Systemic Drug Therapy for Restenosis
“Déjà Vu All Over Again”
The problem of restenosis, a major limitation of angioplasty since its introduction in 1978, may finally be under control. The rate of restenosis has fallen from 30% to 40% to 15% to 20% with the advent and widespread use of coronary stents. Now, with the introduction of intravascular radiation therapy, in-stent restenosis seems to be reduced by 50%, and with the almost unbelievable preliminary results of drug-eluting stents, the rate of restenosis may be reduced to less than 5% in de novo lesions. Although these outcomes are truly remarkable, both intravascular radiation therapy and drug-eluting stents have a number of significant limitations.
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Radiation has safety issues and is limited by geographical miss, edge restenosis, and late stent thrombosis. Drug-eluting stents are likely to be expensive and are unproven in unfavorable anatomy. Even in optimal patients, restenosis can still occur with both types of treatment. A continued search for a simpler and effective means of controlling this problem seems reasonable given these limitations. In this issue of Circulation, Farb et al1 present evidence that everolimus, an oral analog of rapamycin, can reduce neointimal thickness by more than 40% after stent placement in a rabbit model of restenosis. Rapamycin is a naturally occurring macrolide antibiotic produced by the actinomycete Streptomyces hygroscopicus found on Eastern Island. It has been shown to be a potent inhibitor of cytokine and growth factor-mediated cell-proliferation.2 It is known to bind to a cellular receptor FKBP-12 and to inhibit the target of rapamycin (TOR), an important signaling pathway for protein synthesis and cell cycle progression. As a result, rapamycin arrests the cell at the end of the G1 cell cycle. Animal studies have shown a significant reduction in intimal hyperplasia and smooth muscle cell proliferation. Clinical trials have been remarkably positive. The RAndomized study with the sirolimus-eluting Bx VELocity balloon-expandable stent (RAVEL) trial randomized 238 patients to a sirolimus-eluting stent or a bare metal stent.3 The 6-month angiographic late loss was remarkably low at −0.01±0.33 mm for the drug-eluting stent group versus 0.80±0.53 mm for the steel stent (P<0.001). In the study reported by Farb and colleagues,1 everolimus, an orally active derivative of rapamycin (sirolimus) with a hydroxyl chain at position 40, was studied. This drug inhibits growth factor-induced proliferation of hemopoietic and non-hemopoietic cells. While the immunosuppressant activity of everolimus is less than that of rapamycin, it is at least as potent as rapamycin in heart and kidney transplant models. Although everolimus has yet to be tested for the prevention of restenosis in humans, the beneficial effects seen in the rabbit model suggest significant potential for this oral analog.
The use of systemic drug therapy to prevent restenosis is not new and is a return to a treatment strategy that has been extensively studied in the past with dismal success. As Yogi Berra said, “It’s déjà vu all over again.” The concept of drug therapy to prevent restenosis began with the introduction of coronary angioplasty in the late 1970s. Experimental studies suggested that platelets and thrombi could lead to smooth muscle proliferation, an important component of restenosis, largely through the release of platelet-derived growth factor (PDGF). As a result, numerous antiplatelet and anticoagulant drugs were studied, with disappointing results. Subsequently, the role of calcium antagonists, omega 3 fatty acids, lipid-lowering drugs, anti-inflammatory drugs, steroids, growth factor antagonists, angiotensin-converting enzyme inhibitors, and various antiproliferative agents were also studied.4 Although most experimental studies and some small initial studies showed promise, subsequent large, multicenter, randomized trials failed to do so. A recent example of this is the Prevention of REStenosis with Tranilast and its Outcomes (PRESTO) trial. In this study, 11 500 patients were randomized to placebo or tranilast, an antiallergic drug