Coronary restenosis: a review of mechanisms and management

SPECIAL ARTICLE

Coronary Restenosis: A Review of Mechanismsand Management

Vivek Rajagopal, MD, Stanley G. Rockson, MD

Percutaneous coronary interventions represent an attractive al-ternative to surgical revascularization; nevertheless, these tech-niques continue to be characterized by their propensity to elicitrestenosis. Despite an exhaustive search for an effective phar-macotherapy to treat or prevent restenosis, hundreds of clinicaltrials have failed to identify an agent with proven therapeuticbenefit. Recently, however, the Food and Drug Administration

approved intracoronary radiation (brachytherapy) as a viabletherapeutic option for in-stent stenosis. In addition, recent ran-domized trials have shown encouraging results for drug-elutingstents. This article reviews the pathophysiology of restenosis,along with current and future treatment options. Am J Med.2003;115:547–553. ©2003 by Excerpta Medica Inc.

In 1977, Andreas Gruntzig performed the first percu-taneous transluminal coronary angioplasty. Al-though this approach was initially greeted with en-

thusiasm, investigators soon discovered that a substantialpercentage of patients experienced recurrent ischemiawhen the treated arteries renarrowed. Over the years, in-vestigators have confirmed that 30% to 60% of patientsdemonstrate restenosis within 6 months following an an-gioplasty (1). Despite this limitation, angioplasty has be-come the most common revascularization procedure forcoronary artery disease. Although the advent of coronarystents has reduced the incidence of restenosis (1), theproblem still occurs in 20% to 30% of stented vessels (1).Furthermore, the numerous drugs and mechanical inter-ventions that have been used to address restenosis havehad minimal success. Restenosis severely limits the ben-efits of angioplasty in many patients, particularly thosewith diabetes or multivessel coronary artery disease.

PATHOPHYSIOLOGY

Restenosis reflects a cascade of molecular and cellularevents within the vascular wall. Iatrogenic injury of theblood vessel leads to the release of numerous vasoactive,thrombogenic, and mitogenic factors. Within this cas-cade, two major processes can be discerned: arterial re-modeling and neointimal hyperplasia.

Arterial RemodelingVascular remodeling occurs naturally in atherosclerosis.Glagov et al noted that human coronary arteries oftenenlarge in response to plaque formation as a compensa-tory response that limits narrowing of the vessel lumen(2). This so-called positive (favorable) remodeling canoccur after angioplasty, but negative (unfavorable) re-modeling can also ensue, contributing to restenosis (1)(Figure 1). Some investigators propose that the underly-ing mechanism involves a replacement of hyaluronic acidwith collagen in the extracellular matrix, leading to con-traction of the scar (3). Others have suggested that adven-titial thickening is also involved (4). Mintz et al utilizedserial intravascular ultrasound to document negative re-modeling in a series of 209 angioplasty patients (5) andobserved that much of the lumen loss was due to vesselconstriction (area circumscribed by the external elasticlamina), rather than neointimal thickening. It is notknown how much negative remodeling contributes to re-stenosis, but it plays a greater role in angioplasty if stent-ing is not performed (1). In-stent restenosis, in contrast,arises primarily from neointimal hyperplasia (1).

Neointimal HyperplasiaBalloon inflation fractures the atherosclerotic plaque, in-voking platelet adhesion and activation. The activatedplatelets release mitogens, including thromboxane A2,serotonin, and platelet-derived growth factor, which pro-mote smooth muscle cell proliferation (1,6,7). Concur-rently, levels of mitogenic proto-oncogenes, including c-fos, c-jun, fosB, junB, and junD, increase in the smoothmuscle cells (8). This activation of smooth muscle cellsalters their phenotype from contractile to synthetic, and20% to 40% of medial smooth muscle cells enter the cellcycle within 3 days (1). Additionally, smooth muscle cellselaborate promigratory proteins, including CD44v6,

From the Division of Cardiovascular Medicine, Falk CardiovascularResearch Center, Stanford University School of Medicine, Stanford,California.

