Long-Term Risk of Adverse Outcomes and New Malignancies in Patients Treated With Oral Sirolimus for Prevention of Restenosis
Sebastian Kufner, MD*,
Jörg Hausleiter, MD*,
Gjin Ndrepepa, MD*,
Stefanie Schulz, MD*,
Olga Bruskina, MD*,
Robert A. Byrne, MB*,
Massimiliano Fusaro, MD ,
Adnan Kastrati, MD*,
Albert Schömig, MD*,,
Julinda Mehilli, MD*,* for the OSIRIS Trial Investigators
* Deutsches Herzzentrum, Technische Universität, Munich, Germany
1. Medizinische Klinik rechts der Isar, Technische Universität, Munich, Germany
 |
Abstract
|
|---|
Objectives: We sought to investigate the long-term efficacy of oral sirolimus therapy and its impact on the incidence of de novo malignancies in the OSIRIS (Oral Sirolimus to Inhibit Recurrent In-Stent Stenosis) trial population.
Background: The OSIRIS trial showed a significant reduction of angiographic restenosis with an oral adjunctive sirolimus treatment for in-stent restenosis. The long-term efficacy of oral sirolimus therapy is unknown.
Methods: Three hundred patients with in-stent restenosis were randomly assigned to receive placebo, a cumulative loading dose of 8 mg (usual-dose), or 24 mg (high-dose) of sirolimus over 3 days (2 days before and the day of intervention) followed by maintenance therapy of 2 mg/day for 7 days. The primary outcome of this analysis was the incidence of composite of death, myocardial infarction, and target vessel revascularization at 4-year follow-up. Secondary outcome was the incidence of newly diagnosed malignancies.
Results: No significant differences were observed between placebo, usual-, and high-dose sirolimus treatment groups regarding primary outcome (33.3%, 39.4%, and 31.3%, respectively; p = 0.46), death (5.9%, 9.1%, and 11.1%, respectively; p = 0.41), target vessel revascularization (30.4%, 30.3%, and 22.2%, respectively; p = 0.33), and rate of newly diagnosed malignancies (7.8%, 3.0%, and 11.1%, respectively; p = 0.09).
Conclusions: The benefit in the reduced need for repeat intervention observed at 1 year with high-dose oral sirolimus therapy was attenuated over 4 years. Moreover, this regimen was associated with numerical yet not a significant increase in newly diagnosed malignancies without augmenting the malignancy-induced risk of death. (Oral Sirolimus for In-Stent Restenosis [OSIRUS] trial; NCT00859183)
Key Words: angioplasty • restenosis • sirolimus • stents • malignancies
|
Abbreviations and Acronyms
| | DES = drug-eluting stent(s) | | ISR = in-stent restenosis | | MI = myocardial infarction | | PCI = percutaneous coronary intervention | | TVR = target vessel revascularization |
|
The use of immunosuppressive drugs to prevent and treat neointimal hyperplasia after percutaneous coronary interventions (PCIs) heralded a new era in interventional cardiology. Both new stent platforms able to locally release drugs to the vessel wall and orally administered immunosuppressive drugs have been tested (1–7). Due to its ability to inhibit the proliferation of vascular smooth muscle cells, sirolimus was quickly adopted for local drug delivery using a drug-eluting stent (DES) platform or as an adjunctive systemic therapy to catheter-based intervention (8). High-dose oral therapy with sirolimus before and after PCI has been reported to reduce the need for repeat revascularization not only after stenting of de novo lesions (2,4,5) but also after balloon angioplasty for recurrent bare-metal in-stent restenosis (ISR) (1,3). In patients with ISR enrolled in the OSIRIS (Oral Sirolimus to Inhibit Recurrent In-stent Stenosis) trial (3), oral adjunctive sirolimus treatment with an intensified loading regimen before PCI resulted in a 47% reduction in angiographic restenosis and a 40% lower rate of repeat revascularization at 1 year.
