Care of the Patient With Coronary Stents Undergoing Noncardiac Surgery

Key Points

1.
Percutaneous coronary intervention (PCI) with stent placement is frequently performed, with a substantial number of patients requiring subsequent noncardiac surgery (NCS).
2.
Three types of stents are currently available for clinical use: bare metal stents (BMSs), drug-eluting stents (DESs), and bioresorbable stents (BRSs).
3.
The two main stent-related complications are restenosis and thrombosis.
4.
The risk of restenosis peaks within the first year after PCI and is more commonly seen with BMS.
5.
The risk of stent thrombosis (ST) is highest within the first 30 days regardless of stent type. It decreases subsequently. Newer generations of DESs are less thrombogenic than first-generation DESs and even BMSs. Bioabsorbable stents have the highest risk at 12 months.
6.
Treatment with dual antiplatelet therapy (DAPT) is necessary to prevent ST. The optimal duration with any stent must balance the risk of thrombosis versus bleeding.
7.
There are several recognized clinical, procedural, and angiographic risk factors of ST. The most important is premature discontinuation of DAPT, yet many cases of ST still occur in the presence of platelet inhibitors.
8.
The standard combination for long-term DAPT consists of aspirin (ASA) and clopidogrel; however, there is significant variability in patients' response to each drug. The more potent drugs prasugrel and ticagrelor exhibit more predictable antiplatelet effects but are associated with higher bleeding risk.
9.
The use of platelet function tests to individualize antiplatelet therapy (APT) has not proven superior in medical patients, yet it has shown effectiveness before cardiac surgery and may hold promise for NCS.
10.
The incidence of perioperative ST is low, but it is associated with major morbidity and mortality.
11.
The two most important decisions for patients undergoing NCS are the timing of the procedure and management of DAPT.
12.
Most recommendations are not very well defined and are based on low-quality evidence and expert opinion. Management should balance each patient's specific thrombotic risk against a particular surgery's specific hemorrhagic risk.
13.
For patients with stable ischemic heart disease (SIDH) and low thrombotic risk, elective surgery should be delayed at least 6 weeks after BMS placement and 3 months with DESs, with ASA continued for most procedures. For patients with PCI during acute coronary syndrome or at high risk for thrombosis, the waiting period should be at least 6 months or perhaps longer regardless of stent type. For patients with current BRSs, the waiting period appears to be at least 12 months regardless of the indication for PCI. If surgery cannot be postponed, decisions on DAPT should be based on the patient's individual thrombotic or hemorrhagic risk.
14.
Selected patients may benefit from bridging therapy with intravenous platelet inhibitors, but such an approach is not without risks and is associated with increased hospitalization and cost.
15.
The frequency and complexity of this important topic require an interdisciplinary structured approach with input from the different specialties involved in the care of these patients

Percutaneous coronary intervention (PCI) is one of the most common procedures worldwide, with approximately 600,000 performed annually in the United States alone. The term includes balloon angioplasty as well as coronary stent placement, with the overwhelming majority of individuals undergoing the latter because of superior results in preserving vessel patency.

Despite the obvious advantages over balloon angioplasty, the long-term care of patients with coronary stents is haunted by the risk of restenosis and stent thrombosis (ST). Refinements in stent technology, implantation technique, and antiplatelet therapy (APT) have increased stent safety profiles; however, long-term management still faces significant challenges aiming to achieve an optimal balance of maintaining vascular integrity while minimizing thrombotic and bleeding risks.

The reported incidence of noncardiac surgery (NCS) after PCI ranges from 4% to 11% at 12 months, and 7% to 34% by 2 years. One of the greatest causes for clinical concern is how to best manage these patients because the presence of coronary artery stents is a recognized risk for perioperative cardiac morbidity and mortality.

The issue is further complicated by a frequent lack of consensus among perioperative providers, either because of unawareness or personal preferences; as a result, patients may remain uninformed of potential risks. Because of the magnitude of the problem, professional societies have provided guidelines for perioperative physicians to assist in their evaluation and management, but these are mostly based on low-quality evidence and expert opinion, including recent focused updates or consensus-driven documents. Furthermore, rapid improvements in stent technology (e.g., bioresorbable stents [BRSs]) and new pharmacologic agents find their way into clinical use before long-term outcomes from clinical trials are published, adding to the confusion about the best way to manage these patients in the perioperative period.