Requests for reprints should be addressed to Stanley G. Rockson,MD, Division of Cardiovascular Medicine, Falk Cardiovascular Re-search Center, Stanford University School of Medicine, 300 PasteurDrive, Stanford, California 94305, or [email protected].

Manuscript submitted August 5, 2002, and accepted in revised formJune 27, 2003.

© 2003 by Excerpta Medica Inc. 0002-9343/03/$–see front matter 547All rights reserved. doi:10.1016/S0002-9343(03)00477-7

urokinase plasminogen activator receptor, integrin al-pha(v)ss(3), transforming growth factor-ss(1), MDC9,and ss-inducible gene h3 (9). Consequently, many acti-vated medial smooth muscle cells migrate to the intima(8). Although most of these cells originate in the media,adventitial myofibroblasts also migrate to the intima(10). A dysfunctional endothelium might also contributeto smooth muscle proliferation and migration becausehealthy endothelial cells inhibit smooth muscle cellgrowth through nitric oxide production (1).

During the first several months following angioplasty,the neointima expands, and the additional volume com-prises smooth muscle cells and extracellular matrix (Fig-ure 2). Accumulation of collagen fibers increases the vol-ume of the extracellular matrix (11), whereas, in parallel,reduced degradation of collagen in the extracellular ma-

trix contributes to the enhanced presence of collagen inthe matrix (12).

RISK FACTORS

A combination of patient, lesion, procedural, and post-procedural characteristics contribute to an increasedlikelihood of restenosis after angioplasty (1). Diabetesmellitus is a risk factor, possibly because patients withdiabetes display a tendency toward exaggerated intimalhyperplasia (1). Genetic factors may also be involved, in-cluding polymorphisms for the D/D genotype of the an-giotensin-converting enzyme (ACE) receptor (13), gly-coprotein receptor IIIa PIA1/PIA2 (14), 4G/5G promoterof the plasminogen activator inhibitor 1 (15), and hapto-globin 2/2 (16). Additionally, a clinical presentation withunstable angina enhances the likelihood of restenosis af-ter angioplasty (17). Plasminogen activator inhibitor 1,urokinase plasminogen activator, and tissue factor havealso been demonstrated to be risk factors (18,19).

Other predictors of restenosis include stenoses oflonger length (17), chronic total occlusions (20), and an-giographically identifiable thrombus (21). Disease in sa-phenous vein grafts (22) and in small native vessels (�3.0mm) (23) is associated with higher rates of restenosis.One of the leading predictors of angiographic stenosisafter angioplasty is postprocedural diameter (1).

TREATMENT

Shortly after the phenomenon of restenosis was recog-nized, investigators sought to develop devices that couldmore completely debulk the plaque burden at the time ofintervention. The rationale was to maximize the postpro-cedural vessel diameter, thereby reducing the rates of re-stenosis.

One such device was the directional coronary atherec-tomy catheter, developed in the early 1980s, which allowsshaving and extraction of plaque from the diseased vesselwall. Comparisons of directional coronary atherectomyand standard angioplasty for the treatment of de novolesions have shown similar rates of restenosis between thetwo procedures (1).

More recently, rotational atherectomy (rotablation)has been used. Rotablation uses a burr that rotates ex-tremely rapidly, pulverizing plaque with the capacity todebulk even heavily calcified lesions. Its efficacy in reduc-ing restenosis, however, has not been verified. In theComparison of Balloon-Angioplasty versus RotationalAtherectomy (COBRA) study, rotablation was associatedwith similar rates of restenosis as was angioplasty for theinitial treatment of complex lesions (24). Angiographicand procedural success was comparable with each tech-

Figure 1. Positive and negative arterial remodeling in responseto atherosclerotic plaque formation.

Figure 2. Neointimal proliferation and its relation to resteno-sis.

Coronary Restenosis/Rajagopal and Rockson

548 November 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 115

nique, but rotablation yields higher rates of late lumenloss (at 6 months).

