Observational and randomized studies recently showed that sirolimus-coated stents were associated with a lower rate of restenosis than bare stents.1–3 Although the restenosis rate was lower, coated stents have a significantly higher cost than conventional stents and their future use in multivessel disease or in patients with multiple lesions is questionable due to the prohibitive costs of such therapy. Sirolimus (rapamune), a natural macrocyclic lactone, is a potent immunosuppressive agent that was developed by Wyeth-Ayerst Laboratories and is given orally to renal transplant patients to avoid acute or chronic rejection.4,5 Although this drug is chronically taken by renal transplant patients, few side effects have been reported.6 The role of oral rapamune in the prevention of angiographic restenosis in patients undergoing coronary stent implantation is unknown. The purpose of the present pilot trial was to study the role of oral rapamune in preventing restenosis in patients undergoing percutaneous coronary intervention (PCI). Methods From December 2001 though February 2002, thirty-four patients with clinical indications for PCI were included in this protocol. The procedures were performed in the Cardiac Catheterization Laboratories of Otamendi Hospital in Buenos Aires, Argentina. In these 34 patients, fifty-three bare coronary stents were deployed in 49 lesions in native epicardial vessels. Of these 49 lesions, thirty-seven were in vessels with de novo coronary lesions, whereas the other 12 were lesions with in-stent restenosis. Rapamycin (Rapamune, Wyeth Laboratories) was given orally as a loading dose of 6 mg followed by a daily dose of 2 mg/day for 30 days, starting immediately after successful stent deployment. Rapamycin blood levels were measured in all patients in the same central core laboratories after the third week of treatment utilizing high-performance spectroscopy, which is routinely used to follow renal transplant patients.5 Lipid profiles (cholesterol, high-density lipoproteins, low-density lipoproteins and triglycerides) and complete blood counts were drawn before and after 4 weeks of treatment in all patients. A personal clinical interview was required in all patients each week for the first month of treatment and monthly thereafter for the 6-month clinical follow-up. Statins were given to all patients independent of cholesterol levels during the month of rapamycin treatment. Procedural and 6-month angiographic follow-up data were analyzed with quantitative coronary angiography (QCA) by a central core laboratory using a MEDIS computerized system. Angiographic binary restenosis, minimal luminal diameter (MLD), late loss, target lesion revascularization (TLR) and treatment compliance were recorded independent of rapamycin data. TLR was performed at follow-up when the residual stenosis was > 50% and a clinical indication for myocardial revascularization was present. Stent procedure. Different stents designs were implanted, including BX Velocity and Crossflex (Johnson & Johnson), Express (Boston Scientific/Scimed, Inc.), S7 (Medtronic AVE) and Carbostent (Sorin Biomedica). After predilatation of the target lesion, stents were deployed at high pressure (> 13 atmospheres) guided by online QCA. Twenty stents were 12 mm but 20 mm in length. All patients received aspirin (325 mg/day indefinitely), a loading dose of 300 mg clopidogrel on the day of the procedure and 75 mg/day thereafter for 6 months. The protocol was approved by the Medical and Ethics Committee of Otamendi Hospital. Written informed consent was obtained from all patients. Statistical analysis. Continuous variables were expressed as means ± standard deviation. Comparisons between pre- and post-intervention and between post-intervention and follow-up were performed with a 2-tailed paired t-test. Comparisons between groups were performed using the unpaired Students t-test, chi-square or Fisher exact tests as appropriate. Comparisons between rapamycin levels and the amount of late loss at follow-up were performed using linear regression analysis. A p-value 8 ng/ml. Cholesterol and triglyceride levels showed no significant differences compared to baseline. During the 6 months of follow-up, angiographic restenosis and TLR occurred in 13 of 49 lesions (26.5%), including the patient who suffered the in-hospital myocardial infarction. Major adverse cardiac events during the 6 months of follow-up occurred in 13/34 patients (38%). QCA data. Angiographic follow-up was obtained in all patients at 6.6 ± 1.2 months after the initial angiogram. QCA follow-up data of the 49 lesions treated are presented in Table 2. At follow-up, MLD was significantly larger in the de novo lesions compared to the in-stent restenotic lesions (2.1 mm versus 1.6 mm, respectively; p = 0.05). Angiographic restenosis was also lower in de novo versus in-stent restenotic lesions (18.9% versus 50%, respectively; p = 0.08). Restenosis and rapamycin blood levels. Analysis of late loss and rapamycin levels suggested a difference in the 12 patients with de novo lesions and rapamycin levels > 8 ng/ml in comparison to patients with levels 8 ng/ml and the follow-up late loss was also significantly lower (0.3 mm versus 0.9 mm in patients with levels 8 ng/ml (0% versus 24%, respectively; p = 0.07). Discussion In this observational pilot study, oral rapamycin therapy during the first month post-stent deployment was safe, well tolerated and resulted in few side effects. In de novo lesions, high rapamycin blood levels were associated with lower late loss and a lower restenosis rate at 6-month follow-up angiogram. The cytostatic and anti-inflammatory effects of rapamycin were previously demonstrated in preclinical and clinical studies.7–9 Its effects on the inhibition of smooth muscle cell proliferation were previously reported several years ago in animal studies,10–14 and were only recently confirmed with sirolimus-coated stents deployed during PCI.1,2 Several observational and randomized studies have demonstrated a significantly lower restenosis rate with these drug-eluting stents in comparison to bare stents.1–3 