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CLINICAL TRIALS

Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions

The Oral Rapamune to Inhibit Restenosis (ORBIT) study

Ron Waksman, MD^*,*, Andrew E. Ajani, MD, Augusto D. Pichard, MD^*, Rebecca Torguson, BS^*, Ellen Pinnow, MS^*, Daniel Canos, MPH^*, Lowell F. Satler, MD^*, Kenneth M. Kent, MD, PhD^*, Pramod Kuchulakanti, MD^*, Chrysoula Pappas, MD^*, Louise Gambone, RN^*, Neil Weissman, MD^*, Maureen C. Abbott, MS^* and Joseph Lindsay, MD^*

*Cardiovascular Research Institute, Washington Hospital Center, Washington, DC
Royal Melbourne Hospital and NHMRC Centre of Clinical Research Excellence in Therapeutics, Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia

Manuscript received April 6, 2004; revised manuscript received May 25, 2004, accepted June 22, 2004.

^* Reprint requests and correspondence: Dr. Ron Waksman, 110 Irving Street, NW, Suite 4B-1, Washington, DC 20010 (Email: ron.waksman{at}medstar.net).

	Abstract

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OBJECTIVES: The aim of this study was to establish safety and feasibility of oral Rapamycin at two doses—2 mg and 5 mg—in achieving low rates of repeat target lesion revascularization (TLR) in de novo native coronary artery lesions.

BACKGROUND: Drug-eluting stents have shown the ability to limit restenosis. Oral Rapamycin is an alternative strategy that can target multiple coronary lesions suitable for treatment with any approved metal stent and at potentially lower cost.

METHODS: The Oral Rapamune to Inhibit Restenosis (ORBIT) study is an open-label study of 60 patients with de novo lesions treated with bare metal stents in up to two vessels. After a loading dose of 5 mg, patients received a daily dose of 2 mg (n = 30) and 5 mg (n = 30) for 30 days. Six-month angiographic, intravascular ultrasound (IVUS), and clinical follow-up were conducted.

RESULTS: Baseline clinical and procedural characteristics were similar: 10% of patients in the 2-mg group and 30% in the 5-mg group did not complete the course; 43% in the 2-mg group and 66% in the 5-mg group had side effects. At six-month follow-up, late loss (0.6 ± 0.5 mm vs. 0.7 ± 0.5 mm; p = NS), in-stent binary restenosis (7.1% vs. 6.9%; p = NS), in-stent percent volume obstruction by IVUS (29% vs. 24%; p = NS), and clinically driven TLR (14.3% vs. 6.9%; p = NS) were similar in 2-mg and 5-mg groups.

CONCLUSIONS: Oral Rapamycin for the prevention of restenosis is safe, feasible, and associated with low rates of repeat revascularization. Although associated with certain side effects, it may be considered for patients undergoing multivessel stents if proven in larger randomized studies.

Abbreviations and Acronyms   CABG = coronary artery bypass graft surgery   IVUS = intravascular ultrasound   MI = myocardial infarction   MLD = minimal luminal diameter   ORAR = Oral Rapamycin to Prevent Restenosis in Patients Undergoing Coronary Stent Therapy trial   ORBIT = Oral Rapamune to Inhibit Restenosis study   OSIRIS = Oral Sirolimus to Inhibit Recurrent In-stent Stenosis trial   PCI = percutaneous coronary intervention   QCA = quantitative coronary angiography   SMC = smooth muscle cell   TLR = target lesion revascularization   TVR = target vessel revascularization

A number of preclinical studies support the use of systemic administration of Rapamycin in reducing SMC growth, the mediator of neointimal proliferation (18–22). Preclinical studies have demonstrated reduction of neointima formation after balloon injury in the porcine and the rabbit models of restenosis with the use of Rapamycin (18) and its analogue everolimus (Novartis Pharmaceuticals Corp., East Hanover, New Jersey) (19).

Oral Rapamycin is an alternative delivery strategy that can target multiple coronary lesions that are targets for catheter-based revascularization with any approved metal stent and with potentially lower cost. The aim of this pilot study was to establish the safety and feasibility of oral Rapamycin at two dosing strategies (2 and 5 mg) in achieving low rates of repeat target lesion revascularization (TLR) in de novo native coronary artery lesions.

	Methods

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This clinical trial was sponsored by the Medlantic Research Institute at Washington Hospital Center, Washington, DC. The study was approved by the institutional review board and monitored by an independent reviewer. A written informed consent was obtained from all patients before the study drug was administered. A clinical events committee independently adjudicated all clinical events in a blinded fashion.