As part of a multidisciplinary team, anesthesiologists are in a unique position to provide important critical input because they are frequently sought by perioperative providers for their expertise. This chapter addresses the various coronary stents available for clinical use, long-term risks associated with these devices, the use of antiplatelet agents, and implications for those patients undergoing noncardiac procedures.

Types of Stents

The basic concept of a stent is that of a solid scaffold that prevents vessel closure due to elastic recoil or vessel contracture. In general, stents can be categorized according to material composition, durability, thickness of struts, and the presence of eluting drugs for local delivery ( Table 3.1 ).

Table 3.1

Stents Available for Clinical Use

Bare Metal Stents
Name	Manufacturer	Stent Generation	Stent Platform
Veri-FLEX	Boston Scientific	First	Stainless steel
Vision	Abbott Vascular	Second	Cobalt chromium
Integrity	Medtronic	Second	Cobalt chromium
REBEL	Boston Scientific	Third	Platinum chromium

Drug-Eluting Stents
Name	Manufacturer	Stent Generation	Stent Platform	Polymer	Antirestenotic Drug	Elution Kinetics
Cypher ^a	Cordis/J&J	First	Stainless steel	PEVA/PBMA	Sirolimus	80% at 4 wk
Taxus ^a	Boston Scientific	First	Stainless steel	SIBBS	Paclitaxel	10% at 4 wk
Xience	Abbott Vascular	Second	Cobalt chromium	PBMA/PVDF-HFP	Everolimus	80% at 4 wk
Promus	Boston Scientific	Second	Cobalt chromium	PBMA/PVDF-HFP	Everolimus	80% at 4 wk
Endeavor	Medtronic	Second	Cobalt chromium	PPChol	Zotarolimus	95% at 2 wk
Resolute	Medtronic	Second	Cobalt chromium	Biolynx	Zotarolimus	85% at 8 wk
Promus Element	Boston Scientific	Third	Platinum chromium	PBMA/PVDF-HFP	Everolimus	80% at 4 wk
Taxus Ion	Boston Scientific	Third	Platinum chromium	SIBBS	Paclitaxel	10% at 2 wk
Absorb BVS	Abbott	BVS DES	PLLA	PLLA	Everolimus	75% at 4 wk
DESolve ^b	Elixir	BVS DES	PLLA	Bioresorbable polymer	Novolimus	85% at wk
ART Pure ^b	ART	BVS	PDLLA	None	None	3–6 mo
Magmaris ^b	Biotronik	BRS DES	Magnesium alloy	PLLA	Sirolimus	3–6 mo

BRS, Bioresorbable stent; BVS, bioresorbable vascular scaffold; PBMA, poly n-butyl methacrylate; PDLLA, poly (L-lactide-CO-D,L-lactide); PEVA, polyethylene-co-vinyl acetate; PLLA, poly-L-lactide; PPChol, phosphorylcholine; PVDF-HFP, polyvinylidene fluoride–heaxafluoropropylene; SIBBS, styrene-b-isobutylene-b-styrene.

a No longer used (Cypher was discontinued in 2011).

b Not approved for use in the United States.

Bare Metal Stents

Current bare metal stents (BMSs) are made of stainless steel, cobalt chromium, or platinum chromium. Stainless steel BMSs were the first devices used for coronary stenting. They successfully reduced the incidence of abrupt vessel closure and restenosis compared with balloon angioplasty, thereby decreasing the rate of target lesion revascularization (TLR). One advantage of BMSs is that on average, endothelial stent coverage is complete in approximately 12 weeks, which decreases the risk of ST. Nevertheless, despite refinements in stent design, significant restenosis within the stented segment develops in approximately 20% to 30% of lesions.

Current accepted indications to place a BMS include patients who are likely to be noncompliant with long-term dual antiplatelet therapy (DAPT); patients at a higher risk of bleeding, including individuals taking oral anticoagulants; and patients who are scheduled for NCS requiring cessation of antiplatelet therapy beyond 6 weeks post-PCI.

Drug-Eluting Stents

Drug-eluting stents (DESs) consist of a metallic stent platform coated with a polymer carrier vehicle that stores an antiproliferative agent. The carrier releases the drug in a gradual and controlled fashion (elution), allowing local diffusion into the vascular tissue, thus preventing excessive cell growth (neointimal hyperplasia) encroachment into the lumen in response to device implantation. DESs have been shown to outperform BMSs with respect to the rates of restenosis and TLR, particularly within the first year postimplantation. Thereafter it appears that the restenosis rate is similar between DESs and BMSs.

