Oral rapamycin to prevent human coronary stent restenosis: A pilot study
Article Outline
Abstract
Background
Recent human trials with rapamycin-eluting stents have shown very low restenosis rates. However, the high costs of these devices preclude their use in routine angioplasty, especially when considering multiple stenting. We evaluated whether orally administered rapamycin inhibits in-stent neointimal growth in patients with unstable angina.
Methods
We enrolled 15 patients successfully treated with the implantation of a single stent in a single de novo lesion in native coronary arteries. Correct stent expansion and apposition were corroborated with intravascular ultrasound scanning in all patients. Patients received aspirin, clopidogrel, and atorvastatin for 6 months. Rapamycin was administered in a loading dose of 5 mg, followed by 2 mg/day for 4 weeks.
Results
The reference diameter was 3.4 ± 0.4 mm, lesion length was 11.2 ± 2 mm, lesion type B1 was 36%, and lesion type B2 was 64%. After the procedure, in-stent minimal lumen diameter and diameter stenosis (DS) were 3.3 ± 0.4 mm and 0.3% ± 7.5%, respectively. At 10 days, plasma levels of rapamycin were 7.95 ± 2.6 ng/mL. At 6 months, angiographic determinations demonstrated an in-stent minimal lumen diameter of 2 ± 1 mm, an in-stent DS of 41.3% ± 28.0%, and an in-stent late loss of 1.4 ± 1.1 mm. Binary restenosis (>50% DS) was present in 6 of 15 patients (40%). Target lesion revascularization (coronary artery bypass grafting) was performed in 2 of 15 patients (13.3%). There were no serious adverse events during the 6-month period of follow-up, but 1 patient had severe heartburn caused by esophagitis, and another patient had herpes zoster at the end of the protocol.
Conclusions
Oral rapamycin was well tolerated, but did not suppress in-stent neointimal growth in this small group of patients.
Although stent implantation reduces the risk of restenosis compared with other percutaneous coronary interventions (PCI), angiographic in-stent restenosis continues to limit the long-term success of this approach. Only recently, drug-eluting stents with rapamycin or paclitaxel have emerged as a potential solution, by reducing neointimal proliferation.1, 2, 3, 4 However, their high costs, especially when considering multiple stenting, is a limitation for the widespread use of these devices.
Some investigators believe that oral delivery of these drugs might be preferable to their incorporation into stents, because this would enable repeat dosing and would also be much less expensive.5
The purpose of this pilot study was to evaluate the hypothesis that oral rapamycin could decrease neointimal proliferation after elective coronary stenting.
Methods
We studied 15 patients (12 men), aged 58 ± 11 years, with unstable angina who were successfully treated with the implantation of a single stent in a native coronary artery (13 Express II, Boston Scientific; 1 Tetra, Guidant Corporation; 1 S670, Medtronic). Patient inclusion criteria included blood and platelet counts and biochemical and lipid profiles. Lesion location was the left anterior descending coronary artery in 11 patients, the left circumflex artery in 2 patients, and the right coronary artery in 2 patients. Four of the treated lesions were type B1 and 11 were type B2. Two patients had diabetes mellitus, 8 patients had systemic hypertension, and 10 patients had dyslipidemia.
The average left ventricular ejection fraction was 71% ± 10%. Only lesions <18 mm in length and vessels 3 to 3.5 mm in diameter were included. Major exclusion criteria included total occlusion, ostial or thrombus-containing lesions, unprotected left main disease with >50% stenosis, occurrence of myocardial infarction within the preceding 6 weeks, and left ventricular ejection fraction <30%. Stents were implanted according to standard practice,6 after balloon predilatation and followed by high-pressure (>12 atm) balloon dilatation. Correct stent deployment was corroborated with intravascular ultrasound scanning (IVUS) in all patients according to the Multicenter Ultrasound Stenting in Coronaries (MUSIC) study criteria (complete stent apposition, symmetrical expansion, and adequate in-stent cross-sectional dimension).7 With IVUS, the mean stented area was 9.4 ± 0.9 mm2, leaving a 6.8% ± 6.4% stenosis in respect to the proximal reference vessel area.
Postprocedure angiography was performed in at least 2 orthogonal projections, which were repeated at the follow-up studies. Heparin was given to maintain an activated clotting time >300 seconds. Patients received aspirin (325 mg/day, indefinitely) started at least 12 hours before the procedure and a 300-mg loading dose of clopidogrel immediately after stent implantation and 75 mg/day for 6 months. Rapamycin was administered immediately after stenting, with a loading dose of 5 mg, followed by 2 mg/day during 4 weeks. All patients also receive atorvastatin 10 mg/day during the study. During the follow-up period, we were especially careful to detect thrombocytopenia, leukopenia, lipid alterations, and infections. The Medical Ethical Committee of our institution had approved the protocol, and written informed consent was obtained from every patient.
IVUS was performed in all patients after 200 ug intracoronary nitroglycerin. Studies were performed with single-element 30-MHz transducers rotating at 1800 rpm and withdrawn automatically at 0.5 mm/s within a 3.2F short monorail-imaging catheter (Clear View, CVIS, Boston Scientific).
