Coronary Stents

Etiology

Atherosclerosis, which is characterized by the formation of luminal plaques, is the underlying cause of coronary artery disease. Risk factors for the development and progression of atherosclerosis have been studied and classified as modifiable or non-modifiable.[6][7]

Modifiable Risk Factors

• Hyperlipidemia 
• Hypertension
• Diabetes mellitus
• Cigarette smoking
• Physical inactivity
• Obesity 

Non-modifying Risk Factors

• Age
• Sex
• Family history of premature coronary artery disease

Epidemiology

Coronary artery disease (CAD) is the leading cause of morbidity and mortality worldwide and is responsible for approximately 20% of all deaths in the United States. CAD is due to underlying atherosclerosis, which leads to plaque formation in the lumen of coronary arteries. The actual frequency of atherosclerosis cannot be precisely determined as it is mostly asymptomatic until the late stages. It starts early in childhood and develops fatty streaks over time. More advanced and complicated lesions are present in individuals in the fifth or sixth decade of life. In the United States, approximately 14 million individuals experience CAD and its complications, including post-myocardial infarction heart failure (HF) being the most common one.[8] Approximately 1.5 million Americans have an acute myocardial infarction (AMI) annually, of which one-third result in death.

According to 2009 epidemiology data, around 785,000 Americans suffered their first AMI, while 470,000 Americans had a recurrent MI. An estimated 195,000 "silent" heart attacks occur each year. About every 34 seconds, an American will have an AMI. In developed countries, the incidence of AMI is similar to that observed in the United States. The frequency of symptomatic CAD in ethnic immigrant populations in the United States approaches that of the white population, which supports the role of environmental factors. In France, the Mediterranean diet with the use of alcohol and its possible HDL-raising benefit, and the predominant use of monosaturated fatty acids (canola oil or olive oil) and omega-3 fatty acids, leads to a lower risk of atherogenesis with the said factors.[9] The reduced incidence of CAD and AMI is a phenomenon named the "French paradox." The Spanish cohort of the European Prospective Investigation into Cancer and Nutrition suggests that the Mediterranean diet may help lower the risk of CAD.[10] The frequency of symptomatic CAD is also very high in Great Britain, Scotland, Scandinavia, Finland, and Russia. Symptomatic CAD due to atherosclerosis is rare on the African continent. However, recent evidence points to a rapid rise in these statistics due to rapid urbanization and westernization of the rural African populations. The statistics of CAD vary significantly with race. As compared to whites, blacks have higher morbidity and mortality rates of CAD due to higher risk factors such as hypertension, obesity, metabolic syndromes, and physical inactivity. Men have a higher prevalence of CAD than women before menopause, but after menopause, the rates of CAD for both sexes are fairly similar.[11]

Pathophysiology

The early pivotal event in atherogenesis is endothelial cell dysfunction (ED) due to the long-term presence of various cardiovascular risk factors, such as dyslipidemia, chronic uncontrolled hypertension causing shear stress, and uncontrolled diabetes mellitus, which cause non-enzymatic glycosylation of surface lipoproteins on endothelial cells. It is believed that ED causes endothelial nitric oxide synthase (ENOS) dysregulation, which leads to decreased production of vasodilator nitric oxide (NO) and an increased amount of superoxide, which is an oxidant. This imbalance between vasodilators (nitric oxide and histamine) and vasoconstrictive factors impairs vascular hemostasis, which leads to increased turbulence, shear stress, and ED.[12]

ED causes endothelial cell activation, which leads to increased expression of adhesion molecules, activation of platelets and inflammatory cells, and increased permeability of endothelial cells; thus, it promotes the diffusion of lipids and transmigration of the adherent leukocytes in the presence of chemo-attractant cytokines secreted by inflammatory cells. Both innate and adaptive immunity are involved in atheroma formation. Innate immune cells, such as monocytes and dendritic cells and adaptive immune cells, such as T lymphocytes, present antigen on their surface to dendritic cells in the interstitium and regional lymph nodes. Monocytes turn into macrophages when it reaches the intima. It engulfs the lipid and turns into lipid-laden foam cells.[13] Activated macrophages, platelets, and dysfunctional endothelial cells produce growth factors that modulate early atherogenesis. These factors include transforming growth factors alpha and beta, thrombin, platelet-derived growth factor, insulin-like growth factor, and angiotensin II. The relative deficiency of endothelium-derived NO further potentiates the proliferative stage of plaque maturation.

