Restenosis and Drug-Eluting Stents

7 Restenosis and Drug-Eluting Stentsimage



Ahmad Edris, Nauman Siddiqi, Morton J. Kern



Restenosis


Restenosis is defined as vessel narrowing of a previous angioplasty site. After balloon expansion, this narrowing occurs as a result of two mechanisms, negative remodeling (vessel constriction after stretching) and reaccumulation of material within the lumen (or stent). Reaccumulation of cellular material (also known as endothelial proliferation) is initiated by vessel injury with a release of thrombogenic, vasoactive, and mitogenic factors. Endothelial and deeper injury leads to platelet aggregation, thrombus formation, inflammation, and activation of smooth muscle cells and macrophages. The production and release of growth factors and cytokines promotes further synthesis of such factors and release from the cells involved. These factors result in the migration of new smooth muscle cells from their location within the arterial media to the endovascular lumen. These cells become a synthetic type of cell that produces extracellular matrix, leading to cellular proliferation and mechanical obstruction of the vessel lumen.


The second component of restenosis, recoil and negative remodeling of the arterial wall is inhibited by stents. Compared to balloon angioplasty, stents have reduced restenosis from 40% to 50% after percutaneous transluminal coronary angioplasty (PTCA) to 20% after bare-metal stenting. Drug-eluting stents (DESs) have brought restenosis rates to <10% in most patient subgroups. Restenosis still occurs inside stents (called in-stent restenosis [ISR]) mostly, if not exclusively, as a result of endothelial cell proliferation. Rarely does vascular recoil make a contribution, but it must be considered in treating the ISR lesion. Restenosis is not device-specific but rather a function of the anatomic substrate and the type of injury produced (Fig. 7-1).


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Figure 7-1 Interventional devices and presumed mechanisms of action of arterial plaque in vessel wall lead to restenosis. The indication of immediate outcome and restenosis rates depend on both the device and the arterial substrate encountered.


(From Waller BF, Pinkerton CA, Orr CM. Restenosis 1 to 24 months after clinically successful coronary balloon angioplasty: A necropsy study of 20 patients. J Am Coll Cardiol 1991;17:58–70.)



Definitions of Restenosis


There are two types of restenosis recognized in patients, angiographic and clinical, which are not mutually exclusive.



Angiographic Restenosis


Angiographically measured luminal renarrowing after PCI has been the “gold standard” for restenosis. Angiographic restenosis is a continuous phenomenon, with no obvious threshold separating “restenosers” from “nonrestenosers.” Studies have shown that the percentage of stenosis or minimal lumen diameter has a near Gaussian (normal) distribution on follow-up angiograms after balloon angioplasty. Thus, restenosis is best measured as a continuous variable. Nevertheless, because of practicality, the most commonly used definition of restenosis employs a dichotomous value (e.g., 50% diameter narrowing).


Several different angiographic definitions of restenosis have been published with overlapping differences in some patients. Most studies define angiographic restenosis as either a greater than 50% loss of initial gain after intervention or an absolute lesion stenosis of greater that or equal to 50% at follow-up angiogram. The late loss of the acute luminal enlargement, or net gain in millimeters at the lesion site 6 months after treatment by quantitative angiography, should be around 0.7 mm for balloon angioplasty.


The late loss index is the loss at the lesion site divided by the amount of acute gain (Fig. 7-2). The loss index is accepted as the most sensitive measure of the effectiveness of the technique and should range from 0.4 to 0.6 mm for balloon angioplasty. The lower the loss index is, the more effective the antirestenosis treatment will be.


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Figure 7-2 Calculations of acute gain, late loss, and loss index.


Restenosis is both a lumen-related and a vessel wall–related phenomenon. It appears that 40% to 60% of the acute luminal gain is lost during follow-up in all patients treated, independent of the devices. A similar degree of intimal thickening (restenosis by wall measurements) may or may not cause a significant luminal narrowing (restenosis by lumen measurement). As expected, the vessel size itself exerts a significant positive influence on minimal lumen diameter at follow-up and an equally negative effect on late loss. A larger artery will have a larger lumen at follow-up and vice versa for a smaller artery. Using percentage stenosis rather than absolute lumen diameter will neutralize this effect by correcting automatically for artery size.


Intravascular ultrasound (IVUS) imaging is superior to angiography for anatomic and morphologic restenosis definitions. Recent IVUS studies have shown that an important component of restenosis is vessel recoil, a feature prevented by stenting. Normal vessel modeling maintains the coronary lumen. Late negative remodeling of the injured vessel is also prevented by stenting (Figs. 7-3 and 7-4).