The possibility of adverse side effects and the need to achieve therapeutic levels locally at the site of PCI were the major concerns with the systemic use of this drug. In contrast, high local concentrations of the drug and low systemic blood levels would be major advantages of the sirolimus-coated stent. Recently, Brara et al.15 published a small series with oral rapamycin in patients with recalcitrant in-stent restenosis. The study showed poor tolerance to the oral administration of the drug and a high restenosis rate. We believe that the study has major limitations; its conclusions are premature and may be misleading. First, the authors15 studied only 22 patients. Among these, previous radiation failure occurred in 20 patients (91%) and only 50% of the cohort completed the oral sirolimus therapy. The efficacy of drug-eluting stents for the same population was not established. Further, sirolimus drug-eluting stents for patients who failed vascular brachytherapy reported poor results, and some were associated with thrombosis and high rate of restenosis.16 Second, the authors did not assess the rapamycin blood levels; thus, we do not know whether patients received sufficient therapeutic doses or a toxic dose that was associated with the withdrawal of the drug. According to our experience, we can assume that with the dose of 2 mg/day, therapeutic levels of the drug can only be achieved in approximately 30% of the cases. Third, the number of patients with adverse effects and who needed to stop the treatment was higher than reported by other independent series, where the number of patients with side effects with oral administration was lower than 30% even with higher doses of the drug, and less than 10% of those were required to discontinue the medication.17–19 Finally, the authors reported an angiographic follow-up of only 68%”. Study limitations. This was a pilot and observational study in a small group of patients with a follow-up angiogram at 6 months. It is unknown whether these findings will be maintained during more prolonged follow-up (12-month angiographic follow-up is planned) and if a longer duration of oral rapamycin therapy would have altered the findings. In addition, in-stent restenotic lesions did not appear to be favorably affected at this blood level of rapamycin. Conclusion. The results of our study using an oral dose of rapamycin are promising and associated with only a few minor side effects. Furthermore, in de novo lesions, higher rapamycin blood levels appeared to be associated with a lower rate of angiographic restenosis and late loss. These data are the first to suggest a role for oral rapamycin therapy in the prevention of angiographic restenosis in de novo lesions after PCI. We believe these promising preliminary data warrant larger placebo-controlled randomized studies.
1. Sousa JE, Costa MA, Abizaid AS, et al. Lack of neointimal proliferation after implantation of sirolimus-coated stents in human coronary arteries. Circulation 2001;103:192‚Äì195. 2. Morice MC, Serruys PW, Sousa JE, et al. A randomized comparison of sirolimus-eluting stent with a standard stent of coronary revascularization. N Engl J Med 2002;346:1773‚Äì1780. 3. Leon MB. Personal communication. Final angiographic results of the SIRIUS study. Transcatheter and Cardiovascular Therapeutics Meeting (TCT), Washington D.C., September, 2002. 4. Groth CG, Backman L, Morales JM, et al. Sirolimus (Rapamycin)-based therapy in human renal transplantation. Transplantation 1997;67:1036‚Äì1042. 5. Johnson RW, Kreis H, Oberbauer R, et al. Sirolimus allows early cyclosporine withdrawal in renal transplantation resulting in improved renal function and lower blood pressure. Transplantation 2001;72:777‚Äì786. 6. Blum CB. Effects of sirolimus on lipids in renal allograft recipients: An analysis using the Framingham risk model. Am J Transplant 2002;2:551‚Äì559. 7. Ikonen TS, Gummert JF, Hayase M, et al. Sirolimus (rapamycin) halts and reverses progression of allograft vascular disease in non-human primates. Transplantation 2000;70:969‚Äì975. 8. Sehgal SN. Rapamune (sirolimus, rapamycin): An overview and mechanism of action. Drug Monitor 1995;17:660. 9. Groth CG, Backman L, Morales JM, et al. Sirolimus (rapamycin)-based therapy in human renal transplantation: Similar efficacy and different toxicity compared with cyclosporine: Sirolimus European Renal Transplant Study Group. Transplantation 1999;67:1036‚Äì1042. 10. Poon M, Marx SO, Gallo R, et al. Rapamycin inhibits vascular smooth muscle cell migration. J Clin Invest 1996;98:2277‚Äì2283. 11. Marx SO, Jayaraman T, Go LO, et al. Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cell. Circ Res 1995;76:412. 12. Gallo R, Padurean A, Jayaraman T, et al. Inhibition of intimal thickening after balloon angioplasty in porcine coronary arteries by targeting regulators of the cell cycle. Circulation 1999;99:2164‚Äì2170. 13. Burke SE, Lubbers NL, Chen YW, et al. Neointimal formation after balloon- induced vascular injury in Yucatan minipigs is reduced by oral rapamycin. J Cardiovasc Pharmacol 1999;33:829‚Äì835. 14. Farb A, Jhon M, Acampado E, et al. Oral everolimus inhibits in-stent neointimal growth. Circulation 2002;106:2379. 15. Brara P, Moussavian M, Grise M, et al. Pilot trial of oral rapamycin for recalcitrant restenosis. Circulation 2003;107:1722‚Äì1724. 16. Degertekin M, Regar E, Tanabe K, et al. Sirulimos-eluting stent for treatment of complex in-stent restenosis. J Am Coll Cardiol 2003;41:184‚Äì189. 17. Waksman R, Ajani A, Pichard A, et al. Oral rapamune to inhibit restenosis in patients with multiple de novo coronary lesions requiring coronary stenting. J Am Coll Cardiol 2003;41(Suppl A):74A‚Äì1198. 18. Constantini C, Zanuttini D, Tarbine S, et al. Oral sirolimus to prevent restenosis after stenting de novo coronary lesions. J Am Coll Cardiol 2003;41(Suppl A):24A‚Äì1075 19. Rodr√≠guez A, Rodr√≠guez Alemparte M, Fern√°ndez Pereira M, et al. Pilot study with oral rapamycin in patients undergoing stenting in coronary arteries: Buenos Aires Experience (ORAR Trial). J Am Coll Cardiol 2003;41(Suppl A):82A‚Äì879.