CLINICAL RESEARCH: CLINICAL TRIAL
A Randomized, Double-Blind, Placebo-Controlled Trial on Restenosis Prevention by the Receptor Tyrosine Kinase Inhibitor Imatinib
Dietlind Zohlnhöfer, MD*,*,
Jörg Hausleiter, MD*,
Adnan Kastrati, MD*,
Julinda Mehilli, MD*,
Christoph Goos*,
Helmut Schühlen, MD*,
Jürgen Pache, MD*,
Gisela Pogatsa-Murray, MD*,
Uwe Heemann, MD ,
Josef Dirschinger, MD and
Albert Schömig, MD*
* Deutsches Herzzentrum München, Munich, Germany; Klinik an der Technische Universität München, Munich, Germany
2.Medizinische Klinik des Klinikum rechts der Isar, Technische Universität, Munich, Germany
1.Medizinische Klinik des Klinikums rechts der Isar, Technische Universität, Munich, Germany
Manuscript received May 10, 2005;
revised manuscript received July 13, 2005,
accepted July 18, 2005.
* Reprint requests and correspondence: Dr. Dietlind Zohlnhöfer, Deutsches Herzzentrum, Lazarettstrasse 36, 80636 München, Germany. (Email: zohlnhoefer{at}dhm.mhn.de).
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Abstract
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OBJECTIVES: The aim of the present double-blind, placebo-controlled study was to evaluate the efficacy of a systemic imatinib treatment, a potent platelet-derived growth factor (PDGF) receptor kinase inhibitor, for the prevention of recurrent restenosis in patients with in-stent restenosis (ISR).
BACKGROUND: Neointima proliferation after stent placement has been associated with the effect of potent mitogenes such as PDGF, and their inhibition has resulted in reduction of neointima formation in experimental models.
METHODS: A total of 180 patients with either symptoms or a positive stress test in the presence of angiographically signficiant ISR were randomly assigned to two treatment arms: imatinib treatment or placebo. Patients received imatinib (600 mg/day) for 10 days starting 2 days before repeat intervention. Angiographic restenosis at follow-up angiography was the primary end point of the study.
RESULTS: Repeat angiography was performed in 160 of 180 patients (88.9%). The combined rate of death or MI at one year was 1.0% in patients randomized to either group (p = 0.67). Compared with the placebo group, imatinib treatment did not affect the angiographic restenosis rate (38.8% with imatinib vs. 41.3% with placebo; p = 0.75). Similarily, the need for target lesion revascularization did not differ between both groups (28.1% with imatinib vs. 28.6% with placebo; p = 0.94).
CONCLUSIONS: Systemic imatinib therapy does not affect the risk of recurrence in patients with ISR.
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Abbreviations and Acronyms
| | CI = confidence interval | | CML = chronic myeloid leukemia | | GIST = gastrointestinal stromal tumor | | ISR = in-stent restenosis | | MI = myocardial infarction | | MLD = minimum lumen diameter | | PCI = percutaneous coronary intervention | | PDGF = platelet-derived growth factor | | SMC = smooth muscle cell | | TLR = target lesion revascularization |
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In-stent restenosis (ISR) after successful coronary stent placement is still a challenging clinical problem. Plain balloon angioplasty, cutting balloon angioplasty, and rotational atherectomy for ISR are associated with a high recurrence rate (1–3). The use of intracoronary brachytherapy resulted in significant reduction of restenosis at 6 to 12 months, but an increased rate of late recurrences in the irradiated arteries has raised the question about the durability of the early benefit in the long term (4). In contrast, the placement of drug-eluting stents (5) and the systemic treatment with rapamycin (6) have resulted in significant reductions of the risk of restenosis recurrence. The predominant mechanism of ISR is neointimal tissue proliferation (7), and the cellular component of the neointima is mainly comprised of smooth muscle cells (8), attracted from the media through inflammatory chemokines and mitogenes (9). The platelet-derived growth factor (PDGF) was shown to play a pivotal role in the proliferative and migratory response of smooth muscle cells (SMCs) to vascular injury (10), and inhibition of PDGF by blocking antibodies significantly reduced neointima formation in a mouse model of restenosis (11). Furthermore, it has been shown that c-Kit+ progenitor cells are able to differentiate into  -actin positive SMCs in vitro and in vivo and may contribute to neointima formation after vascular injury (12). The proliferation and differentiation of c-Kit+ progenitor cells is regulated by the c-Kit receptor kinase and its ligand, stem cell factor (13).