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Figure 7-3 The Glagov phenomenon. According to serial intravascular ultrasound, normal segments showed proximal enlargement of the vessel as plaque volume increases. Vascular dilatation is compensated for by substantial plaque formation inside the vessel wall leaving the vessel’s angiographic appearance unchanged and normal looking.


(From Glagov S, Wisenberg E, Zarins CK, et al. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987;316:1371–1375.


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Figure 7-4 Adequacy of arterial remodeling with respect to changes in vessel size.


(From Schwartz RS. Pathophysiology of restenosis: interaction of thrombosis, hyperplasia, and/or remodeling. Am J Cardiol 1998;81:16E.)



Clinical Restenosis


Clinical restenosis is defined as recurrent angina or anginal-equivalent symptoms after PCI. Other causes of symptoms might be mistaken for clinical restenosis, such as disease progression in the nondilated arterial segment, which occurs in 10% to 15% of cases late after PCI or new disease elsewhere. Incomplete revascularization also causes symptoms in about 10% of patients. Recurrence of typical angina after an asymptomatic period following angioplasty is a very specific clinical indicator for restenosis. On the other hand, atypical chest pain is a poor predictor. Restenosis is documented in 15% of asymptomatic cases.


Early (<1 month) exercise tests after balloon angioplasty (PTCA) were often persistently positive and failed to predict future restenosis and recurrent events. An exercise test at 6 months in patients who have not yet presented with clinical recurrence shows a modest positive predictive value. Exercise testing early after PCI is not recommended. For symptoms appearing late after PCI in which restenosis is suspected, angiography is recommended. If the angiographic restenosis severity is intermediate (40%–70%), then in-lab functional testing with fractional flow reserve can be helpful in making a decision regarding whether repeat stenting is required.



Risk Factors for Restenosis


It is not possible to predict reliably whether restenosis will occur in a given patient. A multivariate analysis found the following conditions are predictors of restenosis: severe angina, left anterior descending artery lesions, diabetes, a higher degree of residual restenosis, hypertension, absence of an intimal tear, eccentric lesion morphology, and older age.


It is difficult to obtain follow-up angiograms in all patients undergoing coronary angioplasty. Less than complete angiographic follow-up with preferential recatheterization of symptomatic patients creates bias in that symptomatic patients artificially increase the restenosis rate in that population. At the same time, asymptomatic restenosis cases will go unrecognized clinically. This approach may underestimate the actual angiographic restenosis rate. Target vessel revascularization (TVR) rate is another surrogate for angiographic restenosis rates.



Time Course


Stents prevent very early (<24 hr) restenosis due to elimination of acute elastic recoil. The incidence of restenosis increases, peaking around 6 months. Late restenosis occurs uncommonly after 12 months. Restenosis after angioplasty using non-balloon, non-stent devices alone was highly variable with a reported incidence of restenosis between 15% and 55% (see Suggested Readings).


Different mechanisms produce restenosis in a time-dependent manner. Early restenosis is due to thrombus, whereas late restenosis is related more to remodeling (Fig. 7-5).


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Figure 7-5 The four phases of vascular repair after stent-induced arterial injury in terms of time after stenting. A, Platelet-rich thrombus accumulates at areas of deep strut injury and peaks at 3 to 4 days after stent deployment, accounting for most early lumen loss. B, Coincident with thrombus deposition, inflammatory cells are recruited to the injury site, both at and between stent struts. At 3 to 7 days after stenting, the surface-adherent monocytes (SAMs) migrate into the neointima as tissue-infiltrating monocytes (TIMs) and remain in place. C, Proliferation of smooth muscle cells and monocyte macrophages within the neointima peaks at 7 days after implantation and continues above baseline levels for weeks thereafter. D, Collagen deposition in the adventitia and throughout the tunica media and neointima leads to arterial shrinkage or remodeling, causing compression of the artery on stent struts from without.


(Modified from Garasic J, Edelman E, Rogers C. Stent design and the biologic response. In Beyar R, Keren G, Leon M, Serruys PW, eds. Frontiers in interventional cardiology. London: Martin Dunitz, 1997: 95–100.)