Patient population.   Oral Rapamune to Inhibit Restenosis (ORBIT) is an open-label study of 60 patients with de novo coronary artery stenosis treated with stent implantation in up to two vessels. Patients were enrolled between October 2001 and November 2002. The first 30 patients (49 lesions) received rapamycin 2 mg/day for 30 days, and the second 30 patients (37 lesions) received rapamycin 5 mg/day for 30 days. The loading dose for both regimens was 5 mg given either immediately before or after the intervention. Angiographic and clinical follow-up were performed at six months.

Inclusion criteria were age >18 years, stable or unstable angina with evidence of ischemia, treatment of de novo lesions in 2 coronary arteries, target lesion 2.5 to 4.0 mm in diameter, target lesion 15 to 30 mm in length (visual estimate), left ventricular ejection fraction 20%, and condition of patient as being an acceptable candidate for coronary artery bypass graft surgery (CABG).

Exclusion criteria were unprotected left main stenosis, ostial target lesion, in-stent restenotic lesion or prior stent within 5 mm of target lesion, angiographic evidence of thrombus, totally occluded vessel (Thrombolysis In Myocardial Infarction level 0), impaired renal function (creatinine >2.5 mg/dl), hemodynamic instability (hypotension), bifurcation lesions, excess co-morbid illness, contraindications (i.e., allergy) for drug treatments, active peptic ulcer or upper gastrointestinal bleeding, and status of patient as currently being treated with immunosuppressant therapy.

Study definitions.   Q-wave myocardial infarction (MI) was defined by the presence of new pathologic Q waves on the electrocardiogram associated with an elevation of total creatinine kinase elevation at least 2 times the upper normal values. Non–Q-wave MI was defined as a total creatinine kinase elevation 2 times normal, with an elevation of MB isoenzyme of at least 3 times the upper normal value without new Q waves. Angiographic binary restenosis at follow-up was defined as 50% diameter narrowing within the stent and in the segment including the stent plus its edges (within 5 mm). Measurements were performed of the reference vessel, the stented segment, and the lesion segment including the edges of the stent. A lumen diameter of 0 mm was imputed in the presence of a total occlusion at baseline or at follow-up. Acute gain (in mm) was defined as the change in the stent minimum luminal diameter (MLD) from baseline to the final procedural angiogram. Late loss (in mm) was defined as the change in stent MLD from the final to the follow-up angiogram, and the arithmetic loss index within the stent was defined as late loss/acute gain. Leucopenia was defined as white cell count below 3 x 10⁹/l.

Study end points.   The primary end point of this study was angiographic restenosis at six months after procedure. Secondary end points included TLR, target vessel revascularization (TVR), and composite major adverse cardiac events (death, MI [Q-wave and non–Q-wave], CABG, or repeat TLR) at six months after procedure and intravascular ultrasound (IVUS) end points including percent of stent volume obstruction (neointima). A drug safety profile was conducted, and adverse reactions were adjudicated and recorded.

Quantitative coronary angiography (QCA) was performed to assess in-stent and in-lesion MLD and late lumen loss at six months after the procedure using the CMS-GFT system (Medis, Leiden, the Netherlands). The QCA was performed before the procedure, after the procedure, and for the six-month follow-up angiogram.

Intravascular ultrasound studies were performed after intracoronary administration of 200 µg of nitroglycerin with commercially available IVUS system (Boston Scientific Corp./Scimed, Natick, Massachusetts). The IVUS catheter was advanced distal to the lesion, and imaging was performed retrograde, back to the proximal reference at an automatic transducer pullback speed of 0.5 mm/s. Quantitative volumetric IVUS analysis was performed in an independent core laboratory. With the use of computerized planimetry software (TapeMeasure, INDEC Systems Inc., Capitola, California), stent and reference segments were measured every 1 mm. Reference segment external elastic membrane (EEM), lumen, and plaque and media (EEM-lumen) areas were measured over a 10-mm length adjacent to stent edge. Stent, lumen, and intimal hyperplasia (stent-lumen) areas were measured every 1 mm within the stented segment, and volumes were calculated using Simpson's rule. Intimal hyperplasia volumes were corrected for stent length by dividing intimal hyperplasia by stent length.

Statistical analysis.   Continuous variables were expressed as mean ± SD, and categorical data were expressed as percentages. Continuous variables were compared using Student t test, and categorical variables were compared using chi-square statistics or Fisher exact test. Analyses on variables containing non-independent observations were analyzed using the SAS GENMOD procedure. All analyses were performed by intent to treat. A p value of 0.05 was considered statistically significant.