Laser-assisted angioplasty is another approach to per-cutaneous coronary intervention. This technique was in-tended to enhance the plaque-debulking effect of stan-dard angioplasty and is thought to be effective in difficultstenoses, including chronic total occlusions and lengthyor calcified lesions. However, laser angioplasty has notbeen shown to reduce rates of restenosis in clinical trials(25).

The most effective advance in the mechanical ap-proach has been the use of coronary stents, which werefirst used in 1986 (1). In the BElgian NEtherlands Stent(BENESTENT) (26) and Stent Restenosis (STRESS) trials(27), patients with de novo lesions were randomly as-signed to either angioplasty or stenting. Stenting was as-sociated with lower rates of restenosis as compared withplacebo in both the BENESTENT (22% vs. 32%) andSTRESS trials (31.6% vs. 42%) (Table). This beneficialeffect has been confirmed in other randomized trials, inwhich restenosis rates were reduced by 25% to 50% ascompared with angioplasty alone (1). The benefits ofstenting are attributed to larger lumen gain, eliminationof vessel recoil, and prevention of negative remodeling(1). Unfortunately, neointimal hyperplasia remains aproblem after stenting (35).

PROPOSED TREATMENTS

Numerous antirestenosis drugs have been studied fortheir inhibitory effects on native atherosclerosis and

smooth muscle proliferation. In many trials of the phar-macologic prevention and treatment of restenosis, the re-sults have been largely inconclusive or disappointing.

Angiotensin II, for example, stimulates vascularsmooth muscle proliferation (36), yet results of prospec-tive studies of ACE inhibitors and angiotensin receptorantagonists have been inconclusive. A recent randomizedtrial reported that cilazapril was not effective in prevent-ing restenosis (37). Similarly, there is no convincing evi-dence of the benefits of angiotensin receptor blockers.

Another modulator of smooth muscle cells is the vaso-dilator cilostazol, which inhibits platelet aggregation andprevents smooth muscle proliferation by inhibiting cyclicadenosine monophosphate phosphodiesterase III (38).However, one trial did not show a difference in restenosisrates when aspirin plus cilostazol or aspirin plus ticlopi-dine was used, except in patients with diabetes (39).

Trapidil inhibits mitogenesis of vascular smooth mus-cle cells through competitive inhibition of platelet-de-rived growth factor (40). The recent multicentre ran-domized placebo controlled clinical trial of Trapidilfor Prevention of Restenosis after Coronary Stenting(TRAPIST) did not show trapidil therapy to be beneficial,when compared with placebo after coronary stenting(41). Similarly, blockade of thromboxane A2, anotherplatelet mediator of smooth muscle cell growth, has notbeen shown to reduce restenosis in randomized trials (42).

Most recently, tranilast and calcium channel blockers,which inhibit migration and proliferation of vascularsmooth muscle cells, have been studied (43). The Preven-tion of REStenosis with Tranilast and its Outcome

Table. Restenosis Rates and Adverse Events According to Treatment

Study (Reference)

Rate of Restenosis (%)

P Value

Adverse Events* (%)

P ValueTreated Placebo Treated Placebo

Stenting versus angioplasty for de novo lesionsBENESTENT (26) 22 32 0.02 20 30 0.02STRESS (27) 30 42 0.02 20 24 0.2

Brachytherapy for restenotic lesionsSTART† (28) 29 45 0.001 19 29 0.02INHIBIT† (29) 26 52 �0.0001 15 31 0.006SCRIPPS (30)‡ 33 64 �0.05 23 55 0.01WRIST (31)‡ 19 58 0.0001 29 68 �0.001GAMMA-1 (32)‡ 32 55 0.006 28 44 0.02

Sirolimus-coated stents for de novo lesionsRAVEL (33) 0 26 �0.001 6 19 �0.001SIRIUS (34) 9.1 36 �0.001 10.5 19.5 �0.001