Patient Subsets at Higher Risk of Restenosis



Diabetes Mellitus


Poor outcomes can be seen in diabetic patients undergoing percutaneous coronary intervention (PCI). In one study, angiographic follow-up at 6 months in 418 diabetic and 2672 non-diabetic patients undergoing PCI showed that restenosis occurred in 550 of 2672 (20.6%) non-diabetic and 130 of 418 (31.1%) diabetic patients (P = 0.01). Vessel caliber, stented length of vessel, and lower BMI were reported predictors of in-stent restenosis in patients with diabetes. Another study evaluated 1288 patients (263 diabetic patients [21%]) and showed that repeat revascularization of the stented lesion was performed more frequently during the first year in patients with diabetes (16% vs. 10.9%, P = 0.01). Also, cardiac death and myocardial infarction (MI) were more frequent among patients with diabetes (5-year rates, 25.4% vs. 17.9%, P = 0.008) and remained significant after adjustments were made for differences in baseline characteristics.



Chronic Renal Failure


It has been reported that patients with chronic renal failure who undergo PCI have a high restenosis rate (>30%). A study compared 40 lesions in 34 patients with end-stage renal disease (ESRD) with 80 lesions from patients without renal impairment who underwent coronary stenting. Despite comparable initial angiographic results over the 9-month follow-up period, repeat TVR was twice as frequent in the ESRD group compared with the control group (35% vs. 16%, P < 0.05). Another study evaluated the effect of moderate renal insufficiency in patients undergoing primary angioplasty for acute MI and found that significant restenosis was seen more frequently in patients with renal insufficiency compared to those with normal renal function (20.6% vs. 11.8%, P = 0.024).



Transplantation


Cardiac allograft vasculopathy (CAV) is a rapidly progressive form of atherosclerosis and is one of the main limitations to long-term survival after orthotopic heart transplantation. PCI has been used as a palliative treatment option for CAV but is associated with worse clinical outcomes and greater rate of restenosis compared with PCI of native coronary arteries. Several studies have shown that when compared with BMS, PCI with DESs was safe and reduced the rate of angiographic restenosis in patients with CAV. However, treatment of patients with CAV with DESs does not seem to alter the natural deleterious history of this disease process.



Acute Myocardial Infarction


Several randomized trials have demonstrated that PCI is superior to thrombolysis in reducing mortality, the recurrence of MI, and TVR. However, restenosis occurs in 40% to 50% of patients after initial successful angioplasty and in 20% to 30% of patients after stenting. The choice of DESs or bare-metal stents (BMSs) for STEMI PCI is based on vessel size and ability to maintain dual antiplatelet therapy over the following year.



Chronic Total Occlusion


Total occlusion has a higher restenosis rate than subtotal stenosis. The recurrence of total occlusion lesions seldom results in MI because of reformation of prior collateral protection.


A recent study, the ACROSS/TOSCA-4 trial, examined angiographic and clinical outcomes with DESs in coronary total occlusion (CTO) revascularization. Patients with CTO (n = 200) (78.8% >6 weeks CTO age) were enrolled for treatment with DESs. The primary end point was 6-month angiographic binary restenosis within the treated segment. A total of 199 patients (99.5%) were treated with DESs, and procedural success was 98.0%. The 6-month binary restenosis rates were 9.5% in-stent, 12.4% in-segment, and 22.6% in-“working length” representing the entire treatment segment. Rates of 1-year target lesion revascularization (TLR), MI, and target vessel failure were 9.8%, 1.0%, and 10.9%, respectively.



Saphenous Vein Graft Lesions


Saphenous vein graft (SVG) lesions are associated with a higher restenosis rate, particularly in the proximal anastomotic (58%) and body (52%) portions of the graft. Distal anastomotic narrowing responds to angioplasty well, especially in patients with recurrent coronary artery bypass graft surgery. The time course of restenosis in vein grafts is different than in native coronary vessels, with continued significant attrition beyond 6 months.


The long-term patency rate of the SVG has improved with advances in medical therapies but still remains suboptimal. A review of several studies evaluating SVG durability consistently shows poor graft patency and a high rate of total occlusion. One study evaluated 27,211 patients and showed a 5-year SVG patency rate (defined as less than 70% stenosis) of less than 40%.



Internal Mammary Artery Graft Lesions


The internal mammary graft anastomotic site responds very favorably to angioplasty, with a 10% to 15% or less restenosis rate. One study comparing the SVG and internal mammary artery graft showed 10-year patency rate of 57% and 90%, respectively, with patency defined as not totally occluded.



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Jun 5, 2016 | Posted by in CARDIAC SURGERY | Comments Off on Restenosis and Drug-Eluting Stents

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