	Results

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Characteristics of study population.   The two cohorts of 2 and 5 mg Rapamycin were matched for baseline clinical and procedural characteristics (Table 1). Patients treated with 5 mg Rapamycin compared with the 2 mg cohort had a lower number of diseased vessels (1.4 ± 0.6 mm vs. 1.9 ± 0.7; p < 0.01) and had less lesions treated overall. The coronary lesions were evenly distributed in the native coronary system. Lesion length (14.1 ± 6.8 mm vs. 13.6 ± 4.8 mm; p = NS) and reference vessel diameter (3.0 ± 0.4 mm vs. 3.1 ± 0.5 mm; p = NS) were similar in the 2- and 5-mg groups. The predominant interventional approach to treatment was direct stenting in both cohorts (48% overall).

Angiographic and IVUS results.   Six-month angiographic analysis was performed in 86% of lesions (42 of 49) in the 2-mg Rapamycin cohort and 78% of lesions (29 of 37) in the 5-mg Rapamycin cohort (Table 2). The MLD at follow-up (2.3 ± 0.6 mm vs. 2.3 ± 0.8 mm; p = NS) and late loss (0.6 ± 0.6 mm vs. 0.7 ± 0.5 mm; p = NS) were not significantly different in the two groups—indicating no dose-response effect.

Subset analysis of patients (n = 38) who had IVUS follow-up with multi- versus single-stent showed similar corrected intimal hyperplasia volumes between these two groups, respectively (2.27 ± 0.93 vs. 2.08 ± 1.3; p = 0.7). Similar subset analysis of late loss in patients with QCA (n = 53) did not show any statistically significant difference between multi- versus single-stent cohorts (0.7 ± 0.4 vs. 0.5 ± 0.5; p = 0.18). Within an individual patient with multiple stents (n = 13), IVUS analysis showed a similar amount of corrected intimal hyperplasia in each lesion (mean 2.26 vs. 2.07 mm³; p = 0.60). The mean difference of corrected intimal hyperplasia volume between each lesion within an individual patient was –0.191 mm³.

Six-month clinical outcomes.   Clinical follow-up at six months was available in 29 patients (96%) in the 2-mg Rapamycin group and 30 patients (100%) in the 5-mg Rapamycin cohort (Table 3). One patient did withdraw from the 2-mg cohort and was, therefore, unavailable for six-month follow-up. There were no documented deaths, Q-wave or non–Q-wave MIs beyond hospital discharge. The rate of clinically driven TLR (defined as revascularization at the target site associated with any of the following: positive functional ischemia study, ischemic symptoms, and an angiographic minimum lumen diameter stenosis >50% by QCA or revascularization of a target site with diameter stenosis >70% by QCA without either angina or a positive functional study was 14.3% vs. 6.9%; p = 0.33) and TVR (including CABG to non-restenotic vessels (16.7% vs. 20.6%; p = 0.67) were similar in the two groups. The high rate of TVR in this study was a result of patients who went to CABG and had complete revascularization including vessels treated in the study that were non-restenotic at the time of the surgery. Overall, seven patients (three in 2-mg and four in 5-mg group) had CABG to nine target vessels at six months. Although angiographic stenosis did not meet the definition of binary restenosis, one patient in the 2-mg group and three in the 5-mg group had bypass grafts to ORBIT vessels at the time of CABG at the discretion of the surgeons. These patients were referred to elective CABG due to progression of disease in other vessels including one left main disease. Three patients in the 2-mg and one patient in the 5-mg group had repeat PCI at six months. In the 2-mg group, all three PCIs were TLRs, and in the 5-mg group it was TVR-PCI. The pattern of in-stent restenosis was focal, diffuse, and total occlusion in each of the three patients in the 2-mg group. These restenotic lesions were treated with cutting balloon, repeat stenting to optimize the result, and brachytherapy in one patient. The patient in the 5-mg group had no restenosis of the initial stent implanted to right posterior descending artery, but a proximal lesion progressed that required PCI.

	Discussion

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Single-digit restenosis rates have been achieved with Rapamycin-eluting stents (1–7). While the evidence for effectiveness of drug-eluting stents is mounting, their long-term durability and use for multivessel disease remain unknown. Although locally delivered Rapamycin is the subject of intensive investigation, only one published study has assessed oral Rapamycin therapy and found no clinical benefit when administered to patients at high risk for restenosis (23). This cohort of 15 patients had recalcitrant in-stent restenosis that had either failed or were not candidates for intracoronary radiation, a population markedly different from patients with de novo coronary lesions. Lack of efficacy seen with oral Rapamycin in that study may have been due to inadequate drug dosing (2 mg/day for 30 days). Further, serum Rapamycin levels were not reported, and there are no data to support the efficacy of Rapamycin-eluting stents for this subset of patients. It is possible that patients with refractory restenosis, such as those who failed radiation therapy, will not respond well to either eluting or oral Rapamycin. In contrast, the Oral Sirolimus to Inhibit Recurrent In-stent Stenosis (OSIRIS) (24) and Oral Rapamycin to Prevent Restenosis in Patients Undergoing Coronary Stent Therapy (ORAR) (25) trials showed beneficial effects in restenotic and de novo lesions, respectively.

