Article

Ongoing Late Lumen Loss with the CYPHER and TAXUS Drug-eluting Stents Supports a Theory of Catch-up Restenosis

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Abstract

Luminal loss and restenosis are critical problems in coronary artery drug-eluting stents (DES). These implants need to minimise long-term neointimal coverage and maximise blood flow. Two studies compared the effects of different types of DES on lumen loss after surgical implantation. The first study included 2,030 patients and showed that over two years late luminal loss (termed ‘late luminal creep’) progressed for two types of commercially prepared permanent polymer stents containing rapamycin or paclitaxel (CYPHER and TAXUS), but not for a polymer-free in-house coated stent containing rapamycin (YUKON). In a smaller study, luminal coverage was lower with the CYPHER than with the YUKON stent, but struts of the stent structure were better covered with the YUKON stent and less likely to cause an obstruction. Stents should ideally limit luminal loss but also allow for sufficient coverage to prevent thrombotic hazards.

Keywords

Drug-eluting stent, luminal loss, restenosis, neointimal coverage, permanent polymer stent, polymer-free stent, stent-coating machine,

Disclosure:James Gilbart is an employee of Touch Briefings. Editorial support was funded by Translumina.

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Accepted:

DOI:http://doi.org/10.15420/icr.2009.4.1.57

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In coronary artery stents, the coverage of the internal structures with neo-intimal formation has been regarded as a negative development leading to restenosis and loss of luminal space in the blood vessel. However, some coverage of the stent can be beneficial, providing coverage of protrusions in the internal stent structure that may otherwise constitute a thrombotic risk. Recent studies have compared different types of coronary artery stents pre-coated with drug compounds to assess their performance in terms of luminal loss and long-term outcome.

One study comparing the drug-eluting stents (DES) CYPHER (Cordis) and TAXUS (Boston Scientific) and the polymer-free rapamycin-coated YUKON DES (Translumina GmbH) showed that the permanent polymer used on the two most well-known DES is likely to be responsible for the often seen late luminal loss (LLL).1 In-stent LLL after approximately six to eight months and at two years following surgery was compared and showed that both the CYPHER and TAXUS stents appeared to undergo a process described as ongoing erosion of the luminal space, whereas the polymer-free stent showed negligible increases in late loss over the same period. The authors concluded that the findings support the hypothesis of a possible late ‘catch-up’ restenosis. This is a phenomenon that has been seen both anecdotally and in early animal models of DES.

The polymer-free stent was produced using a technology that was clinically tested in the Individualised Drug-Eluting Stent System to Abrogate Restenosis (ISAR) project by the Munich Research Group. This is a two-part system comprising a mobile stent-coating machine for the sterile spraying process and a single-use cartridge containing the pre-mounted microporous DES (Translumina, YUKON) (see Figure 1). The stent can be coated on-site directly in the cath lab with various drugs, e.g. with rapamycin (sirolimus). Previous studies have shown this in-house prepared ISAR DES to be safe and effective when coated with a 2% rapamycin-coating solution.2,3 A commercially available stent-coating machine (Translumina) is pictured in Figure 2.

The present study had a prospective, observational design and was a three-arm comparison of the CYPHER permanent-polymer rapamycin-eluting stent (RES), the TAXUS permanent-polymer paclitaxel-eluting stent (PES) and the YUKON polymer-free rapamycin-eluting stent (ISAR). The study included a total of 2,030 patients who underwent angiography at six to eight months post-stent implantation.1 Of these, 259 subsequently underwent target lesion revascularisation (TLR) and were therefore not included in the follow-up study. The remaining 1,771 patients underwent a second angiogram after two years, allowing investigators to compare LLL changes between six to eight months and two years. Patient disposition throughout the trial is shown in Figure 3. In-stent LLL was lowest for the CYPHER stent at six to eight months compared with both the TAXUS and the polymer-free YUKON stent. Between six to eight months and two years, however, late loss – late luminal creep – continued to progress for the CYPHER and TAXUS stents but not for the ISAR stent (see Table 1). Multivariate analyses indicated that stent type was the only predictor of LLL, and results favoured the polymer-free YUKON stent. A plot of LLL for percutaneous coronary intervention (PCI) at six to eight months and two years for the three different stents is given in Figure 4.