Hand in hand with its desired antiproliferative properties, however, immunosuppressive therapy may increase the risk of malignancy due to its negative impact on immunosurveillance (9). This risk seems to be present not only in patients receiving immunosuppressive drugs for solid organ transplantation but also for other conditions even when treated with a single, low-dose therapy (10). There are no data about the long-term impact of short-term, high-dose immunosuppressive drugs in cardiac patients. In a recently published meta-analysis involving nonindividual patient data, an increased rate of malignancy-induced death at 1 year after sirolimus-eluting stent implantation in cardiac patients has been reported (11).
We extended the follow-up period of the OSIRIS trial up to 4 years to assess: 1) whether the 1-year benefit of oral sirolimus therapy is maintained at long-term follow-up; and 2) whether the high-dose oral sirolimus increases the risk of de novo malignancies over this period.
|
Methods
|
|---|
Patients and protocol.
The OSIRIS trial design and patients were described previously (3). Briefly, patients with symptomatic bare-metal ISR in native coronary arteries and without acute coronary syndromes, severe infectious diseases, or severe renal insufficiency were enrolled. All patients had given their written informed consent for participation in this trial. The study was conducted according to the principles of the Declaration of Helsinki and approved by the institutional ethics committees. Randomization was performed in the catheterization laboratory after the diagnosis of ISR was established by angiography. Patients were assigned in a double-blind fashion to 1 of the 3 study arms: placebo, usual-dose sirolimus, or high-dose sirolimus. The usual- and high-dose sirolimus groups received an oral intensified loading with a total dose of 8 mg and 24 mg of sirolimus, respectively, over 3 days (2 days before and the day of PCI procedure) (3). After repeat PCI, the maintenance dose of 2 mg/day of sirolimus or placebo was continued for 7 days. Recommended procedure to treat ISR was conventional balloon angioplasty with provisional stenting in case of suboptimal results or large residual dissection after angioplasty. The post-procedural antithrombotic regimen consisted of 75 mg of clopidogrel for at least 6 months and 100 mg of aspirin twice daily indefinitely.
Data management, definitions, and study end points.
Angiographic restenosis at 6-month follow-up angiogram defined as diameter stenosis  50% and the combined incidence of death, myocardial infarction (MI), and ischemia-driven target vessel revascularization (TVR) (PCI or bypass surgery) during 1-year follow-up were primary and secondary end points of the OSIRIS trial. The definition of end points and the methodology of their evaluation have been previously described (3). All adverse events were adjudicated and classified by an event adjudication committee whose members were unaware of the patients' assigned treatment after review of original source documentation. Quantitative and qualitative core angiographic laboratory analysis was performed blinded to assigned treatment and clinical outcomes with the use of previously described methodology (3).
The primary outcome of the current study was the composite of death, MI, or TVR at 4 years after randomization. The secondary outcome was the incidence of de novo malignancies over the same period. The incidence of individual components of the primary end point was also assessed. The patients' clinical follow-up consisted of annual telephone interviews, and, in case the patients reported cardiac symptoms during the interview, a complete clinical, electrocardiogram, and laboratory examination was performed in the outpatient clinic or by the referring physician. Questions about the new diagnosis of any kind of malignant diseases as well as its therapy were also part of the interview. Every diagnosis of malignant disease reported by the patient or found out in the Bavarian Tumour Registry, as well as the date of first diagnosis, was evaluated using patients' discharge summaries. No patient moved from the geographic region during the follow-up period. De novo malignancy was defined as any new diagnosed malignant disease after the administration of immunosuppressive therapy.
Statistical analysis.
