New approaches to preventing restenosis

Drugs

Several drugs, including those with antiplatelet, anti-thrombotic, antiproliferative, and anti-inflammatory properties, have been used to prevent restenosis, but except for probucol and prednisolone their contribution has been largely disappointing.^{w14 w15} The role of drugs in preventing restenosis is likely to be small because the principal mechanism of restenosis after balloon angioplasty concerns remodelling of the artery. These drugs might have a role in preventing neointimal proliferation after stenting.

Coronary stents

Coronary stents Stents produce the largest net gain in lumen diameter because they achieve an immediate large gain with modest later loss of diameter. The Belgium Netherlands stent study (BENESTENT) and the stent restenosis study (STRESS) showed that stents reduce restenosis rates after balloon angioplasty.8 9 These studies were conducted on “ideal” lesions, however, and higher restenosis rates have occurred with more complex lesions. Several materials, coatings, and designs have been developed in the quest for the ideal stent (see table A on bmj.com>). Most have shown little success, except for drug eluting stents.

Drug eluting coronary stents

Using a coronary stent for local delivery of drugs combines scaffolding with targeted drug action. Although initial research and clinical trials concentrated on sirolimus and paclitaxel, numerous agents with antiproliferative properties are currently under investigation (see table B on bmj.com>).

Debulking devices

The occurrence of restenosis is reduced when larger minimum lumen diameters are achieved after stenting. This makes a case for the use of debulking devices to mechanically reduce plaque volume. Early trials comparing directional coronary atherectomy with balloon angioplasty showed an increased mortality and Q wave infarction with atherectomy.15 ^w25 Subsequently, strategies to optimally debulk combined with adjunctive balloon angioplasty to achieve the largest possible lumen diameters were tested against conventional balloon angioplasty.16^w26 Less restenosis was shown with directional coronary atherectomy compared with plain balloon angioplasty, but there was no difference in revascularisation of the target vessel at one year. Further, this benefit came at the cost of a higher incidence of increases in periprocedural myocardial enzymes. This failure to show consistent benefit from debulking has been attributed to the late loss in lumen diameter being proportional to the acute gain after the procedure (device “taxing”). A synergistic approach using directional coronary atherectomy and coronary stenting might have a role in reducing restenosis rates in complex lesions.^{w27 w28}

Gene therapy

Vascular gene therapy can potentially control cellular growth related restenosis by modifying gene expression. Antisense oligonucleotides can be used to block gene expression by binding segments of specific mRNA with complementary DNA sequences. In a porcine model of restenosis, intramural delivery of specific antisense oligonucleotides completely eliminated c-myc expression and dramatically reduced neointimal proliferation.^w29 An alternative approach is by transfer of genes, which have beneficial antiproliferative effects (for example, genes for endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor). Gene transfer has mostly been achieved using adenoviruses as vectors, although plasmid DNA and retroviruses have also been used. Animal studies with gene transfer have shown marked inhibition of neointimal proliferation; phase I studies in humans are under way.^w30

Intracoronary radiation

The role of intracoronary radiation in preventing restenosis in de novo lesions is not entirely clear. Although one study showed a dose dependent decrease in the rate of restenosis after angioplasty, data from two studies in the United States were not favourable.17 ^{w31 w32}

Balloon angioplasty

In contrast to the atherosclerotic plaque in de novo lesions, the hyperplastic neointima is relatively less compressible, and therefore the emphasis has been on debulking rather than on plaque compression to prevent recurrent stenosis. Nevertheless, balloon angioplasty has been used extensively. The occurrence of restenosis in this setting largely depends on whether the restenosis is focal or diffuse. The recurrent restenosis rate with diffuse lesions has been shown to be twice that of focal lesions (63% v 31%, respectively).^w33 However, the recent angioplasty versus rotational atherectomy for treatment of diffuse instent restenosis trial (ARTIST) suggests that even for diffuse lesions balloon angioplasty is better than rotational atherectomy.19 Plain balloon angioplasty is also likely to be successful in patients with restenosis due to poorly apposed stent struts, where luminal gain depends more on additional stent expansion than tissue compression.^w34 A meta-analysis concluded that balloon angioplasty should be the procedure of choice when a good immediate outcome can be expected, because the nine month major adverse cardiac event rate is virtually identical with all forms of treatment.^w35 Additional stenting within the region of instent restenosis (“stent sandwich”) improves immediate angiographic outcomes, but long term results are poor.^{w36 w37}