The earliest morphological manifestation of atherosclerosis is fatty streaks, which consist of lipid-laden macrophages, T lymphocytes, and smooth muscle cells (SMC). Fatty streaks go on to transform into fibrous plaque due to SMC activation. SMC secretes the extracellular collagen matrix, which forms the fibrous cap and stabilizes plaque. Due to ongoing inflammation, some macrophages die and release lipids into extracellular space in the intima, resulting in a necrotic core. Matrix metalloproteinases (MMP) are protease enzymes that are secreted by SMC, and they are very crucial for plaque progression due to their role in extracellular matrix destruction. MMP is counteracted by tissue inhibitor of matrix metalloproteinase (TIMP) and statin drugs. The imbalance between MMP and TIMP can lead to the rupture of the fibrous cap due to excessive extracellular matrix destruction and subsequent activation of platelets and acute thrombosis, which leads to a critical level of coronary occlusion.[14] This compromises blood flow to the myocardium. It is manifested as angina to acute myocardial infarction, depending upon the level of arterial occlusion. The luminal obstruction must be between 50% to 70% to cause flow limitation.

Plaque Remodeling

As the plaque progresses, two types of remodeling can occur: positive and negative.

Positive Remodeling

It is the outward growth of plaque due to underlying compensatory arterial dilation. It does not compromise blood flow, but due to the overburden of unstable plaque, it is at risk for plaque rupture and thrombosis, which results in acute myocardial infarction. It does not present as stable angina symptoms because luminal diameters remain the same until the plaque ruptures suddenly and present with acute coronary syndromes.[15]

Negative Remodeling

In this case, the plaque grows inwardly towards the vessel lumen, thereby decreasing luminal diameter over time because there is no compensatory vascular dilation. As soon as the luminal obstruction is between 50% and 70%, blood flow to the myocardium is limited, and stable angina symptoms are more likely to develop. Plaque, in this case, is still at risk of acute rupture, which can result in myocardial infarction.[16]

Histopathology

According to Stary et al., atherosclerosis is classified in Roman numeral numbers in the sequence of lesion progression.[17]

Type I: (initial) contains scattered isolated lipid-laden macrophage, also called foam cells.

Type II: consists of foam cells mainly in the form of layers, also called fatty streaks.

Type III: is the intermediate stage lesion, which contains foam cells in layers and scattered extracellular lipid droplets due to apoptosis of foam cells.

Type IV: consists of an extensive dense accumulation of extracellular lipid, which is also termed as lipid core, also called atheroma.

Type Va: These lesions are also termed as fibro-atheroma, and it consists of the fibrous cap on top of atheroma. There are also smooth muscle cells present in an intimal layer that help in the deposition of the extracellular matrix of the fibrous cap.

• If fibro-atheroma has calcification, then it is termed as type Vb.
• One particular type-V lesion in which a lipid core is absent and lipid, in general, is minimal may be referred to as type Vc.

Type VI: The disruption of the lesion surface leading to thrombosis or hemorrhage into lesion is a hallmark of this complicated lesion. These lesions are associated with high mortality and morbidity. Type VI may be subclassified by the superimposed features.

• Disruption of the surface may be labeled as type VIa.
• Hematoma or hemorrhage indicates type VIb.
• Thrombosis indicates type VIc.
• Type VIabc indicates the presence of all three features.

Toxicokinetics

A major drawback of BMS is in-stent restenosis due to intimal layer injury. Neo-intimal hyperplasia (NIH) is the underlying phenomenon in which intimal injury leads to an increase in SMC migration and proliferation in the intimal layer, thereby leading to restenosis. DES is designed to locally deliver anti-restenotic drugs which act to block SMC migration and proliferation at stent site with no systemic adverse drug outcomes. The efficacy of the drug depends upon the diffusion rate, tissue accumulation, distribution, and local vascular toxicity. Thus, a balance should be achieved between adequate drug amount, delivery, and minimal local vascular toxicity. The rate of diffusion depends upon several factors, such as coating thickness, amount of drug-loaded, a drug to polymer ratio, and partition coefficient (PC) of the drug. PC is directly proportional to the rate of diffusion.