The data are analyzed according to the intention-to-treat principle. Categorical variables are expressed as counts or percentages and compared by chi-square test or Fisher exact test, as appropriate. Survival analysis was performed by applying the Kaplan-Meier method. Differences in survival were assessed with the log-rank test. Survival free of adverse events was defined as the interval from randomization until the event of interest. Data for patients who did not have an event of interest were censored at the date of the last follow-up. All analyses were performed using S-plus statistical package (S-PLUS, Insightful Corp., Seattle, Washington). A p value <0.05 was considered to indicate statistical significance.
|
Results
|
|---|
Detailed information on baseline characteristics of patients assigned to placebo, usual-dose sirolimus, or high-dose sirolimus has been reported in the primary publication. In brief, a quarter of patients were women, one-third of them presented with diabetes mellitus, mean vessel size was 2.6 mm, 50% of lesions were treated for diffuse ISR, and a new stent implantation was needed in 10% to 16% of patients. There were no significant differences in the baseline characteristics between patients in the 3 study groups.
Clinical outcome at 4 years.
Four-year clinical follow-up was completed in all patients. The incidence of the primary outcome of interest—death, MI, or TVR—was 33.3% (n = 34) in the placebo group, 39.4 % (n = 39) in the usual-dose sirolimus group, and 31.3% (n = 31) in the high-dose sirolimus group (p = 0.46) (Fig. 1). Six patients (5.9%) in the placebo group, 9 patients (9.1%) in the usual-dose sirolimus group, and 11 patients (11.1%) in the high-dose sirolimus group died during the 4-year period (p = 0.41). The cause of death for each patient is shown in Table 1. Two patients experienced MI, one in the usual-dose sirolimus group and the other in the high-dose sirolimus group (p = 0.61). No differences were observed in death or MI rates between the 3 groups: 7 patients (6.9%) in the placebo group, 9 patients (9.1%) in the usual-dose sirolimus group, and 12 patients (12.1%) in the high-dose sirolimus group (p = 0.44) (Fig. 2). TVR was required in 31 patients (30.4%) treated with placebo, in 30 patients (30.3%) treated with usual-dose sirolimus, and in 22 patients (22.2%) treated with high-dose sirolimus (p = 0.33) (Fig. 3). Coronary bypass surgery was performed in only 1 patient in the high-dose sirolimus group. Target lesion revascularization was required in 26 patients (25.5%) treated with placebo, in 25 patients (25.3%) treated with usual-dose sirolimus, and 16 patients (16.2%) treated with high-dose sirolimus (p = 0.20) (Table 2). Between 1 and 4 years follow-up, no differences were observed in any of the clinical outcomes (Table 2).
View larger version (10K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 1 Primary Outcome of Interest
Kaplan-Meier curves for survival free of myocardial infarction and target vessel revascularization for placebo, usual-dose, or high-dose sirolimus groups at 4 years.
|
|
Impact of sirolimus dose on malignancies.
The overall incidence of malignancies in the OSIRIS trial population was 14.0% (n = 42). Of them, 7 patients (6.9%) in the placebo group, 12 patients (12.1%) in the usual-dose sirolimus group, and 6 patients (6.1%) in the high-dose sirolimus group (p = 0.24) already had a malignant disease at the time of randomization. At 4 years, a total of 22 patients (7.3%) were diagnosed as having a de novo malignant disease: 8 patients (7.8%) in the placebo group, 3 patients (3.0%) in the usual-dose sirolimus group, and 11 patients (11.1%) in the high-dose sirolimus group (p = 0.09). Second malignant diseases occurred in 3 patients, 1 in each group. The cumulative incidence and the distribution of newly diagnosed malignancies in all 3 groups are shown in Figures 3 and 4. The median elapsed time from oral drug administration to the diagnosis of de novo malignancies was 17 months (range 3 to 48 months).
View larger version (16K):
[in this window]
[in a new window]
[Download PPT slide]
|
Figure 4 Distribution of Different Entities of De Novo Malignancies for Placebo, Usual-Dose Sirolimus, or High-Dose Sirolimus Groups at 4 Years
CNS = central nervous system; CUP = cancer of unknown primary origin; NHL = non-Hodgkin lymphoma.
|
|
|
Discussion
|
|---|
Data of extended follow-up of the OSIRIS trial provide the only currently available randomized evidence comparing the long-term consequences of oral sirolimus at high or usual dose versus placebo in patients undergoing repeat PCI for bare-metal in-stent restenosis. Over 4 years, we observed a decline in the initially demonstrated restenosis reduction effect with the intensive regimen of oral sirolimus therapy compared with placebo. Additionally, the risk of developing de novo malignancies after this high-dose short-term immunosuppressive therapy was not increased.