Imatinib, a potent inhibitor of receptor tyrosine kinases, is known to inhibit simultaneously the PDGF receptor kinase, the bcr-abl tyrosine kinase as well as the c-Kit receptor kinase (14). It has been approved for the treatment of patients with Philadelphia (bcr-abl) chromosome-positive chronic myeloid leukemia (CML) and of patients with c-Kit (CD 117)-positive gastrointestinal stromal tumors (GISTs). Furthermore, imatinib was able to prevent restenosis after repeated vascular injury in a mouse model of restenosis (15). The simultaneous inhibition of the PDGF receptor as well as of the c-KIT receptor kinase by imatinib provides a rationale for its use in the prevention of restenosis after percutaneous coronary intervention. Therefore, the objective of this randomized, placebo-controlled, double-blind trial was to assess whether an oral administration of imatinib, including a pretreatment for two days, is associated with a reduction of restenosis after percutaneous coronary intervention (PCI) in patients with ISR.
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Methods
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Patients.
Eligible patients had angina pectoris and/or a positive stress test and presented with angiographically significant ISR (lumen renarrowing of  50% at a previously stented segment) in native coronary vessels. Patients with acute coronary syndromes, presence of severe kidney failure (serum creatinine >2.2 mg/dl), or contraindications to the medication used in the present study were excluded. The study was conducted according to the principles of the Declaration of Helsinki and approved by the institutional ethics committees. All patients had given their written informed consent for participation in this trial.
Randomization, medication, and coronary procedures.
After diagnosing the presence of significant ISR by coronary angiography, patients were randomly assigned to oral imatinib (Glivec, Novartis International AG, Basel Switzerland) with 600 mg/day or placebo. Randomization was performed in a double-blind manner with the use of sealed envelopes containing the block randomization sequence for each participating center. Double blinding was achieved by the use of similar-appearing capsules containing imatinib or placebo. A pretreatment with imatinib/placebo was started 2 days before repeat PCI, which was performed on day 3. After the PCI, the oral treatment was continued for additional 7 days (day 4 to 10 after PCI).
The protocol of repeat intervention for ISR has been described elsewhere (1). In brief, all patients received clopidogrel 600 mg at least 2 h before and 500 mg intravenous aspirin immediately before the intervention. Conventional angioplasty balloon catheters were used for repeat dilation to achieve a final diameter stenosis of <30% and Thrombolysis in Myocardial Infarction flow grade 3 at the end of procedure. Additional stents were placed in the presence of a suboptimal result or a large residual dissection (>5 mm in length) after angioplasty. The after-procedural antithrombotic regimen consisted of 75 mg of clopidogrel for at least 6 months after repeat intervention; 100 mg of aspirin twice daily was administered continuously. Blood cell counts and liver and kidney function were assessed before and at the end of the treatment.
Angiographic evaluation.
Qualitative and quantitative assessments in the core angiographic laboratory were performed before unblinding of the study. In-stent restenotic lesions were categorized with the classification system proposed by Mehran et al. (16). Digital angiograms were analyzed offline with the automated edge detection system (CMS, Medis Medical Imaging Systems, Nuenen, the Netherlands). The analysis segment comprised the segment injured by balloon angioplasty and the proximal and distal edges, defined as 5 mm proximal or distal to the balloon-injured segment. Matched views were selected for angiograms recorded before and immediately after the intervention and at follow-up. Angiographic sequences were preceded by an intracoronary injection of nitroglycerin. The parameters obtained were minimum lumen diameter (MLD), vessel size, diameter stenosis, and diameter of the maximally inflated balloon. Late lumen loss was calculated as the difference in MLD measured between measurements after the procedure and at follow-up. Net gain was defined as the difference between MLD at follow-up and before balloon dilation.
Definitions and end points of the study.