Drug release has an initial fast phase due to the immediate dissolution of the drug from the outer most layer of the polymer coating. The fast-phase release has first-order kinetic, with the majority of the total available dose-released within the first few days. Later on, a sustained slower-release phase occurs, for the most part, due to slower diffusion-mediated release. The higher loading dose tends to have a greater release during the initial fast-release phase.

The hydrophobic, hydrophilic, or lipophilic nature of a drug also regulates the transport or distribution of the drug in arterial tissue. Hydrophilic drugs mix readily with blood and can distribute into and around local arterial tissue; therefore, there is lower local drug concentration. By contrast, hydrophobic drugs tend to distribute more towards the arterial tissue homogenously, leading to high drug accumulation in arterial tissue and slower clearance. Lipophilic drugs have a slower drug release rate.[18]

Studies have shown that rapamycin and paclitaxel enhance the expression of prothrombotic factors such as tissue factor and plasminogen activator inhibitor-1. In the presence of local drug toxicity in the stent site leading to delayed re-endothelialization, the acidic byproducts (lactic acid and glycolic acid) of polymeric degradation and these prothrombotic factors can cause stent thrombosis due to platelet activation. It is more pronounced when antithrombotic drugs are withdrawn postoperatively. Hypersensitivity towards polymer coating has also been reported, which also augments the stent site for chronic inflammation.[19][20][2]

History and Physical

Coronary atherosclerosis is an underlying pathology in ischemic heart disease. Coronary atherosclerosis is predominantly an asymptomatic condition. It starts at an early age, such as in the 20s, as fatty streaks, but it is clinically silent. It only becomes symptomatic once 50% to 70% of the luminal diameter is obstructed due to growing fibrous plaque, leading to end-organ ischemia or infarction. Clinically, a chronic stenotic lesion i.e., stable CAD, manifests with clinical symptoms of exertional angina, while plaque rupture may result in symptoms of acute myocardial infarction.[21]

Patients with symptomatic coronary artery disease may present with the following signs and symptoms:

• Stable angina
• Unstable (Prinzmetal's) angina
• Acute myocardial infarction (AMI) which consists of ST-elevation (STEMI) and non- ST-elevation myocardial infarction (NSTEMI)
• Sudden cardiac death
• Chronic ischemic cardiomyopathy
• Congestive heart failure (CHF)

The most common symptom associated with coronary artery disease is dull, squeezing, or pressure-like chest pain located in the sub-sternal or left side of the chest and radiating to the left arm, neck, or jaw. It may be associated with dyspnea and increased sweating. In stable angina, it is exertional in nature and relieved on resting for a while or ingestion of nitrates, while pain associated with unstable or AMI (STEMI and NSTEMI) occurs at rest. The pain of AMI is partially relieved with nitrates.[6]

Physical Examination

The following signs can be noted in a patient with AMI.

• Diaphoresis
• Tachypnea
• Dyspnea with crackles on lungs auscultation, orthopnea, and paroxysmal nocturnal dyspnea due to left ventricular infarct, which leads to reduced left ventricular ejection fraction (LVEF) and pooling of blood in the lungs.
• Hypotension or cardiogenic shock due to the following: (1) Left ventricular infarction with reduced LVEF. S3 can be heard on heart auscultation. (2) Right ventricular infarction leading to a decreased venous return to the left heart. The patient can have jugular venous distension (JVD) and pedal edema with normal lung auscultation.
• Mitral regurgitation murmur can be heard, which is either functional or ischemic.
• Xanthoma/xanthelasma may or may not be present secondary to underlying dyslipidemia.
• Arrhythmias

