BALLOON ANGIOPLASTY

The best way to treat in-stent restenosis is not clear. Most patients presenting with clinical recurrence undergo repeat balloon angioplasty using either the same size or a larger balloon. This has been shown to be safe and to increase the lumen size, although intravascular ultrasound has shown that catheter based strategies fail to recover the lumen size achieved during initial stent implantation. In one study it was shown that despite achieving an increase in minimal lumen area from a mean (SD) of 2.1 (1.4) to 6.2 (1.7) mm² and a decrease in intimal area from 5.5 (2.4) to 2.9 (1.6) mm², the final lumen area was 1.3 (1.9) mm² less than the preintervention stent area (p < 0.0001).5 Some have suggested that the predominant effect of balloon angioplasty on in-stent restenosis is overexpansion of the stent rather than any significant effect on intimal tissue within the stent. It is probably a combination of both but a return to the immediate post-stent dimensions does not appear achievable. Part of the reason for this may by the constraints imposed by the stent itself—there appears nowhere for the tissue to go. As the principle of “the bigger the better” is well established it is perhaps not surprising that re-restenosis occurs after balloon treatment.

The outcome of balloon redilatation on re-restenosis appears to depend on the nature of the in-stent restenosis. Diffuse disease (fig 3) has been reported to have a high re-restenosis rate with figures of up to 80% quoted.6 Baim et al reported the US experience of treating in-stent restenosis with catheter based techniques. In patients treated with balloon angioplasty the re-restenosis rate was 54% (with a mean absolute lumen stenosis of 84%).7 Such high rates appear to translate into a high incidence of clinical restenosis. Tan et al reported that 22 of 47 patients with in-stent restenosis treated with angioplasty developed subsequent clinical events.8 Many of the published data apply to the Palmaz-Schatz stent, and whether balloon intervention for in-stent restenosis will be different for other stents is unclear.

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Figure 3

(A) Diffuse in-stent restenosis in a Cook GR II stent placed in the left anterior descending artery; (B) rotational atherectomy treatment; (C) final result after rotational atherectomy and ballooning. Regaining the original in-stent luminal diameter can be difficult.

The original value of stenting was based on the bigger the better principle. Thus it would appear to be a disadvantage if as large a lumen as possible cannot be achieved once restenosis has occurred. As restenosis has been considered a predictor for further restenosis then this makes treatment even more difficult.

ATHERECTOMY

One way of achieving a larger lumen following restenosis is to remove tissue (fig 3). Rotational atherectomy, which has become a niche intervention for treating calcified lesions, is being tested as a treatment for in-stent restenosis.9 Trials such as the ARTIST study have started recruitment. Abstracts and meeting presentations of available data from other sources have suggested some benefit. It appears that a larger lumen can be achieved using atherectomy. In one study the changes in lumen dimeter were increased from 0.7 (0.4) to 2.0 (0.5) mm after atherectomy and then to 2.4 (0.7) mm following adjunctive ballooning.10 It is unclear whether this absolute increase in lumen diameter, achieved through tissue removal, translates into any clinical advantage.

The BARRASTER registry involving 14 institutions has just finished the enrollment of 145 patients. Results presented to date show that the mean (SD) burr size used was 1.9 (0.7) mm, the final burr size 2.1 (0.3) mm, with atherectomy only being used in 26% of cases. The clinical success rate was 90% and the complication rate 4% including four dissections. There were, perhaps surprisingly, three deaths reported. The minimal luminal diameter before treatment was 0.6 (0.4) mm, after rotational atherectomy it was 1.7 (0.4) mm, and after atherectomy plus ballooning it was 2.1 (0.6) mm, compared with a reference minimal luminal diameter of 2.8 (0.5) mm. The mean clinical event rate at follow up in the 87 patients so far presented is reported to be 38%, but it is higher in those who had rotational atherectomy alone compared with those who also had ballooning.

It is unclear how much tissue needs to be removed and whether the principle of following the atherectomy with low pressure ballooning as is used in non-stented arteries (to prevent further injury) applies equally to post-stent atherectomy. Cost-benefit analyses need to be done and may help decide—for example, whether the use of multiple burrs is justified.

Although in-stent tissue can be safely removed with atherectomy, and while such treatments may reduce the re-restenosis within the stent from between 50–80% after ballooning to 30–40%, this cannot be regarded as satisfactory from either the clinical standpoint or the cost-benefit perspective. Prevention may be a better option.

NON-REACTIVE STENTS

Metal has well described effects on flowing blood. Platelets are activated and may initiate smooth muscle cell proliferation through the release of growth factors. Platelet involvement leads to complex thrombus formation containing fibrin, thrombin, and other formed blood elements. The generated thrombin stimulates smooth muscle hyperplasia. Platelets are attracted to metal through the presence of a negative charge and have been shown to cover the struts within the first few minutes after stent placement. The stent itself initiates a well recognised inflammatory reaction within the vessel wall and exerts damage on smooth muscle cells, which in turn produce their own growth factors. There is greater intimal hyperplasia at the points where the stent struts impact on the medial layer. Stents that exert continued outward pressure on the vessel wall may result in an even greater increase in in-stent restenosis. To overcome the effects of the stent on blood and tissue, attempts have been made to produce non-reactive stents.