The late loss reported in RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions (RAVEL), SIRIUS, and TAXUSIV ranged from –0.01 ± 0.33 mm to 0.39 ± 0.5 mm with drug-eluting stents and 0.80 ± 0.53 mm to 1.0 ± 0.7 mm with bare metal stents (6,7). The late loss with oral Rapamycin (0.64 ± 0.52 mm) in the present study was higher than that of drug-eluting stents but was still lower than reported historic controls of standard stent cohorts from these studies. This reduction in the late loss translated into low in-stent (7.1% vs. 6.9%; p = NS) and in-lesion (4.8% vs. 6.9%; p = NS) binary restenosis rates for both 2-mg and 5-mg groups. There were no early or late stent thromboses and no late aneurysms as expected.

In-stent restenosis and cardiac transplantation vasculopathy are both characterized by intense intimal proliferation secondary to SMC proliferation. Rapamycin targets central regulators of cell cycle progression in vascular SMCs, including the cyclin-dependent kinase inhibitor p27^kip1 (21,22). Rapamycin combines anti-proliferative and anti-migratory properties with immunosuppressant activity and has been shown to prevent and treat graft (cardiac transplant) vasculopathy (26). In an open-labeled study of 46 patients with graft vasculopathy, oral Rapamycin reduced the number of primary end points (composite of death, MI, need for revascularization, or angiographic deterioration) and secondary end points (cardiac hospitalizations), with no increase in rate of infection. This effect of rapamycin was seemingly independent of its immunosuppression, implyinga predominant anti-proliferative action (27). Our study supports the feasibility of systemic Rapamycin therapy in the prevention of neointimal proliferation.

To our knowledge, our study is among the first to report of Rapamycin for restenosis prevention of de novo coronary lesions. This study has the inherent limitations of a single-center registry without a control group and a limited follow-up to six months. The lack of statistically significant findings in the study could be due to the small sample size. Further, not all patients were available for angiographic and IVUS follow-up; however, those who were unavailable were asymptomatic.

Interestingly, for patients who completed four weeks of Rapamycin treatment, dose levels did not have any effect on restenosis outcome variables (chi-square test for trend: 2 mg, p = 0.57; 5 mg, p = 0.64). Further, the duration of Rapamycin for patients who withdrew from the drug before the 30 days also did not affect restenosis (chi-square test for trend: 2 mg, p = 0.43; 5 mg, p = 0.76). The cumulative dose of Rapamycin did not have any significant effect on restenosis (chi-square test for trend: p = 0.36).

Thus, the study posed several questions relating to optimal and therapeutic loading doses as well as time and duration of drug administration. The current dose used in patients after renal transplantation is 2 mg/day, and it is possible that a dose of 5 mg is not necessary for the vascular application, because no clinical and angiographic differences were detected between the 2- and 5-mg groups in the present study. Because dose levels and duration of treatment did not have an effect on restenosis outcome variables, perhaps it is the loading dose that can make the difference. The OSIRIS study supports pretreatment, higher loading doses, and short treatment times for patients with in-stent restenosis. Implementation of this strategy may improve the outcome of de novo lesions as well. It is also unclear whether blood levels of the drug should be monitored. For renal transplant patients, a Rapamune level >8 g/ml is recommended. The ORAR study did show beneficial effects when blood levels were >8 g/ml.In the present study, we could not detect correlation between the Rapamune level and clinical events or late loss. Nevertheless, it is possible that larger sample sizes would have detected optimal blood levels. If so, this is a deficiency of this strategy, which would involve extra costs and inconvenience.

Finally, the cost of 2 mg of oral rapamycin for 30 days is nearly $500 per patient. This is significantly lower than the current cost of drug-eluting stents. This difference is more pronounced when multiple stents are required to treat multivessel disease. Another potential benefit of the drug is its anti-inflammatory properties, which may prove beneficial in the setting of acute coronary syndrome in the vulnerable patients.

Conclusions.   In this preliminary analysis, oral Rapamycin administration for the prevention of restenosis is safe and feasible. Lower rates of restenosis and later loss than anticipated were observed in both dosing strategies (without dose-response). The ORBIT II study, an international, multicenter, randomized trial, has been initiated and will determine whether systemic oral administration of Rapamycin will be a therapeutic option for patients undergoing PCI.

	References

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