Cutting balloon angioplasty

Cutting balloon angioplasty utilises a standard balloon catheter with three or four microblades (depth 0.18 mm, thickness 0.70-0.76 mm). The blades, attached longitudinally and folded within the balloon, are exposed on inflation and cut the neointimal tissue, facilitating plaque compression. They also help to anchor the balloon to the neointima (standard balloons tend to slip proximally or distally during inflation). Cutting balloon angioplasty for instent restenosis is associated with lower rates of revascularisation of target lesions and restenosis.^w38-w40 At many centres, cutting balloon angioplasty combined with intracoronary radiation is the treatment of choice for instent restenosis.

Debulking devices

Intracoronary radiation (brachytherapy)

A more recent approach to instent restenosis is intracoronary radiation or brachytherapy, on the grounds that it may control the excessive proliferative response and limit neointima formation, analogous to low doses of ionising radiation to treat benign proliferative disorders such as keloids, heterotropic bone formation, and pterygia.^w43 Different isotopes on various platforms have been used to develop practical systems for endovascular brachytherapy. The platforms are catheter based systems such as line source wires, radioactive beads (delivered hydraulically), and balloons filled with radioactive gas or liquid, or stents incorporating γ (low energy, high penetration) or β (high energy, low penetration) emitters.

The first intracoronary brachytherapy procedure in humans was performed in Caracas, Venezuela in 1994.^w44 Endovascular brachytherapy has since been tested in over 5000 patients, leading to approval by the Food and Drug Administration for the treatment of instent restenosis with both β and γ radiation.^w45

Of the trials for the treatment of coronary instent restenosis by brachytherapy (see table C on bmj.com>), the important ones are catheter based radiotherapy to inhibit restenosis after coronary stenting (SCRIPPS I), intracoronary gamma radiation therapy after angioplasty inhibits recurrence in patients with instent restenosis (WRIST), and localised intracoronary gamma radiation therapy to inhibit the recurrence of restenosis after stenting (GAMMA I).20 21 ^w46 Initiated at the Scripps Clinic in March 1995, SCRIPPS I tested the efficacy of iridium-192 (γ source) in 55 patients with restenosis. At follow up, the patients who received radiation had better mean minimum lumen diameters, less late loss of lumen, and lower restenosis rates. The WRIST trial randomised 100 patients with instent restenosis and 30 patients with instent restenosis in saphenous vein grafts to ¹⁹²Ir or placebo. Restenosis was significantly reduced, particularly in patients with diabetes and those with vein grafts. Similarly, in the GAMMA I study on 252 patients, the primary end point—death, myocardial infarction, and the need for repeat revascularisation of the target lesion during nine months of follow up—occurred in 53 patients assigned to placebo (44%) and 37 patients assigned to ¹⁹²Ir (28%). Similar results have been observed with β radiation in the proliferation reduction with vascular energy trial (PREVENT) and intimal hyperplasia inhibition with beta in-stent trial (INHIBIT).22 ^w47

Two important complications related to brachytherapy are edge restenosis (“candy wrapper” effect) and the risk of late thrombosis. Edge restenosis was first noted with radioactive stents and is possibly the result of radiation dose “fall-off” at the edges of the stent combined with vessel wall injury from inflation of the balloon outside the stent margins. Edge restenosis may be prevented by avoiding the “geographic miss,”—that is, a portion of the vessel that has undergone injury during the procedure, but has not received the intended dose of radiation. The likelihood of geographic miss can be decreased by radioactive coverage of an adequate length of the vessel.^{w48 w49}

Delayed (after one month) thrombosis may occur in up to 9% of patients receiving additional stents at the time of radiation.23 Therefore, such repeat stenting (stent sandwich) is discouraged. Further, a long course (more than six months) of antiplatelet therapy is recommended for all patients undergoing brachy-therapy. Such treatment has reduced the risk of late thrombosis to that of the control population.^w50

Drug eluting coronary stents

Preliminary data on a paclitaxel coated stent has shown a high major adverse cardiac event rate, which was largely due to the need for repeat revascularisation of the target lesion.^w51 The potential for improved results with drug eluting stents in the treatment of instent restenosis is being explored.