with inhibitory effects on PDGF and cytokines. Despite the promising results from 5 smaller clinical studies, the results of this large multicenter study were resoundingly negative. This study combines with over 80 randomized studies of drugs to prevent restenosis conducted over the past 24 years. The critical question is why have these studies been so negative? Of the many potential explanations, the inability to achieve adequate drug levels at the angioplasty site has been most commonly sited. Animal studies have supported this, as efficacy is usually only demonstrated in animal models when high dosages of drugs were used (sometimes 10 times clinical doses).5 The recognition of this fact has lead to the development of local drug delivery systems and drug-eluting stents. Local drug delivery using perfusion balloons has proven difficult, primarily because of a low uptake of drug at the angioplasty site. In contrast, drug-eluting stents have been shown to be highly effective in providing an adequate concentration of drug. The dramatic results of the recent clinical trials of not only rapamycin but also paclitaxel-eluting stents support the hypothesis that local drug delivery is essential to the inhibition of restenosis.3,6–8⇓⇓⇓ The restenosis rate in these studies has ranged from 0% to 4%. Although these results are preliminary and larger multicenter randomized trials are still ongoing, enormous optimism exists that the Achilles’ heel of angioplasty may finally be a thing of the past. Before we celebrate, however, there are a number of lessons to be learned from these preliminary studies. Importantly, not all drug-eluting stents are effective. For instance, the early experience with actinomycin D and Quad DDS-QP2 drug-eluting stents has been very disappointing because of a high restenosis rate and poor long-term outcome.9 So is it the local drug delivery, the drug, or both that is the critical element in reducing restenosis? Although both are likely to be important, picking the right drug is essential.
In the past, choosing the right drug has not been easy because of a poor understanding of the pathophysiology of restenosis. In the early 1980s, it was largely thought that platelets and thrombi were the primary process responsible for restenosis. Subsequent studies demonstrated the important role of smooth muscle cell proliferation, and considerable study of growth factors and cytokines ensued. The importance of inflammation and matrix metabolism is now recognized as a key component as well. However, the most important observation has been the critical role of vascular remodeling in restenosis.10 Experimental studies and subsequent clinical intravascular ultrasound studies have demonstrated that geometric remodeling with constriction of the artery plays an important role in the development of restenosis after percutaneous transluminal coronary angioplasty. The benefit of stenting is largely thought to be its inhibition of this adverse process. In fact, coronary stenting results in more intimal hyperplasia than does balloon angioplasty alone and yet has a lower restenosis rate because of their prevention of unfavorable remodeling. By eliminating the problem of vascular remodeling, stenting has simplified the pharmacological approach to the problem by allowing treatment to focus primarily on smooth muscle cell proliferation.11 The recent success with rapamycin- and paclitaxel-coated stents provides clues for future drug development. A common property of both agents is that they are cytostatic instead of cytotoxic. They are also potent inhibitors of smooth muscle proliferation. There are now an impressive number of newly discovered inhibitors of smooth muscle proliferation that share these features. For instance, the tumor suppressor protein PHEN inhibits growth factor-induced activation of both Akt and p70, thus reducing smooth cell proliferation. It also has effects on TOR similar to those of rapamycin, and it has been suggested as potential new agent to inhibit restenosis.12 There is little doubt that as our understanding of the cellular signaling process advance, new and effective therapeutic agents to inhibit restenosis will be development.