Treatment of ISR remains a formidable challenge. Despite very poor results (20% to 30% repeat revascularization rates), percutaneous transluminal coronary angioplasty alone is the most widely used revascularization strategy in those patients (12–16). Experience with intracoronary radiation therapy has shown excellent acute and short-term results at the expense of increased late stent thrombosis and mortality (17). While repeat implantation of bare-metal stents failed as a treatment option for recalcitrant restenosis (12,18), the excellent results with DES in de novo lesions encouraged their use to treat this disease (16).
Peri-interventional systemic administration of immunosuppressive drugs was associated with a reduction in repeat revascularization rates comparable with that of DES implantation in the de novo native coronary artery lesions (7). In the OSIRIS trial, patients presenting with recurrent bare-metal in-stent restenosis and treated before and after PCI with oral sirolimus showed a significant reduction of restenosis during the first year. We and others have shown a direct association between sirolimus blood concentration at the time of PCI and late lumen loss (3,4,7). A blood level of 18 µg/l with high-dose sirolimus loading and 10 µg/l with maintenance dose for a week was associated with late lumen loss of 0.49 mm, which is very similar to the late loss values observed with polymer-based, paclitaxel-eluting stents or polymer-free, sirolimus-eluting stents (19,20).
However, expanding the follow-up up to 4 years in this analysis of the OSIRIS trial, the initially observed benefit for reduction of restenosis particularly with the high-dose regimen was not sustained. Although the absolute difference in the target lesion and vessel revascularization rates remained nearly constant, the observed relative reduction of repeat revascularization rates by 40% within the first year after peri-interventional administration of high-dose sirolimus therapy declined at year 4 to a nonsignificant 27%. To our knowledge there are no long-term data about the antirestenotic effects of any oral immunosuppressive therapy in patients with coronary artery disease. However, the same phenomenon of attenuation of antirestenotic efficacy at long-term angiographic surveillance has been reported for DES—albeit to a lesser degree (21).
Among other factors, the long-term outcome of patients receiving systemic immunosuppressive drugs depends on the development of de novo malignancies. Data from large registries have shown an overall 3- to 5-fold increase in malignancy risk in transplant recipients compared with the age-matched general population (22). While there is a general agreement about the pro-neoplastic effect of some immunosuppressive drugs such as azathioprine or cyclosporine, there are conflicting data about the role of mammalian target of rapamycin inhibitors (10,23). The drastic regression of the human herpes virus 8-induced Kaposi sarcoma after administration of sirolimus is clear evidence of antineoplastic effect of mTOR inhibitors (24). However, in the ELITE (Efficacy Limiting Toxicity Elimination)–Symphony study, which investigated 4 different immunosuppressive drugs in 1,645 kidney transplant recipients, the highest de novo malignancy rate was observed in the sirolimus group (25). The carcinogenic effect seems to be present not only for solid organ recipients requiring maintenance immunosuppressive therapy but also for patients suffering from other conditions even when treated with a single, low-dose therapy (10). Moreover, the first experience with first-generation sirolimus-eluting coronary stents has shown some worrisome signals of increased long-term cancer-induced mortality in patients receiving these stents compared with the control group, who received bare-metal stents (11).
Although only for a short-time of 10 days, in the OSIRIS trial we used a high-dose of sirolimus. However, the overall incidence of de novo malignancies during the 4-year follow-up was nearly 8%, very similar to that of the general population (between 11% and 13%) (26). Immunosupressive drugs favor the development of rare tumor entities, which tend to be biologically more aggressive than those that occur in the general population (23). The distribution pattern of different types of de novo malignancies in the OSIRIS trial population reflects the same distribution as in the general population (26).