Angiographic follow-up was performed at 6 months. Analysis was performed with an automatic edge-detection algorithm incorporated in the angiographer Advantx DLX-C (General Electric), and corroborated by 2 independent experts who were blinded to the clinical protocol. Intracoronary nitrates were administered immediately before each angiographic acquisition. We analyzed in-stent and in-lesion segments. The in-stent analysis encompassed only the segment covered by the stent. The in-lesion segment was defined as the stent plus 5 mm proximal and 5 mm distal to the edge. In-stent and in-lesion re-stenosis were defined as 50% diameter stenosis (DS) at follow-up, located within the stent and target lesion, respectively. Minimal lumen diameter (MLD) and percent DS were calculated for each segment.
Statistical analysis
Data were expressed as means plus or minus SD.
Results
Plasma levels of rapamycin were 7.95 ± 2.6 ng/mL at 10 days. There were no inhospital complications in this group. Metabolic, lipid and liver function tests, and blood cell counts performed on day 10 and 30 and at 6 months showed no abnormalities that demanded discontinuation of rapamycin. One patient had severe heartburn. One patient had herpes zoster that appeared 1 week after discontinuation of rapamycin at day 30. There were no cases of hypertriglyceridemia.
The angiographic control was performed at 6 ± 0.7 months. Binary restenosis (<50%) was present in 6 of 15 patients. Angiographic characteristics are shown in Table I. At follow-up, late loss was 1.4 ± 1.1 mm, mostly in-stent stenosis; 1 patient had restenosis in the segment proximal to the stent. During the 6-month follow-up, 2 patients had angina, and both required coronary artery bypass grafting. The angiogram revealed 95% in-stent restenosis in 1 of these patients and 75% in-stent restenosis in the other. The other 4 patients with angiographic restenosis had no symptoms and remained so during the follow-up (extended as long as 1 year).
Table I. Quantitative angiography
| Before procedure | |
| Reference diameter (mm) | 3.4 ± 0.4 |
| MLD (mm)* | 0.8 ± 0.6 |
| Diameter stenosis (%) | 78 ± 15 |
| Lesion length (mm) | 11.2 ± 2 |
| Lesion type B1* (%) | 27 |
| Lesion type B2* (%) | 73 |
| After procedure | |
| Reference diameter (mm) | 3.4 ± 0.3 |
| In-stent MLD (mm) | 3.3 ± 0.4 |
| In-stent diameter stenosis (%) | 0.3 ± 7.5 |
| Follow-up | |
| Reference diameter (mm) | 3.4 ± 0.3 |
| In-stent MLD (mm) | 2.0 ± 1 |
| In-stent diameter stenosis (%) | 41.3 ± 28 |
| In-stent late loss (mm) | 1.4 ± 1.1 |
| Binary restenosis (%) | 40 |
* According to AHA/ACC classification. |
Discussion
Recent randomized clinical trials have found that implantation of rapamycin- or paclitaxel-eluting stents resulted in very low in-stent restenosis rates, with no adverse reactions. The aim of this pilot investigation was to determine whether oral rapamycin produced a similar effect in patients with a low risk of restenosis. Our results did not show any benefit in these patients, because angiographic binary restenosis rate was 40% at 6 months, similar to the restenosis rate (36%) in the control arm (uncoated stent) of the randomized trials studying rapamycin-eluting stents4 or balloon angioplasty alone.8, 9 Because the reported angiographic restenosis rate for most of the stents used in our study was 26.6%,10 we cannot exclude the possibility that oral rapamycin might have induced neointimal proliferation in our patients. However, we were not able to find data supporting such speculation. Indeed, 2 of 15 patients required coronary artery bypass grafting (target vessel revascularization [TVR], 13%), whereas in the drug eluting trials, the rate of TVR had been <5% at 1 year. Furthermore, angiographic late loss was 1.4 ± 1.1 mm, again demonstrating that oral rapamycin was not able to inhibit tissue proliferation and perhaps even promoted tissue growth. Recently, Brara et al11 reported their experience with oral rapamycin in 22 patients with a high risk of restenosis. They used a loading dose of 6 mg followed by 2 mg/day for 30 days. Their TVR rate was 59.1%. Half of their patients discontinued rapamycin use because of adverse reactions, mainly hypertriglyceridemia (they did not use atorvastatin) and leukopenia. They performed a second, clinically oriented angiogram in 15 of 22 patients and found a restenosis in 13 patients (86.7%). They concluded oral rapamycin was not of clinical benefit in patients with a high-risk restenosis.
The inability of oral rapamycin to improve restenosis rates in these studies might have been related to tissue levels of the drug being much lower than those obtained with local delivery. We used the doses suggested for patients who had undergone renal transplants, in whom chronic useful blood levels of rapamycin are 5 to 15 ng/mL. Higher levels increase the chances of adverse reactions.12 In our study, the blood level of rapamycin was 7.95 ± 2.6 ng/mL, and we did not observed serious adverse reactions; all the patients finished the 30-day period of drug administration.
Recently, Farb et al showed that oral everolimus, a macrolide from the same family as rapamycin, demonstrated a significant reduction in in-stent neointimal growth at 28 days in rabbits.5 It is not known whether this drug may work in humans.
According the paper of Brara11 and ours, there is no apparent support for the use of oral rapamycin for the prevention of human coronary stent restenosis, and this argument should be considered when planning a large randomized trial.
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PII: S0002-8703(04)00206-6
doi:10.1016/j.ahj.2004.03.046
© 2004 Elsevier Inc. All rights reserved.
