Percutaneous Coronary Intervention (PCI) Technique

Coronary angiography and percutaneous coronary intervention (PCI) are more commonly performed via the femoral or the radial artery and less commonly performed via the brachial or ulnar artery. Overall, the femoral artery is the most common route of access for these procedures in the United States; however, the use of radial access is increasing. In selected labs in the United States and in some parts of Europe, radial artery access exceeds 90%.

Two randomized, controlled trials reported equal or better outcomes with transradial access than with femoral access in ST-segment elevation myocardial infarction (STEMI) patients undergoing PCI. In the RIFLE STEACS (Radial Versus Femoral Randomized Investigation in ST-Elevation Acute Coronary Syndrome) study, a multicenter randomized trial involving 1001 STEMI patients, radial access was associated with significantly lower rates of cardiac mortality (5.2% vs 9.2%) and bleeding (7.8% vs 12.2%) than femoral access was. ^[83]

The RIVAL (Radial Versus Femoral Access for Coronary Intervention) trial compared the efficacy and bleeding outcomes of radial and femoral access separately in patients with STEMI and non-STEMI (NSTEMI). ^[84] Radial access was associated with reduced all-cause mortality (1.3% vs 3.2%) and reduced death/myocardial infarction (MI)/stroke (2.7% vs 4.6%) in STEMI patients but not in NSTEMI patients. In both STEMI and NSTEMI groups, radial access was associated with significantly reduced ACUITY major bleeding and major vascular access site complications.

The MATRIX trial compared outcomes of radial access with those of femoral access in 8404 patients with acute coronary syndrome. ^[85] The radial group had lower all-cause mortality as well as Bleeding Academic Research Consortium (BARC) major bleeding unrelated to coronary artery bypass grafting (CABG).

The European Society of Cardiology (ESC) guidelines on STEMI patients recommend preference of radial over femoral access, if it is performed by an experienced radial operator (class IIa, level B). The Society for Cardiovascular Angiography and Interventions released a consensus statement on best practices for the use of radial access for diagnosing and treating coronary artery disease (CAD), focusing on avoiding radial artery occlusion, reducing radiation exposure, and using the transradial approach in STEMI. ^[86]

Recommendations for STEMI patients include the following:

• Before integrating the radial approach into practice, clinicians should gain experience with at least 100 elective radial procedures and have a femoral crossover rate lower than 4%
• Practitioners should start with easier cases and ensure that all laboratory personnel are comfortable with the procedure
• A bailout approach to either contralateral radial or femoral access should be prepared in advance

The patient is prepared as described earlier (see Patient Preparation).

For transradial catheterization, an arteriotomy is made approximately 2 cm proximal to the radial styloid process so as to avoid the distal bifurcation and diminutive vessels. While palpation is being done, the radial artery is punctured with a micropuncture needle, and a hydrophilic sheath is placed by means of the modified Seldinger technique.

Once the sheath is in place, an intra-arterial vasodilator is given (nicardipine 500 µg or verapamil 5 mg), with half the dose administered at the beginning of the procedure and the other half at the end. Intravenous (IV) heparin dramatically reduces the risk of radial artery occlusion and is therefore often used in transradial catheterization (usual dose, 50 units/kg; maximum total dose, 5000 units).

For transfemoral catheterization, the arteriotomy site is the common femoral artery, above its bifurcation into the deep femoral artery (profunda femoris) and the superficial femoral artery and below the inferior epigastric artery. Because the skin crease can sometimes be misleading, a combination of various other anatomic landmarks may be used, such as bony landmarks (aiming 2 cm below the center of the inguinal ligament) and the point of maximal palpable impulse.

Fluoroscopy is often used to mark the femoral head, and the target zone for the arteriotomy is the middle of the femoral head. A micropuncture (21-gauge) or 18-gauge needle is used to puncture the femoral artery, and a sheath is placed with the modified Seldinger technique. Sheath size varies according to the preference of the operator; in general, it is in the range of 4-6 French.

Once access is obtained, catheters are advanced over a 0.035-in. J-tip guide wire into the ascending aorta. Various different catheter shapes are available; the choice depends on the operator’s preference and the patient’s anatomy. Selective coronary angiography is performed in different views (at least two orthogonal views for each segment of the coronary) using hand or power injections of iohexol.

Guide catheters have the same external diameter as diagnostic catheters but a larger lumen and are used for PCI. Once the catheter has engaged the coronary ostium and diagnostic angiograms have been obtained, weight-based IV anticoagulant (unfractionated heparin [UFH], bivalirudin, or low-molecular-weight heparin [LMWH]) therapy may be administered. If the patient is not on long-term dual antiplatelet therapy (DAPT), a loading dose of a P2Y12 inhibitor is also given. As noted above, all patients should have been pretreated with aspirin.

