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 Prevention of Neointimal Hyperplasia - Taxol, Rapamycin, and Radiation

Alexander Clowes, MD

The animal and clinical studies of intimal hyperplasia during the last two decades have documented over and over again that it is a response to injury and a complication of all forms of arterial reconstruction.

Although pathological remodeling (a decrease in overall arterial cross-sectional area) is an important mechanism for luminal narrowing in vessels treated by balloon angioplasty, intimal hyperplasia followed by stenosis or restenosis is the principal cause for failure in vein and synthetic grafts and in stented atherosclerotic arteries. Restenosis affects ca 20-30% of coronary and other small arterial reconstructions, and the treatment of restenosis is further vascular reconstruction.

The arterial wall thickens and the lumen narrows because vascular smooth muscle cells (SMCs) accumulate in the intima and secrete matrix proteins. We know from animal studies that SMCs are derived from adventitial cells and blood borne stem cells as well as populations of SMCs in and around the zone of injury.

The migration of these cells from one tissue compartment to another followed by proliferation in the intima are required for intimal thickening and are regulated by factors released from thrombus (thrombin, PDGF), inflammatory cells (TNF, IL1b), or the vascular wall cells themselves (basic FGF, TGFb, etc.).

The growth and migratory factors as well as critical intracellular signaling pathways represent logical targets for pharmacological blockade and the prevention of intimal hyperplasia.

Adjuvant Therapy for Coronary Interventions

Approaches to prevention including adjuvant pharmacology (taxol and rapamycin) and radiation have been developed for coronary stent angioplasty and are now being tested in the peripheral arterial circulation. Both taxol (e.g. Paclitaxel) and rapamycin (e.g. Sirolimus) and related drugs released from coated stents effectively suppress intimal hyperplasia and prevent late lumen loss following coronary intervention (review: Byrne et al. Drug Safety 2009;32(9):749). Late coronary occlusion possibly related to sudden thrombosis does occur and appears to be due to incomplete endothelial regeneration and intimal healing (Camenzind et al. Circulation 2007;115:1440; Joner et al. J AM Coll Cardiol 2006;48:193; Luscher et al. Circulation 2007;115:1051). Because of the small risk but catastrophic consequences of coronary thrombosis, long term treatment with dual antiplatelet therapy with aspirin and a thienopyridine (e.g. Clopidogrel) is recommended.

Locally delivered radiation also prevents further narrowing in human coronary arteries treated with stents for restenosis after balloon angioplasty (Teirstein et al. N. Engl. J. Med 1997; 336:1697). Enthusiasm for this form of adjuvant therapy has diminished as longer term studies have revealed two important and serious limitations. It appears that the stented and irradiated arteries are at risk for sudden thrombosis, because the luminal endothelial layer is not reestablished. In addition, although the radiation effectively suppresses intimal hyperplasia and lumenal narrowing in the stented zone, the neighboring artery at the margin of the radiation field appears to develop exuberant intimal hyperplastic ("candy wrapper ") lesions (Albiero et al. Circulation 2000; 101:18).

Adjuvant Therapy for Peripheral Vascular Interventions

The experience with adjuvant therapy to suppress intimal hyperplasia and lumen loss for peripheral vascular reconstructions is considerably less extensive than for coronary stent angioplasty, and furthermore it is not at all clear that the approaches that work in coronary arteries will work equally well in the peripheral circulation. For example, in the SIROCCO trial, sirolimus-eluting and bare nitinol self-expanding stents were compared in 93 patients undergoing treatment for superficial femoral artery stenoses or occlusions (average lesion length 8.3 cm); at 24 months, the restenosis rate was the same (Duda et al. J Endovasc Ther 2006; 13:701). However, two trials comparing paclitaxel-coated to uncoated balloon catheters for the treatment of superficial femoral artery disease (Werk at al. Circulation 2008; 118:1358; Tepe et al. N Engl J Med 2008; 358:689) have demonstrated a significant reduction in late lumen loss and target-lesion revascularization in the drug treated groups at 24 months. Approximately 10% of the patients received stents. Greater than 90% of the drug was released at the time of balloon distension. In one of the trials (Tepe et al. N Engl J Med 2008; 358:689), an additional group of patients received treatment with an uncoated balloon and paclitaxel delivered regionally in the contrast medium; the late lumen loss in this group was the same as in the control group and significantly worse than in the paclitaxel-coated balloon group. These findings support the conclusion that locally delivered drugs are efficacious in preventing lumen loss after superficial femoral artery angioplasty, but the amount and mode of delivery may affect the outcome.

Endovascular brachytherapy also prevents restenosis after femoropopliteal angioplasty (Pokrajac et al. Radiotherapy and Oncology 2005; 74:3), but its widespread application has been somewhat limited by the requirement for radiation oncology equipment.

Conclusions

Until very recently, symptomatic restenosis of a stented artery or stenosis of a bypass graft could not be prevented and usually required further vascular reconstruction. A number of drugs have been tried including antithrombotic agents, anticoagulants, ACE inhibitors, and cytotoxic agent, and they have all failed.

Taxol, rapamycin, and radiation have achieved some success in preliminary trials in suppressing intimal hyperplasia, in part because the drugs and radiation are particularly effective when they are delivered or released into the injured artery. This form of delivery targets the vascular bed at risk and prevents systemic toxicity.

It is unfortunate that none of them is specific for the SMC, the cell responsible for the intimal lesion, and it is possible that failure of endothelial regeneration may leave the reconstructed vessel vulnerable to late thrombosis as has been shown in irradiated and stented coronary arteries. Adjuvant therapy currently under development and targeted specifically at the SMCs would be expected to circumvent this problem.

Updated November 2009

Copyright © 2009, Society for Vascular Surgery. All rights reserved.

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