Angiographic restenosis at follow-up, defined as diameter stenosis 50%, was the primary end point. Secondary end points were the combined incidence of death or myocardial infarction (MI), as well as target lesion revascularization (TLR), PCI, or bypass surgery during one-year follow-up. The diagnosis of MI was based on typical chest pain combined with either new pathologic Q waves or creatinine kinase rise >3 times the upper limit of normal with concomitant increase in the MB isoenzyme. Creatine kinase was determined before and immediately after the procedure, every 8 h for the first 24 h after the procedure, and daily afterward until discharge. Target lesion revascularization was performed in the presence of angiographic restenosis and symptoms or signs of ischemia. Adverse events were monitored throughout the follow-up period by a clinical visit at six months and an additional telephone interview at one year after the intervention. If patients reported cardiac symptoms during the telephone interview, at least a clinical and electrocardiographic follow-up examination were performed in the outpatient clinic or by the referring physician. All events were adjudicated and classified by an event-adjudication committee whose members were unaware of the patients’ assigned treatment.
Statistical analysis.
The sample size estimation was based on the following assumptions: a two-sided alpha-level of 0.05 and power of 80% and an angiographic restenosis rate of 40% in the placebo group and 20% in the imatinib group. Accordingly, a sample size of 70 patients in each group was calculated; we enrolled a total of 180 patients to accommodate for missing angiographic follow-up studies.
The main analysis was performed on an intention-to-treat basis and the discrete variables are expressed as counts or percentages and compared with chi-square or Fisher exact test (whenever an expected cell value was <5); for the outcome variables, the relative risk and its 95% confidence interval (CI) were computed for outcome measures. Continuous variables are expressed as mean ± SD and compared by means of the unpaired two-sided t test. Statistical significance was accepted for p < 0.05.
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Results
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Between December 2002 and June 2003, a total of 180 consecutive patients were randomized to receive imatinib (n = 89) or placebo (n = 91). Baseline clinical, angiographic, and procedural characteristics are shown in Table 1. A diffuse ISR morphology was less prevalent in the imatinib group; all other characteristics were comparable between both groups.
Early clinical follow-up.
Twenty patients (22.5%) treated with oral imatinib experienced potential drug-related side effects. The majority of these patients complained about mild to moderate gastrointestinal complaints, including nausea, vomiting, and diarrhea; the medication needed to be discontinued in four (4.5%) patients owing to extensive diarrhea. Additional side effects included pruritus and exanthema. At the end of the treatment duration, no hematologic adverse effects were observed. Furthermore, bilirubin levels did not differ between both treatment groups. In contrast, a significant increase in serum creatinine was found in the imatinib group. Although the creatinine values did not differ before the treatment, with 1.28 ± 0.36 mg/dl versus 1.25 ± 0.46 mg/dl (p = 0.72), the creatinine values increased at the end of the 10-day treatment to 1.56 ± 0.37 mg/dl versus 1.29 ± 0.40 mg/dl (p < 0.001) for imatinib versus placebo, respectively.
None of the patients had a thrombotic vessel occlusion or died within the 30 days after PCI. One patient in each group developed a non-fatal MI (1.1% in each treatment group; p = 0.67).
Angiographic and late clinical follow-up.
Repeat angiography was performed in 160 of 180 patients (88.9%) at a median time interval of 198 days (interquartile range: 182 and 219 days). The angiographic results are summarized in Table 2. The primary end point of the trial, angiographic restenosis, was reached in 38.8% of imatinib patients and 41.3% of the placebo patients (relative risk 0.94; 95% CI 0.62 to 1.41; p = 0.75). Figure 1 illustrates the restenosis rates in each group. Consequently, the MLD, the diameter stenosis at follow-up, and the late lumen loss and the net lumen gain did not differ between both groups. Cumulative distribution curves for the degree of percent diameter stenosis at follow-up are demonstrated in Figure 2.
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Figure 1 Bar graph demonstrating angiographic restenosis rates at six months and clinical restenosis rates at one year (need for target lesion revascularization [TLR], repeat coronary intervention, or bypass surgery). White bars = placebo; black bars = imatinib.
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At one-year clinical follow-up the combined incidence of death or MI was 1.1% in both groups (p = 0.67). The need for target lesion revascularization at 1 year was 28.1% in the imatinib group and 28.6% in the placebo group (relative risk 0.98; 95% CI 0.59 to 1.63; p = 0.94). Accordingly, the cumulative rate of major adverse cardiac events was 29.2% and 29.7% in the imatinib and placebo groups, respectively (p = 0.75). Table 3 summarizes the clinical outcome at one year.