Older DESs (so called first generation) are composed of stainless steel platforms with thick struts and durable polymers. These have been shown to produce long-term inflammatory reactions, resulting in delayed vascular healing and endothelial stent coverage. Durable DESs (second and third generation) consist of thin cobalt or platinum chromium scaffolds coated with polymers that cause less local inflammation and interference with reendothelialization ( Box 3.1 ).

Box 3.1

Advantages of Second- and Third-Generation Drug-Eluting Stents

Improved flexibility
Thinner struts
Enhanced polymer biocompatibility
Better elution kinetics

Bioabsorbable DESs consist of either a metallic or polylactate scaffold coated with polymers. After drug elution, either the polymer or the polymer and scaffold reabsorb over time, leaving a BMS or in some instances, no stent at all.

All DESs contain a reservoir of one of two classes of antiproliferative agents to prevent vascular smooth cell replication and thus stent restenosis.

1.
Sirolimus and derivatives (Everolimus, Zotarolimus, Myolimus, Neolimus, and Biolimus) have potent cytostatic properties.
2.
Paclitaxel is an antineoplastic agent that stabilizes cellular microtubules before cell division, thus arresting the mitotic cell cycle.

First-Generation Drug-Eluting Stents

Although widely used since first introduced in 2003, first-generation DESs are rarely used today because they have been largely replaced by safer and more refined stents. However, first-generation DESs are still represented in the majority of the existing body of literature regarding perioperative risk and management of surgical patients.

Second- and Third-Generation Drug-Eluting Stents

Second- and third-generation DESs offer numerous improvements that increase their safety profile over their first-generation counterparts. They have decreased strut thickness, improved flexibility, enhanced polymer biocompatibility and drug elution profiles, and superior reendothelialization kinetics. These devices are now the predominant coronary stents implanted worldwide.

Differences Among Drug-Eluting Stents

All DESs are superior to BMSs by reducing the incidence of restenosis and TLR, particularly at 12 months. First-generation DESs are inferior to newer DESs regarding TLR and late thrombosis. With respect to second- and third-generation DESs, very little differences in outcomes are apparent between zotarolimus and everolimus DES, although a slight decrease in ST may be associated with the cobalt chromium everolimus stents. Published data have shown that newer generation DESs are associated with lower rates of ST than BMSs.

Biodegradable Coronary Stents

Although newer generation DESs are known to be safer, the stent platform and polymer matrix are permanent. This is associated with decreased late lumen enlargement, lack of reactive vasomotion, the development of neoatherosclerosis, and the persistent risk of reintervention on the stent. A potential method to overcome these limitations would be to shorten the length of exposure to either the polymer or to the scaffold with the use of BRSs, in which either the polymer or the scaffold itself can degrade over time. The main rationale to use a bioabsorbable polymer is based on the expectation of decreased chronic inflammation and improved vascular healing. The principle behind a BRS platform is based on the fact that restenosis is uncommonly seen after 12 months after a procedure; thus the clinical need for stent scaffolding is likely to be very limited.

Some of the potential advantages of BRSs relate to restoration of normal vascular physiology of the stented segment, as well as maintaining suitability for future therapeutic options in conditions such as multivessel disease. Currently, there are four available BRSs for clinical use (see Table 3.1 ). Of these, only the Absorb stent has been tested in several clinical trials. Results have been somewhat concerning because of the higher incidence of complications from periprocedural myocardial infarction (MI) as well as ST during a 2-year follow-up. Earlier complications seem to be related to the fact that a different technique is required for BRS deployment compared with metallic durable DESs. The higher occurrence of long-term ST may be additionally explained by thicker struts and discontinuity of biodegradation. Table 3.2 shows the advantages and limitations of available BRSs. At present, more than 21 second-generation BRSs, with thinner struts, are being tested to overcome the drawbacks associated with first-generation BRSs.