On physical examination, tachycardia is common in a patient with AMI. While bradycardia can occur due to blockage of the right coronary artery branch, which supplies the sino-atrial node. Arrhythmias of different types also can be seen as secondary to ischemia of myocardium. Acute ischemia or infarction causes hypoxia and depletion of intracellular adenosine triphosphate, which shifts the cell to anaerobic glycolysis and lactic acid is accumulated inside the cell. This intracellular acidic environment lowers the pH and activates Na+/H+ and Na+/Ca++ ion exchange channels to dump H+ ion out of the cell and raise intracellular pH. This is accompanied by intracellular calcium overload and increased late sodium current. A lower resting membrane potential is generated in this manner, which turns infarcted tissues more excitable and leads to arrhythmias. There are many types of ventricular tachyarrhythmias (VA) present after AMI, such as non-sustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (VT), or ventricular fibrillation (VFIB). VA is the most common cause of sudden cardiac death, occurring within 1 hour of AMI. Thrombolysis and percutaneous coronary intervention have reduced the incidence of VA and reduced the burden of sudden cardiac death (SCD) over the past decades. The incidence of VA is directly proportional to the size of an infarct and inversely related to the left ventricular ejection fraction after AMI.

Evaluation

The following tests may be ordered in patients with suspected coronary artery disease:[22]

• Complete blood count (CBC): Anemia can present with chest pain and dyspnea due to the decreased oxygen content of the blood.
• Thyroid function test (TSH and free T4): Hyperthyroidism can cause palpitation, arrhythmias, or chest pain.
• Fasting lipid profile: Triglyceride, total cholesterol, and low-density lipoproteins (LDL).
• Electrocardiogram (EKG): Ischemia can result in T wave abnormalities ranging from T-wave flattening to inversions and ST-depressions. In STEMI, ST-segment elevation is present. Thus it helps to diagnose the condition. In NSTEMI, ischemic ECG changes previously described may be present.
• Cardiac enzymes: Creatine kinase such as MB isozymes (CKMB), troponins, and lactate dehydrogenase (LDH) is diagnostic for AMI. Troponins are more specific than others, but CKMB is diagnostic for re-infarction cases because its level starts to rise in blood within 4 to 6 hours after AMI. Troponins, peak level, is achieved in 12 to 24 hours after AMI. CKMB level drops to baseline after 36 hours. This is why CKMB may be more specific to diagnose re-infarction.
• Echocardiography: Echocardiogram can be useful to detect new-onset of wall motion abnormalities in myocardial infarction and also gives a cardiac function quantification. 
• Exercise tolerance test (ETT) or nuclear stress imaging: Stress testing is helpful for the evaluation of underlying stable CAD.
• Coronary angiography: Coronary angiography is an invasive evaluation which delineates significant obstructive CAD. Coronary angiography is usually followed by a percutaneous intervention and stent deployment, which serves curative for the target lesion.
• Intravascular ultrasonography (IVUS): IVUS can accurately comment on a plaque with positive remodeling, which grows outwardly, where vessel lumen is not significantly stenosed. IVUS demonstrates the presence or absence of a fibrous cap, calcification, and ulceration, or cracks on plaque surface.
• Fractional flow reserve (FFR): Fractional flow reserve (FFR) is measured during coronary angiography by transducing a pressure wire to calculate the ratio between coronary pressure distal to focal coronary artery stenosis and the aortic pressure under conditions of induced maximum myocardial hyperemia. This ratio represents a potential decrease in coronary flow distal to the stenosis and guides whether the percutaneous intervention is warranted in moderately stenotic lesions.

Treatment / Management

Coronary angioplasty with stent placement is utilized in the following indications [23][24][25][26]:(A1)

• Non–ST-elevation myocardial infarction or acute coronary syndrome
• Acute ST-elevation MI (STEMI)
• Stable angina refractory to optimal guideline-directed therapy for CAD including antianginal regimen
• Anginal equivalent symptoms including dyspnea, arrhythmia, dizziness or syncope
• Symptomatic patients with objective evidence of medium to large-sized area of moderate to severe intensity ischemia on noninvasive testing

In this section, we define and discuss different types of coronary stents in detail used for the treatment of symptomatic CAD.

