Review of the RAVEL trial

Drug-eluting stent vs bare metal stent

N Engl J Med 2002;346:1773-1780

Background: Percutaneous revascularization of the coronary arteries is frequently performed for patients with stable and unstable angina. By the late 1990s and early 2000s, most percutaneous coronary interventions (PCI) were performed with intracoronary stent placement rather than balloon angioplasty alone given lower rates of angiographic detected restenosis with stent placement. However, stent restenosis was a common cause of repeat revascularization. Unlike the process of atherosclerotic plaque development, stent restenosis is caused by a distinct process of neointimal proliferation.

When a blood vessel is injured during a procedure like coronary stenting, the body's natural healing response triggers the migration and proliferation of smooth muscle cells from the vessel wall into the inner lining (intima), creating a new tissue layer called neointima. If the neointima grows excessively, it can narrow the blood vessel lumen, leading to restenosis, which can cause symptoms like angina.

Early coronary stenting was performed using bare-metal stents that were prone to neointimal proliferation. Animal studies and a small clinical study at the time suggested that the systemic or local administration of the drug sirolimus could reduce neointimal proliferation. Sirolimus is a macrocyclic lactone that inhibits cytokine-mediated and growth-factor–mediated proliferation of lymphocytes and smooth-muscle cells.

The RAVEL trial sought to assess the performance of stents coated with sirolimus (drug-eluting stents ”DES”) compared to uncoated stents (bare-metal stents “BMS”).

Patients: Eligible patients had stable angina, unstable angina, or silent ischemia. Only patients with single target lesions in a native coronary artery were included. The stenosis had to be 51-99% and could be covered by an 18 mm stent. The coronary artery had to be 2.5 – 3.5 mm in diameter.

Patients were excluded if they had evolving myocardial infarction, left main disease unprotected by a graft, ostial lesions, calcified lesions that couldn’t be completely dilated, angiographically visible coronary thrombus, ejection fraction <30% or intolerance to antiplatelets.

Baseline characteristics: The trial randomized 238 patients – 120 randomized to receive a sirolimus DES and 118 to receive a BMS.

The average age of patients was 61 years and 76% were men. Approximately 61% had hypertension, 36% had prior myocardial infarction, 19% had diabetes, 40% had hyperlipidemia, and 30% were current smokers. Approximately 50% had unstable angina, 39% had stable angina, and 11% had silent ischemia.

The target lesion was left anterior descending artery in 50% of the patients, left circumflex artery in 23% and right coronary artery in 27%. The average target vessel diameter was 2.6 mm.

Procedures: Stenting without pre-dilation was not allowed. After pre-dilation, patients were assigned in a 1:1 ratio to either of the stents. The trial was double-blinded and the two types of stents were indistinguishable except under the microscope.

Coronary angiograms before dilation, after PCI and at six months were assessed by a core laboratory to determine the luminal diameter of the coronary artery and the degree of stenosis.

Dual antiplatelets were continued for eight weeks.

Endpoints: The primary outcome was in-stent luminal loss at six months, defined as the difference between the minimal luminal diameter immediately after PCI and the diameter at six months. Restenosis defined as a luminal stenosis of 50% or more was assessed as a secondary endpoint. The study also assessed a clinical endpoint at 12 months. This endpoint included death, myocardial infarction, coronary artery bypass grafting and PCI of the target lesion.

Analysis was performed based on the intention-to-treat principle. A total of 207 patients were needed to have 90% power with a two sided alpha of 0.05, to detect a difference in the mean late luminal loss of 0.25 mm between the two treatment groups.

Results: Successful stent placement was 97% in the sirolimus DES arm and 93% in the BMS arm.

Angiographic data at six months were available from 89% of the patients. At six months, the primary outcome of in-stent luminal loss was significantly lower in the sirolimus DES arm (-0.01 mm vs 0.80 mm; p< 0.001). Luminal restenosis of 50% or more was also significantly lower with the sirolimus DES (0.0% vs 26.6%; p< 0.001).

At one year, the clinical endpoint of death, myocardial infarction, coronary artery bypass grafting and PCI of the target lesion was lower with the sirolimus DES (5.8% vs 28.8%; p< 0.001). This was driven by lower repeat revascularization in the sirolimus DES arm (0.0% vs 22.9%). There were four patients who died; two in each group.

Conclusion: Sirolimus drug-eluting stents reduced neointimal proliferation and in-stent restenosis compared to bare-metal stents. These findings are very promising as in-stent restenosis is a major concern with the use of bare-metal stents. The study focused on single lesions in coronary arteries measuring 2.5 – 3.5 mm in diameter and more validation is required. Additionally, the study was not adequately powered to evaluate clinical outcomes and these findings need to be confirmed in larger studies.