An important question raised by the study of Farb and colleagues1 is whether we have adequately evaluated systemic drugs in the current stent era. Whereas there have been more that 60 major randomized clinical trials of pharmacological agents before stents were introduced,13 there have been only 16 after. Of these, 8 have been positive and include such agents as probucol, the anti-oxidant AG1-1067, cilostazol, troglitazone, valsartan, pemirolast, and folic acid. Although drug-eluting stents have a number of potential advantages, they also have a significant number of limitations. The key advantage of drug-eluting stents is that they effectively provide a locally delivered drug without any systemic toxicity. The drug can be given over a defined period of time with kinetics, which is appropriate to the vascular healing process. However, they cannot be given indefinitely or for a long period of time given a physical limitation of the amount of drug that can be placed on the stent. In addition, drug-eluting stents need to be placed carefully to avoid geographical miss. Perhaps the most serious concern of drug-eluting stents is their cost. It’s estimated that these stents may cost 2 to 3 times more than conventional stents, and in a number cost analyses, the use of drug-eluting stents in patients with multivessel disease was shown to escalate the cost of the procedure to exceed that for bypass surgery. The use of oral agents in combination with standard metal stents may offer a potentially cheaper and more effective means of dealing with restenosis. If an oral agent were effective, it would allow more flexibility in the choice of the type of stent to be used. It could also be used as an adjunct in very high-risk cases or in recurrent restenosis. It’s also possible that an effective oral agent might reduce the need for stenting altogether, as stents have not been shown to be of value in certain circumstances, such as in small vessels <2.5 mm in diameter. We also know that certain types of lesions, such as discrete lesions in large vessels, have a relatively low restenosis rate, and the use of a less expensive pharmacological therapy may prove to be far more cost effective than the use of a more expensive drug-eluting stent. The return to oral drug therapy is not inappropriate and may offer a simpler and equally effective method to help control the problem of restenosis in the future. Whether drug-eluting stents, oral drugs, or both eventually prove to be effective, the future is extremely bright. There is little doubt that the control of restenosis will revolutionize the field of interventional cardiology, and without the problem of restenosis, the benefits of interventional therapy can be finally fully appreciated.
The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association.
- ↵Farb A, John M, Acampo E, et al. Oral everolimus inhibits in-stent neointimal growth. Circulation. 2002; 106: 2379–2384.
- ↵Marx SO, Marks AR. The development of rapamycin and its application to stent restenosis. Circulation. 2001; 104: 852–855.
- ↵Mody VH, Durairaj A, Mehra AO. Pharmacological approaches to prevent restenosis.In Faxon DP, ed. Restenosis: A Guide to Therapy. London, UK: Martin Durnitz; 2001: 97–112.
- ↵Lafont A, Faxon DP. Why do animal models of post-angioplasty restenosis sometimes poorly predict the outcome of clinical trials? Cardiovasc Res. 1998; 39: 50–59.
- ↵Grube E, Silber SM, Eugene K, et al. Taxus I: prospective, randomized, double-blind comparison of NIRx stents coated with paclitaxel in a polymer carrier in de-novo coronary lesions compared with uncoated controls. Circulation. 2001; 104 (suppl II): II-463. Abstract.
- ↵Gershlick AH, Descheerder I, Belgium L, et al. Local drug delivery to inhibit coronary artery restenosis: data From the ELUTES (EvaLUation of pacliTaxel Eluting Stent) clinical trial. Circulation. 2001; 104 (suppl II): II-416.Abstract.
- ↵Park SJ, Shim WH, Ho DS, et al. The clinical effectiveness of paclitaxel-coated coronary stents for the reduction of restenosis in the ASPECT trial. Circulation. 2001; 104 (suppl II): II-464.Abstract.
- ↵Grube E, Hauptmann K, Colombo A, et al. SCORE trial interim safety results: despite efficacy, late stent thrombosis with the QuaDDS-QP2 stent. J Am Coll Cardiol. 2002; 39: 38A.Abstract.
- ↵Lafont A, Topol E, eds. Arterial Remodeling: A Critical Factor in Restenosis. Boston, Mass: Kluwer Academic Publishers; 1997.
- ↵Farb A, Sangiorgi G, Carter AJ, et al. Pathology of acute and chronic coronary stenting in humans. Circulation. 1999; 99: 44–52.
- ↵Hung J, Kontos CD. Inhibition of vascular smooth muscle cell proliferation, migration, and survival by the tumor suppressor protein PTEN. Atheroscler Thromb Vasc Biol. 2002; 22: 745–751.
- ↵Faxon DP, ed. Restenosis: A Guide To Therapy. London, UK: Martin Dunitz; 2001.