Grüntzig developed the concept of percutaneous treatment of obstructive coronary lesions by using balloon dilatation in 1977.[27] This was a revolutionary approach, as it avoided open thoracotomy and also became a preferred therapeutic measure in the setting of acute emergencies such as myocardial infarction. The long-term results of balloon angioplasty were, however, limited by the risk of acute vessel recoil, restenosis, and also abrupt vessel closure during the early post-intervention period. To overcome the limitations of the balloon angioplasty, Puel and Sigwart developed bare-metal stents (BMS) in 1986. BMS reduced the risk of abrupt vessel closure resulting from local dissections. In addition, BMS also eliminated vascular wall elastic recoil and constrictive remodeling. Further optimization of stent implantation techniques, along with the use of dual antiplatelet therapy, yielded better results supporting the widespread use of BMS. By the late 1990s, BMS use approached almost 80% of all PCIs. Stent implantation, however, causes an arterial injury, which leads to vascular smooth muscle cell activation and proliferation, resulting in neointimal hyperplasia, which, if excessive, can lead to in-stent restenosis.[28]

Long-term follow-up of BMS patients showed that about 30% of patients experienced neointimal hyperplasia and in-stent restenosis. This appeared to be a significant limitation of BMS. New strategies were thus proposed to address this issue, which included systemic administration of anti-inflammatory agents, antiproliferative agents, and stent surface coatings. This ultimately led to the development of drug-eluting stents (DES).

In the early 2000s, DES rapidly became the favored choice due to its improved anti-restenotic efficacy. DES has three components: a. a metal stent backbone; b. an antiproliferative agent; and c. drug carrier (often a polymer coating). Although these devices offer similar skeletal framework as BMS, they yield an additional site-specific release of antiproliferative agents that suppress neointimal hyperplasia and stenosis. Although DES prevents delayed restenosis, early stent thrombosis is a more prevalent adverse event observed with DES due to a delay in the healing of the stented arterial segment/endothelialization. This risk is mitigated by the use of dual antiplatelet therapy (DAPT) with aspirin and a thienopyridine in the early period after stent implantation. Evidence from systematic reviews and meta-analyses demonstrates a minimal risk of delayed stent thrombosis in the early-generation CYPHER® sirolimus-eluting stents and TAXUS® paclitaxel-eluting stents beyond one year of stent implantation. New-generation DES has thus emerged to counter-act this limitation, which is built using the novel metallic alloys (such as cobalt-chromium and platinum-chromium), allowing thinner strut stent platforms and use of new drug carriers offering improved anti-restenotic properties.

Early-generation DES used a stainless steel platform with a strut thickness of 130-150 μm while new-generation DES now usually have stent struts measuring 50-90 μm. Thinner stent struts (less than 100 μm) however, improve hemodynamic flow and drug distribution and also cause less vessel injury at implantation site leading to a lesser chance of restenosis in comparison with stents with thicker struts. Thinner struts also have a lower degree of thrombogenicity. Newer-generation DES also has a more biocompatible durable polymer coatings such as the vinylidene-fluoride hexafluoropropylene copolymer or biodegradable polymer coatings, composed of lactic or glycolic acids that fully resorb by hydrolysis after completion of drug release. Some new DES uses a technology which is known as 'polymer-free coating,' which releases antiproliferative agents directly from the stent surface without the use of a polymer coating. Older DES used paclitaxel and sirolimus drug platforms. Paclitaxel interferes with microtubule dynamics during mitosis by binding to the microtubular β-tubulin subunit. Sirolimus, however, blocks protein synthesis, cell cycle progression, and cell migration by inhibiting the target of mammalian rapamycin. The anti-restenotic efficacy of sirolimus is higher than the paclitaxel. Thus, new-generation DES use sirolimus or its analogs such as everolimus, zotarolimus, biolimus, and novolimus, which offer a better therapeutic profile for the reason mentioned above. XIENCE®/Promus polymer-based everolimus drug-eluting stent (DP-EES) has perhaps the largest body of evidence from trials.

Differential Diagnosis

Chest pain is the most common symptom of symptomatic coronary artery disease. Other causes of chest pain should also be ruled out while making the correct diagnosis.