Study limitations.
First, the OSIRIS study was powered to detect differences in ISR. Although the 4-year clinical follow-up was complete for all patients, the relatively low number of patients enrolled precludes definitive conclusions about differences in clinical outcomes. Second, after the first follow-up year, there were no repeat angiographic studies planned. This reduced the ability of the study to assess the very long-term effect of different drug regimens in angiographic restenosis. However, this allowed us to evaluate more reliably the incidence of clinically driven repeat revascularization in this population. Third, analysis regarding malignancies was not pre-specified in the study protocol. Fourth, we do not have any information about disease progression after immunosuppressive therapy in patients with established cancer diagnoses. Moreover, a time interval of 4 years probably is not long enough to fully capture the pro-neoplastic effects of a certain drug. Finally, this study includes multiple statistical tests. This should be taken into account when considering the statistical significance of the differences among the 3 groups.
|
Conclusions
|
|---|
The benefit in the reduced need for repeat intervention observed at 1 year with high-dose oral sirolimus therapy was attenuated over 4 years. Moreover, this regimen was associated with a numerical, yet not significant, increase in newly diagnosed malignancies without augmenting the malignancy-induced risk of death.
* Reprint requests and correspondence: Dr. Julinda Mehilli, Deutsches Herzzentrum, Lazarettstr. 36, 80636 München, Germany (Email: mehilli{at}dhm.mhn.de).
Manuscript received June 1, 2009;
revised manuscript received August 17, 2009,
accepted August 20, 2009.
|
REFERENCES
|
|---|
- Brara PS, Moussavian M, Grise MA, et al. Pilot trial of oral rapamycin for recalcitrant restenosis Circulation 2003;107:1722-1724.[Abstract/Free Full Text]
- Waksman R, Ajani AE, Pichard AD, et al. Oral rapamycin to inhibit restenosis after stenting of de novo coronary lesions: the Oral Rapamune to Inhibit Restenosis (ORBIT) study J Am Coll Cardiol 2004;44:1386-1392.[Abstract/Free Full Text]
- Hausleiter J, Kastrati A, Mehilli J, et al. Randomized, double-blind, placebo-controlled trial of oral sirolimus for restenosis prevention in patients with in-stent restenosis: the Oral Sirolimus to Inhibit Recurrent In-stent Stenosis (OSIRIS) trial Circulation 2004;110:790-795.[Abstract/Free Full Text]
- Rodriguez AE, Rodriguez Alemparte M, Vigo CF, et al. Role of oral rapamycin to prevent restenosis in patients with de novo lesions undergoing coronary stenting: results of the Argentina single centre study (ORAR trial) Heart 2005;91:1433-1437.[Abstract/Free Full Text]
- Rodriguez AE, Granada JF, Rodriguez-Alemparte M, et al. Oral rapamycin after coronary bare-metal stent implantation to prevent restenosis: the Prospective, Randomized Oral Rapamycin in Argentina (ORAR II) study J Am Coll Cardiol 2006;47:1522-1529.[Abstract/Free Full Text]
- Kastrati A, Mehilli J, Pache J, et al. Analysis of 14 trials comparing sirolimus-eluting stents with bare-metal stents N Engl J Med 2007;356:1030-1039.[CrossRef][Medline]
- Rodriguez AE, Fernandez-Pereira C. Systemic immunosuppressive therapy with oral Sirolimus after bare metal stent implantation: the missing alternative in the prevention of coronary restenosis after percutaneous coronary interventions Recent Pat Cardiovasc Drug Discov 2008;3:201-208.[CrossRef][Medline]
- 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;33:829-835.[CrossRef][Web of Science][Medline]