* Death, myocardial infarction, or target lesion revascularization.† Beta radiation.‡ Gamma radiation.BENESTENT � BElgian NEtherlands Stent; INHIBIT � Intimal Hyperplasia Inhibition With Beta In-stent; RAVEL � Randomized Double-BlindStudy with the Sirolimus-Eluting BX Velocity Balloon-Expandable Stent in the Treatment of Patients with De Novo Native Coronary Lesions;SCRIPPS � Scripps Coronary Radiation to Inhibit Proliferation Post Stenting; SIRIUS � Sirolimus-Coated BX Velocity Balloon-Expandable Stentin the Treatment of Patients with De Novo Coronary Artery Lesions; START � Stents and Radiation Trial; STRESS � Stent Restenosis; WRIST �Washington Radiation for In-Stent Restenosis Trial.


November 2003 THE AMERICAN JOURNAL OF MEDICINE� Volume 115 549

(PRESTO) trial, which randomly assigned 11,500 pa-tients to tranilast or placebo after coronary intervention,showed no benefit of active therapy (44). Likewise, amlo-dipine has not been shown to reduce restenosis rates (45).

Because statins are effective in the primary and second-ary prevention of atherosclerosis, they have been studiedas inhibitors of restenosis. Several randomized trials havefailed to show a benefit of statins in reducing restenosis(46). Omega-3 fatty acids, which are found in fish oils, arealso effective in the secondary prevention of coronary ar-tery disease (47), yet randomized trials have demon-strated no benefit in restenosis (48).

Oxidative stress is involved in native atherogenesis,and might therefore participate in neointimal formation.Carvedilol, a beta-adrenergic antagonist with alpha-blocking and antioxidant properties, was studied in theEuropean Carvedilol Atherectomy Restenosis (EURO-CARE) trial (49), in which 400 patients were randomlyassigned to receive either placebo or 25 mg of carvedilol,twice daily for 5 months, following atherectomy. Angio-graphic restenosis rates were similar in the two groups. Inthe Multivitamins and Probucol (MVP) study (50), pro-bucol, an antioxidant, and multivitamins (vitamins E andC and beta carotene) were administered after angioplasty.Although the multivitamins did not have an effect onrepeat angioplasty, the rates were 11% in the group thatreceived probucol, given at a dose of 500 mg daily for 1month before angioplasty and for 6 months afterwards,and 27% in the placebo group (P � 0.009). Despite theseobservations, the Food and Drug Administration (FDA)did not approve probucol because of concerns about thepotential for arrhythmias in the setting of QT prolonga-tion.

Another modulator of oxidant stress, and a risk factorfor native atherosclerosis, is homocysteine (51). A ran-domized trial (52) of a combination of folic acid (1 mg),vitamin B12 (400 �g), and pyridoxine (10 mg) versus pla-cebo for 6 months after angioplasty showed that com-pared with placebo, treatment was associated with a lowerrate of both angiographic restenosis at 6 months (21% vs.38%, P � 0.01) and target lesion repeat revascularization(11% vs. 22%, P � 0.05). These results should be con-firmed in a larger study and in stented patients. Never-theless, this inexpensive and nontoxic therapy is a prom-ising treatment strategy.

Often, the clinical endpoint of native atherosclerosis isan acute coronary event, namely, an unstable plaque withsuperimposed thrombus formation. Unfractionated hep-arin, low molecular weight heparin, and platelet glycop-rotein IIb/IIIa inhibitors improve mortality in this set-ting, and also reduce the incidence of acute stentthrombosis after angioplasty. Accordingly, investigatorshave used these agents to limit restenosis after angioplastyalone or stent implantation. Low molecular weight hep-arin, given systemically for up to 3 months (53) after an-

gioplasty, does not reduce the incidence of restenosis.Unfractionated heparin has been studied in several trials,such as Hirudin in a European Trial versus Heparin in thePrevention of Restenosis after PTCA (HELVETICA)(54), and has not been shown to reduce the incidence ofrestenosis. Similarly, platelet glycoprotein IIb/IIIa inhib-itors have no proven efficacy in reducing late restenosis.

