patients with coronary artery disease, it is difficult to expect that a placebo-controlled, randomized study with a large sample size will be conducted in the future. Second, we did not control for the type of ACE inhibitor therapy, and our patients received various ACE inhibitor drugs. We cannot exclude that this may have influenced the results of the present study, although a drug-specific rather than a class-specific interaction with the DD genotype is difficult to be conceived.
Our results indicate that ACE inhibitors have no influence, neither beneficial nor detrimental, on angiographic and clinical indexes of restenosis in patients of the DD genotype. Therefore, we conclude that in the setting of coronary artery stenting, it is safe to treat patients who have the DD genotype with ACE inhibitors.
- angiotensin I–converting enzyme
- myocardial infarction
- minimal lumen diameter
- target vessel revascularization
- Received July 25, 2002.
- Revision received September 18, 2002.
- Accepted September 26, 2002.
- American College of Cardiology Foundation
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