Polymer and polymer covered stents have been investigated extensively in animal models and it has been shown that the polymer itself may produce an excess tissue response.11 The degree of response varies with the type and amount of polymer—for example, it occurs with poly-L-lactide but not with others. Van der Giessenet al evaluated the biocompatibility of five different polymers and found extensive inflammatory responses with both biodegradable and non-biodegradable forms.12 This, together with the difficulty in developing a non-metal stent with sufficient radial strength, has led to a waning of interest in the pure polymer stent. Polymers are available that do not induce an inflammatory response and these have been used to coat stents.

RADIATION EMITTING STENTS

External radiation is a well established treatment for benign and malignant proliferative conditions. Such treatment has been shown to benefit keloid formation. The potential for local radiation to inhibit the arterial response to injury is currently the focus of major research programmes. King13 has recently highlighted the potential of radiation to deal with in-stent restenosis. Both γ radiation in the form of ¹⁹²Iridium given via an external source placed within the stented artery and β radiation, delivered either locally by the positioning of intrastent Strontium/Yittium coils (⁹⁰Sr) or by making the stent itself the radiation source, are being evaluated. The stent is made radioactive by placing it in a nuclear reactor so that it delivers sufficient amounts of³²P to the artery. The advantage of using β emitters is their short penetration and because only 1/10 000^th of the dose is present at five months. Initial studies have demonstrated an inhibitory effect on smooth muscle cells growing in culture. A dose of³²P as small as 0.006 μCi/cm of wire significantly inhibited smooth muscle cell growth.14 A single dose of external radiation has been shown in an animal model to reduce intimal hyperplasia following balloon angioplasty by up to 37%.15In variations on a porcine model a number of investigators have delivered endovascular radiation in the form of ¹⁹²Iridium and showed a dose-response relation with the greatest benefit at doses of 3.5–25 Gy. Again there appeared to be about a 40% reduction in intimal hyperplasia. β Emitting stents in a porcine model have also resulted in the development of less intimal area reduction compared with controls (2.4 (0.8) v 1.6 (0.7) mm²) with the degree of reduction being dose dependent.16 These radiation effects are not species specific.

There seems little doubt that radiation given as either as a γ emitter delivered endoluminally after stent deployment or as a β emitter given endoluminally after stenting or incorporated into the stent itself significantly inhibits the smooth muscle cell response. Such findings have led to a number of clinical trials. Initial studies in the peripheral circulation have shown a variable effect with⁹⁰Yittium delivered locally. Early reports of a clinical evaluation in the coronary artery by Popowski et al have been disappointing,17 and dose adjustments are planned. The effect of ¹⁹²Iridium on re-restenosis rates in patients randomised to stent plus radiation treatment or stent plus placebo has recently been published.18 The SCRIPPS trial enrolled patients presenting with restenosis after angioplasty, a potentially high risk group for re-restenosis that probably accounts for the high incidence of further restenosis in the control group. Patients were randomised to either stent plus radiation or stent plus placebo. The 55 randomised patients were re-evaluated at six and 12 months. The late loss in the treated group at six months was 0.38 (1.06) compared with 1.03 (0.97) mm in the control group (p = 0.03). The categoric restenosis rate was reduced dramatically to 17% in the treated group compared with 54% in control patients (p = 0.01).18

Despite the positive nature of this exciting study it is clear that the global application of such treatments will have a major impact on how interventionists work. Anxiety about the potential adverse effects of radiation both locally and generally still exists in some quarters and it has been suggested that much longer follow up to determine safety is required. Radiation protection for the interventionist may become an issue. The local effects of radiation on the vessel wall have been shown to lead to adverse changes such as stromal fibrin exudate, thinning of the media, and adventitial fibrosis,19 and these may explain the occurrence of one false coronary aneurysm and two occlusions in 21 patients in a clinical trial of ¹⁹²Irdium. The results of the IRIS study evaluating ³²P emitting stents in man are awaited. Storage problems and decay in radiation activity may be major drawbacks of β emitting stents.

DRUG ELUTING STENTS

Delivering drugs that prevent restenosis on to the stent itself has a number of advantages. The dose of drug required is less than would be needed systemically reducing the incidence of systemic side effects. The drug can be tailored to the pathological process and can be retained for the duration of the process. Achieving the correct balance between rate of elution and degree of retention is clearly important. Efficient ways of attaching the chosen agent to the stent are required. Ideally the agent should elute off the stent to influence the interstitial spaces, something that is less likely to happen if the agent is covalently bonded to the metal as with the Carmeda AB. This process was used to bind heparin to the Palmaz-Schatz stent in the Benestent II trial.20

An alternative way to deliver drugs with the stent is to incorporate them passively into a polymer coating already attached to the stent. The advantages are a lack of affect of the binding process on the biological activity of the agent, although the absolute quantity of the drug loaded by this method is less than if it were covalently bound.

Polymer coatings have been the subject of much discussion as they can be responsible for local inflammation and neointimal proliferation. The choice of the coating is therefore as important as that of the agent adsorbed to it. Studies in our laboratory using cellulose polymer coated stents in injured internal iliac arteries showed no increase in neointimal hyperplasia with a cellulose polymer compared with plain wire stents.21