Background: Drug-eluting stents have been broadly available for more than 2 years. Several studies have shown the efficacy of both sirolimus- and paclitaxel-eluting stents for prevention of coronary in-stent restenosis (1, 2). In-stent restenosis is usually detectable in bare-metal stents within the first 6 to 9 months after stent placement; therefore, this time frame is commonly used as follow-up in trials of drug-eluting stents (3). Angiographic results in bare-metal stents approximately 6 months after placement constitute the peak of neointimal obstruction in most patients (3), and angiographic follow-up at later time points often demonstrates decreased neointimal burden, most likely because of apoptotic or remodeling processes (4). Current commercially available drug-eluting stents use a nonbiodegradable polymeric surface, and there is ongoing discussion about increased late stent thrombosis in patients who receive them (5, 6). Besides late thrombotic events, especially after discontinuation of antiplatelet therapy with clopidogrel, the development of late in-stent restenosis is an important unresolved issue.

Objective: We describe 2 patients who presented with late in-stent restenosis and recurrent angina pectoris, but no evidence of acute coronary syndrome, 20.4 and 18.9 months, respectively, after placement of a sirolimus-eluting stent. Of importance, both of our patients had an excellent angiographic result immediately after stent placement and at the scheduled 7-month follow-up visit, with no or minimal in-stent restenosis (Figures 1 and 2).

View larger version (116K): [in this window] [in a new window]   Figure 1. Coronary angiograms of 2 patients who received sirolimus-eluting stents and presented with late in-stent restenosis. The first patient received a sirolimus-eluting stent to treat proximal left anterior descending stenosis (part A, white arrow) with an appropriate angiographic follow-up result at 7 months (part B). Later, after 20.4 months, the patient presented with late restenosis in the sirolimus-eluting stent (parts C and D). Of note, a bare-metal stent implanted around the same time did not reveal progressive restenosis (parts A through C, black arrows). The second patient received a sirolimus-eluting stent for treatment of de novo right coronary artery stenosis (part E, arrow) with adequate result at angiographic follow-up at 7 months (part F). Later, after 18.9 months, the patient presented with late restenosis in the sirolimus-eluting stent (parts G and H). Of note, a bare-metal stent implanted around the same time showed regression of in-stent neointima (see Figure 2).

View larger version (24K): [in this window] [in a new window]   Figure 2. Development of in-stent minimal lumen diameter as a measure of neointimal growth in patients receiving a sirolimus-eluting stent and a bare-metal stent at approximately the same time. Minimal lumen diameter in bare-metal stents reached the minimum at 7-month follow-up in both patients and increased thereafter. In contrast, minimal lumen diameter steadily decreased in both polymer-coated sirolimus-eluting stents, demonstrating delayed neointimal growth.

Case Report: A 52-year-old man with arterial hypertension and hypercholesterolemia presented with stable angina pectoris that had lasted for more than 12 weeks. Three years earlier, he had received a bare-metal stent, 3.0 mm in diameter and 18 mm long, to treat a left circumflex lesion. Twenty months before the admission discussed here, he presented with stable angina. The left circumflex bare-metal stent showed no clinically significant in-stent restenosis; however, he received a sirolimus-eluting stent (Cypher, Cordis Corp., Miami Lakes, Florida) of the same dimensions to treat a proximal left anterior descending de novo lesion (Figure 1, part A). Scheduled follow-up coronary angioplasty 7 months later showed no restenosis in the sirolimus-eluting stent (Figure 1, part B). At that time, clopidogrel therapy was discontinued. Thirteen months later, the patient was admitted with stable recurrent angina. His medication consisted of a statin, an angiotensin-converting enzyme inhibitor, a ß-blocker, and low-dose aspirin. His total cholesterol level was 4.24 mmol/L (164 mg/dL), and his low-density lipoprotein cholesterol level was 1.97 mmol/L (76.3 mg/dL). Results of electrocardiography performed at rest were normal, but exercise electrocardiography revealed significant ST-segment depression at 100 W. Levels of creatine kinase, creatine kinase-MB, troponin T, and C-reactive protein were within normal ranges. Coronary angiography revealed marked late in-stent restenosis within the sirolimus-eluting stent (Figure 1, parts C and D) 20 months after implantation. In-stent restenosis was treated by percutaneous coronary intervention with no concomitant increase in myocardial markers. Of note, the bare-metal stent located in the left circumflex coronary artery showed no clinically significant restenosis, consistent with the preceding angiographic evaluation 13 months before. The patient's recovery was uneventful.

