Long-term Outcomes in Patients Undergoing Percutaneous Coronary Intervention with Drug-eluting Stents

Roberta Rossini; Giuseppe Musumeci; Alessandro Aprile; Orazio Valsecchi

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(1):49-61. 

In This Article

History of Drug-eluting Stents

The treatment of coronary artery disease (CAD) has been dramatically revolutionized since the introduction of percutaneous coronary intervention (PCI) by Andreas Gruentzig in 1977.[1,2] Balloon angioplasty and, subsequently, coronary stenting has significantly influenced the management of stable and unstable CAD.[3]

Initial results with percutaneous balloon angioplasty only, although encouraging, raised concern regarding periprocedural complications, such as plaque rupture and coronary dissection, which are often clinically translated into acute myocardial infarction (MI), especially in the days following the procedure. Emergency coronary artery bypass grafting (CABG) due to acute vessel closure as a result of dissection was not uncommon. In addition, at follow-up, the benefits derived from revascularization were further counterbalanced by the high incidence of restenosis, which could reach 40%.[4]

The advent of stents in the early 1990s significantly reduced these side effects and contributed to the widespread use of PCI. Nowadays, in the USA, more than a million patients are treated with PCI every year, often for nonacute CAD.[5]

The beneficial angiographic and clinical effects of stents were documented by several trials that demonstrated a significant reduction of restenosis and target-vessel revascularization (TVR) in patients allocated to bare-metal stent (BMS) implantation compared with those with percutaneous transluminal coronary angioplasty (PTCA).[6] Compared with balloon angioplasty, coronary stenting has been proven to decrease rates of TVR for a broad variety of lesion types. The advantage of coronary stents in reducing the occurrence of restenosis after PCI is essentially due to the ability to eliminate the elastic recoil and negative vessel remodeling that occurs after balloon dilation.

However, with the widespread use of BMS, two notable complications emerged: in-stent restenosis and stent thrombosis. Although stent thrombosis was significantly reduced with the use of dual antiplatelet therapy for the first weeks after stent implantation, in-stent restenosis still remains a challenge.[7] In-stent restenosis is a more simple reaction to the coronary intervention, resulting from an excessive proliferative neointimal response. In the pathophysiology of in-stent restenosis, there are four clear but overlapping components: platelet deposition, leukocyte recruitment, smooth muscle cell migration and proliferation and matrix deposition. These are common events, with an expected rate in the real world of between 20 and 40%. While the risk of developing in-stent restenosis is linked to a variety of clinical and procedural factors (particularly diabetes, long lesions, small vessels and procedural failure), all BMS, regardless of the thickness of the struts, provoke a considerable proliferative response.

In the late 1990s, great efforts were made in order to find a definitive solution to in-stent restenosis, which led to the development of systemic drugs that are able to reduce intimal proliferation. Over 80 randomized studies were carried out with antiplatelet agents, anti-inflammatory drugs, steroids, growth factor inhibitors and antiproliferative drugs; all were substantially negative, despite promising experimental studies.[8,9] After the disappointing results, the systemic administration of drugs to prevent restenosis was abandoned and the concept of delivering the drugs by the stents was conceived. Drug-eluting stents (DES) were based on the concept of local drug release at the site of tissue injury to resist smooth muscle proliferation. The local release of the drug under controlled form offered three advantages: high local concentration, absence of systemic toxic effects, and the use of an identical device to that used up to this point. The astonishing results of the first studies performed with rapamycin- and paclitaxel-eluting stents confirmed the concept that a high local concentration was essential in order to control the excessive proliferative response.

The past 10 years witnessed the extraordinary promise of DES and several stents with different types of drug were tested. Some drugs, such as paclitaxel, can be coated directly on a metal stent, whereas the majority of the drugs need to be attached to a polymer, which acts as a drug reservoir.[10]

Among the antimitotic agents tested in the late 1990s, sirolimus and paclitaxel were proven to significantly inhibit or substantially reduced intimal hyperplasia both in animals and man.

Sirolimus (rapamycin) is a sophisticated natural antibiotic, developed for its powerful immunosuppressive activity. Approved for the prophylaxis of rejection in kidney transplant patients, it showed an extensive level of tolerability and safety for systemic human use. Sirolimus inhibits the cellular cycle in the G1–S phase.

The Sirolimus-Eluting Stent (SES) Cypher™ (Cordis, Johnson & Johnson, PA, USA) obtained the unanimous consent of the US FDA expert panel for the approval of new devices for the circulatory system in 2003. The decision was based, in addition to the animal data, upon the analysis of the results of two prospective, multicenter, randomized, triple-blind clinical trials (Randomized Study with the Sirolimus-Coated Bx Velocity Balloon Expandable Stent [RAVEL] and Sirolimus-Eluting Stent in De Novo Native Coronary Lesions [SIRIUS] trials) and the First-in-Man (FIM) experience observational register.[11–13] All these studies demonstrated the significant net clinical benefit in the SES group due to the significant reduction of target lesion revascularization (TLR). Quantitative angiography and intravascular ultrasound assessments have shown a marked and protracted inhibitory effect on in-stent neointimal formation. The safety profile of SES was also demonstrated (Table 1).[14–17]

Paclitaxel (Taxol®), is a unique antiproliferative agent for many reasons: mechanism of inhibition of cellular proliferation (it makes the microtubules completely rigid, preventing the changes in conformation that are necessary for replication), very high level of lipophylicity (it can be linked to the stent without any polymer), dose-dependent efficacy and toxicity (the higher the dose, the greater the inhibition of proliferation, the higher the level of toxicity). The drug is cytostatic in low doses (stoppage in phase G1) and cytotoxic in high concentrations (mitotic stoppage in phase M). The most important aspect of paclitaxel-eluting stents (PES) Taxus™ (Boston Scientific, Natick, USA) was the selection of the lowest dose capable of blocking the immediate response to stent injury, then providing continuous low-level release of drug to maintain the blunted response, avoiding doses that may induce local vascular damage. Based upon the velocity of its release, slow, moderate- and fast-release formulations were assessed, but only the first two were used in clinical trials.[18]

The proof that low doses of paclitaxel could interrupt the cascade of restenosis without toxicity was demonstrated by TAXUS trials.[19–22] PES were demonstrated to determine a significant reduction in neointimal hyperplasia, which translated into a clinical benefit, with a significant reduction of repeated revascularization. These trials also documented the safety of PES (Table 2).

Zotarolimus is an analogs of sirolimus, designed to have a shorter in vivo half time, but with the same high-affinity binding to the immunophilin FKBP12 and comparable potency to inhibit in vitro T-cell proliferation. It acts by substituting a tetrazole ring for a hydroxyl group at position 42. This substitution makes the compound highly lipophilic, which favors crossing of cell membranes and delivery to targeted cells.

In vivo trials (ENDEAVOR II) demonstrated zotarolimus-eluting stents (ZES) Endeavor™ (Medtronic, MN, US) to be superior over BMS in terms of TVR, with a similar rate of major adverse cardiac events (MACEs).[23] Compared with the other DES, ZES appeared less effective than SES but better than PES at 3 years follow-up, as confirmed by the 3-year results of the ENDEAVOR IV trial, presented at the Transcatheter Cardiovascular Therapeutics (TCT) 2009 meeting by Martin Leon (Table 3).

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