Approximately 17 million deaths occur globally each year due to cardiovascular related problems. Cardiovascular is the largest therapy area in the global healthcare market with its value expanding from a value of $60 billion in 1997 to $351.8 billion in 2003 (see our feature "The cardiovascular report"). More than 1 million angioplasties are performed worldwide each year making interventional therapies including angioplasty a key sector within the cardiovascular market. Early experiences with angioplasty demonstrated that 30% of all coronary arteries were found to suffer restenosis. This situation has been improved through the use of stents to maintain patency and still further through the introduction of drug eluting stent. The global market for drug-eluting stents has been predicted to reach $5bn in 2005 with the market reaching $3bn in the US. Guidant have recently published data from the FUTURE I study of their everolimus eluting stent system.

Approximately 17 million deaths occur globally each year due to cardiovascular related problems. Cardiovascular is the largest therapy area in the global healthcare market with its value expanding from a value of $60 billion in 1997 to $351.8 billion in 2003 (see our feature "The cardiovascular report").

Angioplasty was first performed in 1977, and now more than 1 million procedures are performed worldwide each year making interventional therapies including angioplasty a key sector within the cardiovascular market. Following their success in the treatment of coronary heart disease, interventional therapies are becoming increasingly common in the treatment of other cardiovascular disease. For example the number of endovascular procedures performed for the treatment of peripheral arterial disease has almost trebled between 1983 and 2000 (see our feature "Peripheral arterial disease (PAD): A Significant Opportunity for Interventional Therapies").

Early experiences with angioplasty demonstrated that restenosis (when the vessel re-closes after angioplasty) is a common problem. Approximately 30% of all coronary arteries were found to suffer restenosis and to overcome this problem stents were developed which are inserted into the vessel at the time of angioplasty so as to maintain long-term patency. In the US about 70 to 90% of all angioplasty patients now receive a stent. Although this reduced the rates of restenosis, bare metal stents still experienced reblocking (typically at six-months) in about 25% of cases, necessitating a repeat procedure. Drug-eluting stent have therefore been developed and have further reduced the risk of restenosis from the 20-30% range to single digits.

There are three major components to a drug-eluting stent: the stent; the coating of the stent which is commonly a polymer; and the drug itself which elutes out from the stent coat. The global market for drug-eluting stents has been predicted to reach $5bn in 2005 with the market reaching $3bn in the US. Guidant is one of the leaders in stent technology and their CHAMPION everolimus eluting stent system is one technology that has been extensively tested.

Described as a proliferation inhibitor, everolimus (Certican) was developed by Novartis for the prevention of transplant rejection (during chronic graft rejection, the arterial endothelium displays extensive proliferation that may gradually occlude the vessel lumen, resulting in ischemia and fibrosis of the graft). Everolimus is an orally active derivative of the immunosuppressant sirolimus (Rapamune, Wyeth Laboratories, Philadelphia, PA), a macrolide synthesized by Streptomyces hygroscopicus. Everolimus, like sirolimus, blocks growth-factor derived cell proliferation, arresting the cell cycle in the late G1 phase. The effect of everolimus is not restricted to T lymphocytes, but potentially affects other hematopoietic and non-hematopoietic cells, including smooth-muscle cells. The IC50 for inhibition of smooth muscle cell proliferation with everolimus and sirolimus are similar. In 2002 Novartis licensed everolimus out to Guidant for use in drug eluting stents for the treatment of coronary and peripheral arterial diseases.

Four key studies have been conducted or are in progress/planning. Data from the FUTURE I study was published in the Am J Cardiol in 2005. This report presents the angiographic findings of FUTURE I which was designed to evaluate the safety and performance of Guidant's everolimus eluting stent. After 30 days there was no in-stent restenosis or major adverse cardiac events in patients treated with the everolimus eluting stent indicating safety. At 6-month follow-up, the everolimus eluting stent had a much lower in-stent late lumen loss (due to endothelial proliferation) than controls and the extent of stenoses within the lesioned segment of vasculature were only 20% of the overall vessel diameter compared to 37% in controls. Data from a 12 month follow-up demonstrated that both the safety and efficacy results from FUTURE I at six months were sustained. No new major adverse cardiac events occurred between six and 12 months, with no incidence of repeat intervention required.

FUTURE II, a prospective, randomized, multi-center double-blinded trial, confirmed the six-month results of the FUTURE I clinical trial. FUTURE II, which included diabetics therefore making the study cohort much more complex than that of FUTURE I, met its primary safety endpoint at six months. Angiographic endpoint results were similar to those reported for FUTURE I.

The FUTURE III trial has now commenced and will provide additional safety and performance data from an 800-patient trial and is designed to demonstrate the superiority of the everolimus eluting stent over a bare metal stent. This data is intended to support the market launch of the CHAMPION System outside the US. Another planned trial, FUTURE IV, is a 975-patient US pivotal trial.

Entry date Friday, January 28, 2005

Am J Cardiol. 2005 Jan 1;95(1):113-6.