Table 3.2

Features of Bioabsorbable Stents

Advantages	Limitations
Preservation of vessel geometry	Limited expansion during placement
Restoration of physiological vasomotion and shear stress	Risk of strut fracture Low tensile strength
Late luminal gain	Larger, thicker struts
Restoration of endothelial coverage	Different implantation techniques
Feasibility of noninvasive imaging	Late discontinuity
Suitability for potential future interventions

Responses to Stent Placement

Most clinical decisions surrounding the perioperative evaluation and management of patients with coronary stents are based on the body's natural responses to the presence of a foreign body in the coronary lumen; therefore it is important to review the associated pathophysiology as well as the therapeutic interventions aimed to counteract such reactions.

Balloon dilation of an atheromatous lesion with concomitant stretching of the vascular wall initiates three sequentially distinct responses:

1.
Immediate vessel recoil
2.
Negative arterial remodeling
3.
Neointimal hyperplasia

Elastic recoil represents the immediate shrinkage of the vessel after PCI caused by the elastic properties of the arterial wall, which usually occurs within 24 hours after the procedure. This is followed by negative remodeling, which is the process of local contraction of the arterial wall and narrowing of the lumen of the injured vascular segment. The etiology of negative remodeling is not well established but may be related to the healing process as well as interactions between the vascular endothelium and laminar flow. Neointimal hyperplasia constitutes a delayed healing response. This is represented by proliferation and migration of smooth muscle cells from the media and perhaps circulating endothelial progenitor cells from the bone marrow into the intima.

Placement of an intracoronary stent eliminates the first two processes, leaving only that of neointimal hyperplasia playing a role in normal healing as well as the exaggerated response responsible for restenosis. Additionally, unlike plain balloon angioplasty, the permanent presence of a foreign body serves as a constant stimulus for thrombus formation caused by activation of platelet function and coagulation mechanisms, which persist until complete endothelial stent coverage occurs.

Stent-Related Complications

In-Stent Restenosis

This process involves a gradual renarrowing of the stented segment or immediately proximal or distal to it because of excessive neointimal growth. Restenosis occurs because of peak neointimal thickening mostly between 4 and 12 months after stent placement.

The incidence of restenosis within the first year after PCI in patients with BMSs is approximately 20% to 30%. Thereafter, myocardial ischemia, if present, occurs mostly from progression of native vessel disease. DESs consistently reduce the incidence of in-stent restenosis and the rate of TLR by about 75%, with the benefits seen across all subgroups of patients.

Although less frequent with DES, restenosis still occurs depending on periprocedural challenges and the complexity of the initial lesions. Thus, unlike BMSs, it seems that most predictors of restenosis with DESs may relate more to lesion characteristics and technical aspects of stent deployment rather than to the clinical status of the patient.

Clinical Presentation

Stent restenosis is primarily suspected by recurrent symptoms of myocardial ischemia. The most common syndrome is that of stable or progressive angina, but up to 10% of patients present with acute MI. The diagnosis of in-stent restenosis is confirmed by coronary angiography.

Treatment

In patients who are symptomatic or fulfill anatomic criteria, repeat PCI is frequently required. Patients for whom repeat PCI is not likely to be successful should be considered candidates for surgical myocardial revascularization.

Stent Thrombosis

Definition

Thrombosis of a coronary stent is one of the most serious complications of PCI and is associated with major morbidity and mortality. It is defined as an abrupt occlusion at the site of the stent resulting from a platelet-rich thrombus, which can occur any time from the moment of stent placement to years after PCI.

Clinicians in the past have used various definitions of ST, which made interpretation of events very difficult. Since 2006, the Academic Research Consortium (ARC) has proposed criteria for the diagnosis of ST and timing of events in relation to the index procedure ( Tables 3.3 and 3.4 ). These criteria, although imperfect, have allowed fairly consistent interpretations in comparing outcomes among different trials of DESs.

Table 3.3

Timing of Stent Thrombosis

Modified from Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation. 2007;115:2344–2351.

Acute	Within 24 h of stent implantation
Subacute	From 24 h to 30 d
Late	From 30 d to 12 mo
Very late	More than 1 year

Table 3.4

Diagnosis of Stent Thrombosis

Modified from Cutlip DE, Windecker S, Mehran R, et al. Clinical end points in coronary stent trials. Circulation 2007;115:2344–2351.

Definite	Angiographic evidence of stent thrombosis and Chest pain with new ECG or echocardiographic changes or cardiac biomarker elevation Pathologic evidence on autopsy
Probable	Unexplained death within 30 days of PCI MI in the location supplied by the stented vessel
Possible	Unexplained death >30 days after PCI

ECG, Electrocardiogram; MI, myocardial infarction; PCI, percutaneous coronary intervention.