The late luminal creep seen with the permanent-polymer stents was considered to be due to neointimal formation occurring later in the healing process than has typically been seen with bare-metal stents (BMS). This may be due to a delayed healing process or to a persisting inflammatory response to permanent polymer. While LLL was the primary end-point, the study also monitored clinical outcomes at six to eight months and two years. TLR and death rates over the whole twoyear period were numerically lowest in the polymer-free YUKON stent group and highest in the TAXUS group, although the differences were not statistically significant for TLR or mortality (see Table 1).

When only TLR rates between six to eight months and two years are considered, rates were markedly lower in the polymer-free YUKON group, a 2.6% difference, whereas rates for both the CYPHER and TAXUS stents increased by 7.9 and 10.2%, respectively. For binary angiographic restenosis between six to eight months and two years post-PCI, the CYPHER stents showed a mean 1% decrease, the TAXUS stent showed a 2.2% decrease and the YUKON/ISAR stent showed a 10% decrease (p=0.002). A complete overview of the angiography results of the Byrne study is given in Table 2.

A commentary on the Byrne study4 noted that the data support the notion of a ‘catch-up phenomenon’ hitherto seen primarily in preclinical animal studies. In a stented porcine model, neointimal thickness in coronary artery stents continued to increase in the period 28–90 days after the insertion of a DES, whereas for BMS this increase stabilised after 28 days.5 Long-term major clinical trials show that TLR increased from 4.9 to 9.4% from one to five years post-PCI for CYPHER stents and from 4.4 to 9.1% for TAXUS stents.6,7 The commentary suggested that restenosis may be inevitable and questioned whether DES halt the restenotic process or merely delay it. The findings reported by Byrne et al. are important on two levels. First, angiographic studies two years after DES implantation are rare. The study demonstrated that polymeric stents increase LLL over time, and that a polymer-free stent such as the YUKON DES that also releases a drug did not have increasing late loss over time. This suggests that it is possible to modulate arterial response by changing the technology and omitting the polymer. Second, clinicians tend not to recognise that restenosis in DES can occur later than in BMS. With the latter, it was assumed that after six months the risk of restenosis is diminished because the intima has become stable or regresses.

However, after six months with DES the outcome is less certain. Clinicians should therefore be aware that a patient presenting with chest pain two years after DES placement could have restenosis. The findings may also have implications for the ongoing follow-up of the Synergy between PCI with Taxus and Cardiac Surgery (SYNTAX) trial,8 which compared DES with coronary artery bypass grafting (CABG) in 1,800 patients with three-vessel or left main coronary artery disease. A protracted LLL among DES-treated patients in this study may translate into higher than expected TLR rates over the full five-year follow-up. The study supports the concept that a polymer-free stent can limit the delay in healing and reduce any harmful inflammatory response to the polymer. The authors comment that there are also implications for clinical trial design. For stents with permanent polymers still in clinical development, they suggest that angiographic studies should potentially be delayed in order to capture the type of delayed healing found in their study.

In another study, coverage of the CYPHER and YUKON rapamycin-eluting coronary artery stents was investigated in a randomised trial using optical coherence tomography (OCT).9 Two groups of 12 patients were implanted with either a CYPHER (n=12) or YUKON (n=12) stent and monitored for 90 days. Mean neointimal thickness and binary stent strut coverage were significantly lower for the CYPHER stent than the YUKON stent (see Table 3). Mean binary stent strut protrusion (i.e. the degree to which uncovered stent structures extended into the vessel lumen) was significantly lower for the YUKON than the CYPHER stent. The authors commented that such uncovered protrusions could increase the thrombotic risk and may have important implications for stent design.

The findings oppose the generally accepted principle that less in-stent restenosis in a coronary stent is advantageous; it appeared that at least enough neointima to cover the stent struts and prevent protrusion may be important for safety.

Overall, the studies show that limiting neo-intimal coverage and thickness is important in improving long-term stent function and that different types of stents are covered at variable rates post-PCI. The degree of neo-intimal coverage is an important concept; there should be sufficient to cover protrusions in the vessel but not so much that it leads to restenosis and limits blood flow.

References

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