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Discussion
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Imatinib is a tyrosine kinase inhibitor that inhibits three different tyrosine kinases. In patients with CML, imatinib blocks the constitutive activated bcr-abl tyrosine kinase created by the Philadelphia chromosome abnormality, resulting in an inhibition of proliferation and induction of apoptosis in Bcr-Abl positive cell lines. The expected effect of imatinib on restenosis prevention after PCI was based on its ability to simultaneously inhibit two further tyrosine kinases: the PDGF receptor and the c-Kit receptor tyrosine kinase (17). In experimental studies, PDGF was shown to play a pivotal role in the proliferative and migratory response of SMCs to vascular injury, leading to neointima formation (10,18). The blocking of the PDGF-associated signal transduction pathway by antibodies against PDGF or by tyrosine kinase inhibitors significantly reduced neointima formation in various restenosis models (11,15,19). Furthermore, recruitment and differentiation of c-Kit+ hematopoietic progenitor cells may play an important role in neointima formation after vascular injury (12). Additionally, treatment of circulating progenitor cells with stem cell factor, the ligand of the c-Kit receptor kinase, leads to an increase in their adhesiveness (20,21). Therefore, the systemic inhibition of the c-Kit receptor kinase by imatinib may reduce the adhesiveness of hematopoietic progenitor cells as well as their proliferation and differentiation into -actin–positive SMCs.
In the current randomized, double-blind, and placebo-controlled trial, the impact of a systemic administration of imatinib was investigated in the prevention of restenosis after PCI in patients at high risk for recurrence. All factors associated with systemic imatinib administration were addressed to account for an optimal treatment effect. The dose of 600 mg imatinib was chosen because of its proven effects in the treatment of patients with CML, blast crisis, or with GIST (22,23). Furthermore, we initiated imatinib treatment two days before repeat intervention to allow for an effective drug concentration at the time of intervention. Finally, imatinib was administered for a total of 10 days, a period that has been demonstrated to be effective with systemic rapamycin administration for restenosis prevention in a comparable patient cohort (6). The trial demonstrates that imatinib did not affect angiographic and clinical parameters of recurrent restenosis after treatment of ISR. Moreover, the relatively high number of observed adverse effects in combination with the significant nephropathic effects makes imatinib an unsuitable drug candidate given systemically for restenosis prevention. Although a positive effect of imatinib used locally cannot be ruled out, the results of this study do not encourage this approach.
The negative finding of the current study could be explained by two potential reasons: First, the role of PDGF and of the recruitment of c-Kit+ progenitors for the development of restenosis after coronary intervention might be overestimated. Second, the systematic inhibition of c-kit and the PDGF receptor tyrosine kinase by imatinib may not be sufficient to antagonize the local effects of these cytokines at the site of vascular injury. Further studies in animal models may help to understand the effect of imatinib on the molecular mechanisms of neointima formation.
Study limitations.
We tested only one dose of imatinib in this study. Although the dose of 400 to 600 mg imatinib daily is effective for treating patients with CML and GISTs (24), the effective dose for treating patients with ISR is unknown. Therefore, we cannot rule out that a higher dose of the drug may show an inhibitory effect on restenosis. However, increasing doses of imatinib were associated with a higher incidence of adverse effects, resulting in a higher rate of discontinuation of imatinib therapy (22). Although the rate of 22.5% drug-related adverse effects seems high compared with the treatment-related effects in similar studies, such as the Oral Sirolimus to Inhibit Recurrent In-stent Stenosis (OSIRIS) study (6), the toxicity of imatinib in this trial was generally lower compared with that observed in previous studies at comparable doses (23,24). This might be due to the relative short imatinib treatment of 10 days compared with the sustained treatment over months and years in cancer patients.
Furthermore, we tested only one duration of imatinib treatment. Although this duration was effective in reducing recurrence of ISR in the OSIRIS trial (6), we cannot rule out that longer treatment duration could have beneficial effects.
Conclusions.
The systemic administration of the tyrosine kinase inhibitor imatinib, including a pretreatment for two days, did not inhibit restenosis formation after repeat coronary intervention in patient with ISR.
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Footnotes
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The first two authors contributed equally to this work.
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Abstract
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