The common denominator is heightened platelet activation and aggregation by one or more of the following mechanisms ( Box 3.2 ).

1.
Persistent slow coronary flow, which may occur with wall dissection or hypoperfusion.
2.
Exposure of blood elements to prothrombotic constituents in the vasculature (e.g., tissue factor, collagen) or to the stent itself before reendothelial stent coverage.
3.
Failure to suppress platelet aggregation during the period of high thrombotic risk, such as premature cessation of antiplatelet therapy or drug resistance.
4.
In some patients (particularly with DESs) who develop very late stent thrombosis (VLST), other factors such as hypersensitivity reactions, excessive fibrin deposits, and ruptured neoatherosclerotic plaques within the stent struts play an important role.

Box 3.2

Mechanisms of Stent Thrombosis

Slow blood flow around stent
Exposure of platelets to nonendothelial surface
Absence of or low response to platelet inhibition
Local hypersensitivity or inflammation of the vascular wall
Presence of neoatherosclerotic plaques

Timing

Most cases of ST occur within 30 days after placement irrespective of stent type, ranging from 0.5% in low-risk patients to 2.5% in high-risk patients. Episodes of ST during this period are commonly related to periprocedural complications or abrupt interruption of DAPT, such as major bleeding or emergency high-risk surgery.

Stent thrombosis with BMSs occurs much less often after 6 weeks. This observation is consistent with angioscopic studies that have shown complete reendothelialization by 3 to 6 months. VLST is even more uncommon with BMS, and it occurs most often after a repeat procedure performed in the stented segment.

Similar to BMS, most episodes of ST associated with DESs occur in the first year, with the majority of these occurring within the first 30 days after PCI. The cumulative incidence of ST with DESs at 1 year also is approximately between 0.5% and 1%. Events thereafter continue at a rate between 0.4% and 0.6% per year.

Risk Factors for Stent Thrombosis

The complex interaction among the presence of a stent, blood elements, and vascular wall is a strong stimulus for thrombus formation. Thus it is not surprising that multiple factors have been shown to predispose patients for LST and VLST ( Table 3.5 ).

Table 3.5

Risk Factors for Stent Thrombosis

Stent Type	Procedure	Lesions	Clinical
First generation > Absorb (BRS) > BMS ≥ DES second and third generation	Stent underexpansion or malposition	Ostial, long, bifurcations, multiple stents	Premature discontinuation of DAPT
	Vessel dissection	Small vessel diameter (<2.5 mm)	Prior stent thrombosis
	Incomplete strut coverage	Overlapping stents	PCI for ACS
	Pre- or poststent vessel stenosis	Calcified lesions	Documented HTPR
	Stent deployed on necrotic plaques	Prior brachytherapy	Diabetes mellitus
		Saphenous grafts	Chronic kidney disease
			HF with low LVEF
			Cancer
			Systemic inflammatory conditions
			Cigarette smoking Cocaine use

ACS, Acute coronary syndrome; BMS, bare metal stent; BRS , bioresorbable stent; DAPT, dual antiplatelet therapy; DES, drug-eluting stent; HF, heart failure; HTPR, high on-treatment platelet reactivity; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention.

Stent Type

Historically, the rates of LST and VLST were highest with first-generation DESs. The risk was lowest with second- or third-generations DESs, even when compared with BMSs. Regarding BRS, the only available BRS for widespread clinical use (Absorb) has a higher thrombotic potential compared with second-generation metallic DESs.

Procedure-Related Factors

Several features have been correlated with higher rates for ST such as incomplete stent apposition, persistent vessel dissection, and incomplete strut coverage. These factors highlight the importance of achieving optimal results via appropriate stent selection as well as the right technique, determined by the clinical circumstance, location, and characteristics of the lesion.

Lesion-Related Factors

Lesion characteristics may present a risk for ST, for example, plaques with a necrotic-filled lipid core during acute coronary syndromes (ACSs), in which struts have demonstrated reduced neointimal coverage. Other factors include complex anatomy such as multiple lesions, small vessel size, lesions larger than 3 cm, ostial and bifurcation lesions, total occlusions, saphenous vein graft stenosis, previous ST, and prior brachytherapy.

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