- Dantal J, Pohanka E. Malignancies in renal transplantation: an unmet medical need Nephrol Dial Transplant 2007;22(Suppl 1):i4-i10.[Abstract/Free Full Text]
- Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review Drugs 2007;67:1167-1198.[CrossRef][Web of Science][Medline]
- Nordmann AJ, Briel M, Bucher HC. Mortality in randomized controlled trials comparing drug-eluting vs. bare metal stents in coronary artery disease: a meta-analysis Eur Heart J 2006;27:2784-2814.[Abstract/Free Full Text]
- Elezi S, Kastrati A, Hadamitzky M, Dirschinger J, Neumann FJ, Schömig A. Clinical and angiographic follow-up after balloon angioplasty with provisional stenting for coronary in-stent restenosis Cathet Cardiovasc Intervent 1999;48:151-156.[CrossRef][Web of Science][Medline]
- Radke PW, Kaiser A, Frost C, Sigwart U. Outcome after treatment of coronary in-stent restenosis; results from a systematic review using meta-analysis techniques Eur Heart J 2003;24:266-273.[Abstract/Free Full Text]
- Alfonso F, Auge JM, Zueco J, et al. Long-term results (three to five years) of the Restenosis Intrastent: Balloon angioplasty versus elective Stenting (RIBS) randomized study J Am Coll Cardiol 2005;46:756-760.[Abstract/Free Full Text]
- Alfonso F, Perez-Vizcayno MJ, Hernandez R, et al. A randomized comparison of sirolimus-eluting stent with balloon angioplasty in patients with in-stent restenosis: results of the Restenosis Intrastent: Balloon Angioplasty Versus Elective Sirolimus-Eluting Stenting (RIBS-II) trial J Am Coll Cardiol 2006;47:2152-2160.[Abstract/Free Full Text]
- Dibra A, Kastrati A, Alfonso F, et al. Effectiveness of drug-eluting stents in patients with bare-metal in-stent restenosis: meta-analysis of randomized trials J Am Coll Cardiol 2007;49:616-623.[Abstract/Free Full Text]
- Waksman R, Ajani AE, White RL, et al. Five-year follow-up after intracoronary gamma radiation therapy for in-stent restenosis Circulation 2004;109:340-344.[Abstract/Free Full Text]
- Alfonso F, Zueco J, Cequier A, et al. A randomized comparison of repeat stenting with balloon angioplasty in patients with in-stent restenosis J Am Coll Cardiol 2003;42:796-805.[Abstract/Free Full Text]
- Stone GW, Ellis SG, Cox DA, et al. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease N Engl J Med 2004;350:221-231.[CrossRef][Web of Science][Medline]
- Mehilli J, Kastrati A, Wessely R, et al. Randomized trial of a nonpolymer-based rapamycin-eluting stent versus a polymer-based paclitaxel-eluting stent for the reduction of late lumen loss Circulation 2006;113:273-279.[Abstract/Free Full Text]
- Byrne RA, Kufner S, Tiroch K, et al. Randomised trial of three rapamycin-eluting stents with different coating strategies for the reduction of coronary restenosis—two-year follow-up results Heart 2009;13:13.[Web of Science]
- Andres A. Cancer incidence after immunosuppressive treatment following kidney transplantation Crit Rev Oncol Hematol 2005;56:71-85.[Web of Science][Medline]
- Domhan S, Zeier M, Abdollahi A. Immunosuppressive therapy and post-transplant malignancy Nephrol Dial Transplant 2009;24:1097-1103.[Free Full Text]
- Stallone G, Schena A, Infante B, et al. Sirolimus for Kaposi's sarcoma in renal-transplant recipients N Engl J Med 2005;352:1317-1323.[CrossRef][Web of Science][Medline]
- Ekberg H, Tedesco-Silva H, Demirbas A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation N Engl J Med 2007;357:2562-2575.[CrossRef][Medline]
- Tumorregister München Jahresbericht 2001/2002 W. Zuckschwerdt Verlag München http://www.tumorregister-muenchen.de/annals 2002Accessed February 2009.
|
Top
Abstract
Methods