RECENT ADVANCES

The most recent advances in the treatment of restenosisinclude intracoronary radiation (brachytherapy) anddrug-coated stents (Table 1).

BrachytherapyIn animals, intracoronary radiation reduces neointimalproliferation after angioplasty, presumably by decreasingsmooth muscle cell mitosis and by inducing apoptosis(55). Investigators have used both beta and gamma radi-ation for this purpose.

Beta particles are emitted electrons from a radioactiveisotope. The most extensively studied isotopes have beenphosphorus 32 (32P) and strontium 90. In the Prolifera-tion Reduction with Vascular Energy Trial (PREVENT),patients with naıve or restenotic lesions who had beentreated with stenting or balloon angioplasty were ran-domly assigned to intervention with placebo or 16-, 20-,or 24-gray radiotherapy (intracoronary 32P) (56). Radio-therapy reduced the restenosis at the target site as com-pared with placebo (8% vs. 39%, P � 0.01). The angio-graphic and clinical benefits, however, were limited byrestenosis adjacent to the target site (14% in the treatedgroup vs. 11% in the placebo group) and by late throm-botic events in the treated group. More recently, in theStents and Radiation Trial (START) (28), patients within-stent restenosis were randomly assigned to brachy-therapy or placebo after receiving mechanical treatment(primarily angioplasty) for in-stent restenosis. Restenosiswithin the entire segment treated with radiation was re-duced in 45% of controls and 29% of treated patients at 8months (P � 0.001). Because of this trial, the FDA hasapproved beta radiation for the treatment of in-stent re-stenosis.

In the Intimal Hyperplasia Inhibition With Beta In-stent (INHIBIT) trial (29), patients with in-stent resteno-sis who had been treated with repeat percutaneous inter-vention were randomly assigned to beta radiation orplacebo. Angiographic restenosis was lower in the radia-tion group (26%) than in the placebo group (52%, P�0.0001). In a trial of escalating doses of beta radiationafter angioplasty alone for de novo lesions, restenosis oc-curred in 4% of patients who had been treated with thehighest radiation dose (57). Conversely, the preliminaryresults from the randomized BETA-CATH trial did notshow beta radiation to be beneficial as a primary inter-



vention strategy in de novo lesions (58). The study ran-domly assigned 1455 patients who had been treated withangioplasty, with or without stenting, to beta radiation orplacebo. At 8 months, restenosis rates in the analysis seg-ment (treated segment plus 5 mm on either side) did notdiffer significantly between radiation and placebo groups(31% vs. 36%, P � 0.3).

Gamma radiation entails photon emission by radioiso-topes such as iridium 182, which has shown efficacy inreducing restenosis in the Scripps Coronary Radiation toInhibit Proliferation Post Stenting (SCRIPPS) trial (30),the Washington Radiation for In-Stent Restenosis Trial(WRIST) (31), WRIST PLUS (59), and Gamma-1 trial(32). The FDA approved gamma radiation for the treat-ment of in-stent restenosis based on the Gamma-1 trialresults (32). In this investigation, 252 patients with in-stent restenosis were randomly assigned to either a pla-cebo “hot wire” or an iridium 192 “hot wire” after under-going angioplasty, atherectomy, or laser angioplasty. At 6months, the incidence of restenosis was 55% in the pla-cebo group and 32% in the treated group.

