ACTIVE Trial



Aggressive Cholesterol Therapy to Inhibit Vein Graft Events (ACTIVE Trial):

Does High-Dose Postoperative Statin Therapy Improve Graft Patency after Coronary Bypass?

Version 8 – November 20th 2012

Principal Investigator: Alexander Kulik, MD MPH

Co-Investigator: James J. Morris, MD

Lynn Heart and Vascular Institute

Boca Raton Regional Hospital

800 Meadows Rd

Boca Raton, Florida, 33486

Statement of Main Objectives

Primary End Point

To evaluate the efficacy of high-dose statin therapy for the prevention of saphenous vein graft occlusion after coronary artery bypass graft surgery (CABG) compared to standard moderate-dose statin therapy, as assessed by 1-year computed tomography (CT) coronary angiography.

Secondary End Points

To evaluate the efficacy of high-dose statin therapy for the prevention of saphenous vein graft stenosis after CABG.

To evaluate the safety of high-dose statin therapy following CABG.

Study Rationale

More than 250,000 coronary artery bypass graft surgery (CABG) procedures are performed annually in the United States [1]. Because of its ease of use and ready availability, the saphenous vein is the most commonly utilized conduit during CABG. While convenient as a conduit however, the saphenous vein is severely limited by the development of saphenous vein graft disease, a process influenced by hyperlipidemia [2-3]. Developing in the months that follow surgery, saphenous vein graft disease begins with intimal hyperplasia, a thickening of the inner lining of the vein resulting from smooth muscle cell proliferation and extracellular matrix protein synthesis. Intimal hyperplasia forms a template for the development of vein graft atherosclerosis leading to eventual graft stenosis, occlusion, and recurrent ischemic events [4-8]. Up to 20% of saphenous vein grafts (SVG) occlude within the first year after bypass surgery [9-10]. By 10 years after surgery, only 60% of SVG are patent and half of those that are patent have clinically important stenosis [4, 6]. As a result of graft and native vessel attrition, patients who have undergone CABG are at risk for subsequent ischemic events, including death, myocardial infarction (MI) and stroke [4, 6].

First discovered in 1973 [11], statins inhibit the enzyme 3-hydroxy 3-methylglutaryl CoA (HMG CoA) reductase which catalyzes the rate-limiting step in cholesterol biosynthesis [12-13], ultimately leading to a reduction in low-density lipoprotein (LDL) cholesterol levels [14]. Since their approval for clinical use in 1987 [12], strong evidence has accumulated supporting their administration in patients with native coronary artery disease [15-16]. Statins have been shown to reduce the progression of atherosclerosis, improve survival, and reduce the risks of vascular death, non-fatal MI, stroke and the need for coronary revascularization across a wide range of cholesterol levels [15-16]. The benefits of statin treatment appear to be applicable to men and women as well as older and younger patients [15]. Statins are now the most widely prescribed medications in the world [17] and are believed to be one of the safest classes of drugs ever developed [18-19].

Over 20 years of experience has accrued with the use of lipid-lowering agents in patients undergoing CABG [20], and a number of studies have demonstrated that lipid-lowering agents reduce postoperative myocardial events and graft occlusions. Prior to the introduction of statins in the 1980’s, the CLAS (Cholesterol-Lowering Atherosclerosis Study) Trial was a randomized placebo-controlled study conducted to evaluate the combination of colestipol and niacin therapy on the progression of atherosclerosis in native coronary arteries and saphenous vein grafts. One hundred sixty two patients with a mean age of 54.2 years were enrolled, on average 3.6 years after having undergone CABG. In an era prior to the routine use of postoperative antiplatelet therapy, this study illustrated that the combination of colestipol and niacin lowered serum LDL levels from 160 to 97 mg/dL (P ................
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