• Unstable angina
• Acute myocardial infarction (ST elevation and Non-ST elevation)
• Aortic dissection
• Takotasubo cardiomyopathy
• Vasculitis (Kawasaki Disease in children)
• Acute pericarditis
• Myocarditis
• Gastroesophageal reflux disease (GERD)
• Pleuritis
• Costochondritis
• Pulmonary embolism

Pertinent Studies and Ongoing Trials

Two pivotal randomized controlled trials named the Belgium Netherlands Stent Arterial Revascularization Therapies Study (BENESTENT) and the North American Stent RestenosisStudy (STRESS) – showed a significant decrease in the incidence of restenosis and repeat revascularization procedures with the use of BMS when compared to balloon angioplasty in patients with stable CAD.[29][30][29]

CYPHER® sirolimus-eluting stents (now Cardinal Health, Milpitas, CA, USA) demonstrated a reduced risk of restenosis as compared to BMS in the RAVEL trial.[31] TAXUS™ paclitaxel-eluting stents (Boston Scientific, Marlborough, MA) demonstrated a reduced risk of restenosis as compared to BMS in the TAXUS-IV trial. A collaborative network meta-analysis that included 38 randomized trials with over 18,000 patients showed an overwhelming benefit of DES (CYPHER and TAXUS stents) when compared to BMS in terms of the risk of target lesion revascularisation. A comprehensive pairwise meta-analysis including 22 randomized trials and 34 observational studies with at least one year of follow-up showed similar findings and demonstrated a significant risk reduction for target vessel revascularisation (HR 0.45, 95% CI: 0.37-0.54 in randomized studies; and HR 0.54, 95% CI: 0.48-0.61 in observational studies).

A systematic review by the Task Force of the European Society of Cardiology (ESC) on coronary stent evaluation and the European Association for Percutaneous Cardiovascular Interventions (EAPCI) analyzed a total of 158 randomized trials. It showed that the early-generation DES was associated with a lower risk of target lesion revascularization when compared with BMS, while new-generation DES provided a further risk reduction when compared to early-generation DES (median rates per 100 person-years at 12 months: BMS 12.3%, early-generation DES 4.3%, new-generation DES 2.9%).

NORSTENT trial directly compared DES with BMS in 9,013 patients. DES were associated with a lower risk of stent restenosis when compared to BMS (0.8% vs. 1.2%; HR 0.64, 95% CI: 0.41-1.00, p=0.0498) at six-year follow-up.[32] It did not, however, show any significant difference between DES (mostly new-generation) and BMS for the composite primary endpoint of death and myocardial infarction on a six-year follow-up (16.6% vs. 17.1%; HR 0.98, 95% CI: 0.88-1.09, p=0.66).

EXCEL trial demonstrated a non-inferiority of PCI with new-generation drug-eluting stents DP-EES as compared to CABG in patients with low-to-moderate anatomical complexity of CAD (that is SYNTAX score <33) with respect to the significant adverse cardiovascular events with a composite of death, stroke, and MI at three-year follow-up.[33] The NOBLE trial, however, failed to show non-inferiority between PCI with biodegradable polymer-based biolimus-eluting stents and coronary artery bypass graft (CABG) surgery in patients with the left main disease, irrespective of anatomical complexity of CAD.[34] It showed that the composite of death, MI, stroke, and repeat revascularization, were lower in CABG surgery at five years of follow-up.

Prognosis

CAD remains the number one cause of death for men and women worldwide. In the United States, around 1.5 million Americans suffer from AMI annually, and one-third of these die. Survivors of AMI have a poor prognosis with a 1.5 to 15 times greater risk of mortality and morbidity than the rest of the population. Historical figures among survivors of AMI show that 25% of the men and 38% of women die within one year after having an AMI, 18% of men and 34% of women have a second MI within six years of AMI, and 22% of men and 46% of women are diagnosed with congestive heart failure (CHF) due to ischemic cardiomyopathy.[35]

The prognosis depends on the following factors:

• Presence of angina symptoms
• Left ventricular ejection fraction
• Number, location, and extent of coronary artery involvement
• Coronary revascularization status
• Cardiac arrhythmias
• Compliance with medical therapy
• Aggressive risk control

Complications

Coronary artery disease has the following complications.

• Angina pectoris
• STEMI or NSTEMI
• Sudden cardiac death
• Congestive heart failure due to ischemic cardiomyopathy
• Ventricular arrhythmias
• Pulmonary edema due to reduced LVEF
• Mechanical complications of AMI, such as ventricular free wall rupture leading to cardiac tamponade, interventricular septal rupture