These results indicate that brachytherapy is beneficial,albeit with several limitations. The procedure is expen-sive, inconvenient, and requires the services of a radiationoncologist. Also, use of gamma radiation requires thatpersonnel leave the room during the 20 minutes of radi-ation exposure. The increased incidence of late thrombo-sis and myocardial infarction is a major concern. In theGamma-1 trial, for example, there was a trend toward latethrombosis (5% vs. 0.8%, P � 0.07) and myocardial in-farction (10% vs. 4.2%, P � 0.09) in the treated groupwhen compared with the placebo group. All of the latethrombosis events occurred in stent recipients. Specifi-cally, 6% of patients who received new stents at the timeof intervention had late thrombosis as opposed to none ofthe nonstented patients. Similarly, late thrombosis oc-curred in 10% of treated patients in PREVENT, 3% oftreated patients in the INHIBIT trial, and 6% in theBETA-CATH trial. Prolonged antiplatelet therapy mightameliorate these adverse effects. In the nonrandomizedWRIST PLUS, late thrombosis was reported in only 3% ofpatients who had undergone prolonged antiplatelet ther-apy (6 months of clopidogrel in addition to aspirin) (59),similar to the placebo historical control group fromWRIST. Longer therapy with clopidogrel (12 months)did not reduce the incidence of late thrombosis, but de-creased the number of major cardiac events and rate ofrepeat revascularization (60). Finally, follow-up of thesepatients has been short, and it is unclear whether unto-ward effects of radiation, including the potential for fi-brosis and oncogenesis, might emerge.

Drug-Coated StentsThe most promising prospect for reducing restenosis hasbeen the recent development of drug-coated stents. Sev-

eral drugs are being tested for local delivery through elut-ing stents, including estradiol and paclitaxel. The mostextensively studied, to date, is sirolimus (rapamycin).

Sirolimus is an immunosuppressive drug that is tradi-tionally used to prevent organ transplant rejection.Within the last 10 years, animal experiments have dem-onstrated its efficacy in reducing restenosis, and recentlyhuman clinical trials have been completed. In the Ran-domized Double-Blind Study with the Sirolimus-ElutingBX Velocity Balloon-Expandable Stent in the Treatmentof Patients with De Novo Native Coronary Lesions(RAVEL), patients were randomly given a sirolimus-elut-ing stent or placebo (33). The restenosis rate at 6 monthswas 0% in the sirolimus group compared with 26% in theplacebo group (P �0.001). In the subgroup of diabeticpatients, none of the patients with drug-coated stents hadrestenosis compared with 42% of those with standardstents (P � 0.002). Preliminary results were recently pre-sented for the Sirolimus-Coated BX Velocity Balloon-Ex-pandable Stent in the Treatment of Patients with DeNovo Coronary Artery Lesions (SIRIUS) trial (34). In thistrial, 1058 patients were randomly given a sirolimus-coated stent or a bare stent. At angiographic follow-up at8 months, in-segment restenosis (stent plus 5-mm prox-imal and distal borders) occurred in 9% of sirolimus-stent patients compared with 36% of control patients (P�0.001). Adverse effects did not differ between groups,including stent thrombosis (0.6% in the sirolimus groupvs. 1.1% in the placebo group) and aneurysm formation(0.6% in the sirolimus group vs. 1.1% in the placebogroup).

Recently, paclitaxel-coated stents have also shownpromise in reducing restenosis. In a randomized studyinvolving patients assigned to low-dose paclitaxel-coatedstents, high-dose paclitaxel-coated stents, or placebo(61), restenosis occurred in 27% of control patients, 12%in the low-dose group, and 4% in the high-dose group at4- to 6-month follow-up.

CONCLUSION

Given the prevalence of coronary artery disease and thewidespread dissemination of technology and expertise,the number of percutaneous coronary interventions willcontinue to increase aggressively. Interventional cardiol-ogists will treat more patients, including those with co-morbid conditions that may complicate percutaneoustreatment, such as diabetes, multivessel disease, andchronic total occlusions. Therefore, expanding our un-derstanding of restenosis and treatment options becomesmore pressing. Although many patients can benefit frompercutaneous intervention, many can also suffer from itslimitations, with restenosis causing recurrent angina,ischemic events, and repeat interventions. For these pa-



tients, there are other treatment options. Intracoronaryradiation, despite its limitations, has been shown to beeffective in ameliorating restenosis. The early data re-garding drug-coated stents are promising. Ultimately,these advances offer a great hope for markedly lower ratesof restenosis and a new era in interventional cardiology.

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Coronary restenosis: a review of mechanisms and management

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