In March 2003, an 82-year-old man with 3-vessel coronary artery disease received a sirolimus-eluting stent (Cypher), 2.5 mm in diameter and 23 mm long, to treat severe stenosis of the distal right coronary artery (Figure 1, part E) with an adequate postinterventional result. His risk factors were arterial hypertension and hypercholesterolemia. Medical treatment included low-dose aspirin, a statin, an angiotensin-converting enzyme inhibitor, a ß-blocker, and clopidogrel. His total cholesterol level was 4.53 mmol/L (175 mg/dL), and his low-density lipoprotein cholesterol level was 3.18 mmol/L (123 mg/dL). In September 2003, he presented for scheduled angiographic follow-up, which revealed an excellent angiographic result in the sirolimus-eluting stent (Figure 1, part F). However, because the patient's coronary artery disease had progressed, a bare-metal stent was placed into the left circumflex artery and clopidogrel therapy was continued. In January 2004, the patient presented with atypical angina and no signs of acute coronary syndrome. Coronary angiography showed adequate results within both the sirolimus-eluting stent and the bare-metal stent (images not shown). In September 2004, while still receiving combined antiplatelet therapy, including both aspirin and clopidogrel, the patient presented with recurrent angina at exertion, which lasted for approximately 6 weeks. Electrocardiography results and laboratory values ruled out acute cardiac syndrome, and the C-reactive protein level was normal. Coronary angiography revealed marked restenosis (Figure 1, parts G and H) within the sirolimus-eluting stent, whereas the bare-metal stent maintained its initial, adequate angiographic result. Percutaneous intervention and in-hospital stay were uncomplicated.

Discussion: To our knowledge, this is the first published report of recurrent angina and severe in-stent stenosis in patients presenting more than 18 months after receiving a sirolimus-eluting stent. Scheduled follow-up coronary angiography at 7 months revealed no evidence of sirolimus-eluting stent restenosis in either patient. Of note, bare-metal stents implanted at about the same time did not show clinically significant restenosis at any point in time or any significant decrease of minimal lumen diameter more than 7 months after stent placement (Figure 2).

Preclinical porcine studies have consistently demonstrated effective limitation of coronary neointima formation with several drug-eluting stents, in particular polymer-coated stents eluting paclitaxel (7) or sirolimus (8) 30 days after stenting. However, a recent study reports ongoing neointimal growth in sirolimus-eluting stents in this model and "catch-up" of neointimal formation after 90 days in pigs receiving sirolimus-eluting stents compared with bare-metal stents (9), thus indicating delayed neointimal growth. In a human trial, patients who received 7-hexanoyltaxol-eluting polymer stents (QuaDDS-QP2, Quanam, Santa Clara, California) to treat de novo coronary lesions had appropriate 6-month angiographic results but developed late, accelerated in-stent restenosis after 12 months (10). Examinations of tissue atherectomies from these patients suggested that ongoing inflammation might have caused the negative outcome (11).

In our patients, the exact mechanism for the development of late in-stent restenosis in sirolimus-eluting stents despite excellent immediate and 7-month angiographic results remains elusive. The regression of neointimal hyperplasia in the bare-metal stents of both patients (Figure 2) suggests that the delay of neointimal growth and consequently the development of late restenosis are due to the stent coating. Whether the polymeric coating, for which hypersensitivity reactions and delayed vascular healing are described (5), or the pharmacologic compound sirolimus or both are primarily responsible remains elusive.

Since long-term studies in "real-world" patients with drug-eluting stents are lacking, it is uncertain whether the phenomenon we observed is rare. Considering the clinical course and the angiographic appearance in our patients, late stent thrombosis is unlikely to have caused stent obstruction, although it cannot be ruled out entirely. Further studies should investigate the clinical relevance of this phenomenon and the appropriate length of follow-up in patients who receive drug-eluting stents.