A 0.014-in. guide wire is then advanced into the coronary artery across the stenotic lesion. All balloon catheters and other devices will be tracked over this wire. In some cases, direct stenting of the lesion can be done; however, in most cases, vessel preparation with either predilation with a semicompliant balloon or an atherectomy device is performed. The balloon is then withdrawn, and a stent of appropriate length and diameter is advanced over the coronary guide wire, positioned across the lesion, and deployed.

Depending on the angiographic appearance of the stent, postdilation of the stent may or may not be performed with a noncompliant balloon. An intravascular imaging tool, such as intravascular ultrasonography (IVUS) or optical coherence tomography (OCT) (see Anatomic and Physiologic Assessment), can be used for further delineation and assessment of the anatomy including plaque burden, vessel size, and stent deployment.

After the PCI result is deemed adequate, the coronary wire is removed and final angiograms are taken.

Access sheath removal

In transradial catheterization, the sheath is removed immediately after the procedure, and a compression band is applied to the wrist. With a goal of patent hemostasis, this band is left inflated for 90-120 minutes and then gradually deflated.

In transfemoral catheterization, hemostasis is achieved either by the use of vascular closure devices (inserted at the end of the case) or by manual compression (a few hours later when activated clotting time [ACT] is in the appropriate range).

Intravascular ultrasonography

Although coronary angiography provides a display of luminal narrowing in multiple planes and is useful in guiding PCI, it provides only limited information about the vessel wall, which is where the atherosclerotic process resides.

IVUS (see the image below) was developed to provide information about the plaque, the vessel wall, and the degree of luminal narrowing. It provides a tomographic cross-section of the vessel, allowing operators to gather significant qualitative and quantitative information that is potentially valuable for assessing stenosis severity and determining the true extent of atherosclerotic involvement.

The lumen border and the media-adventitia interface are the key landmarks that should be identified during interrogation. Plaque can be distinguished from the lumen on the basis of differences in echogenicity. In addition to providing information about the amount and distribution of plaque, IVUS can identify features of plaque composition (eg, calcification and lipid collections) that may not be appreciated by angiography alone.

Frequent uses of IVUS include assessment of indeterminate lesions and evaluation of adequate stent deployment. The latter is particularly important, in that proper deployment of drug-eluting stents (DESs) is critical for reducing thrombosis rates. Development of other technologies (eg, OCT and plaque thermography) have enhanced our ability to interrogate coronary arteries.

Optical coherence tomography

OCT uses light-based imaging to capture micrometer-resolution images of the artery wall. It has 10 times higher resolution than IVUS does but is unable to penetrate as deep into the vessel wall. OCT’s high resolution enables it to better evaluate stent strut apposition and neointimal stent strut coverage.

Coronary physiologic assessment

Intracoronary Doppler pressure wires are used to characterize coronary lesion physiology and estimate lesion hemodynamic severity. Comparison of the pressure distal to a lesion with aortic pressure at maximal coronary hyperemia enables determination of fractional flow reserve (FFR) (see the image below).

An FFR measurement lower than 0.80 during maximal hyperemia (induced via administration of adenosine) is consistent with a hemodynamically significant lesion. This determination is useful in deciding whether to perform PCI in an angiographic intermediate lesion. Clinical data—namely, the findings from the DEFER (Deferral of Percutaneous Coronary Intervention) study—support using this approach; a low event rate was seen in medically managed patients with angina and an FFR measurement greater than 0.75.

The FAME (Fractional Flow Reserve versus Angiography for Guiding PCI in Patients with Multivessel Coronary Artery Disease) trial showed that routine measurement of FFR during angioplasty reduced the risk of death, MI, or repeat revascularization by 30% and the risk of death or MI by 35%, compared with the current practice of using angiography to guide stenting decisions. ^[87]

In this study, a cutoff FFR value of 0.80 was used to define a nonischemic lesion. A 2-year follow-up of the FAME trial showed continuing significant reductions in the combined endpoint of death and MI with the use of FFR in comparison with standard angiography-guided PCI. ^[88]

The FAME 2 trial randomly assigned patients with stable CAD who had at least one stenosis with an FFR less than 0.8 to receive either FFR-guided PCI plus optimal medical therapy or optimal medical therapy alone. ^[89] The occurrence of the primary endpoint—a composite of any-cause mortality, nonfatal MI, or urgent revascularization within 2 years—was significantly lower in the PCI group than in the medical therapy group (8.1% vs 19.5%).

However, it is important to note that this difference in primary endpoint was primarily driven by a reduction in the rate of urgent revascularization in the PCI group (4% vs 16.3); there were no significant between-group differences in mortality and MI rate. ^[89]

The FAME 3 study, currently under way, is a multinational multicenter trial designed to compare FFR-guided PCI (using second-generation DESs) with coronary artery bypass grafting (CABG) in patients with multivessel CAD.

Currently, the use of FFR is recommended to assess the hemodynamic significance of angiographically intermediate (40-70%) stenosis. Both FFR and IVUS have shown favorable outcomes when used to assess angiographically intermediate lesions; however, the data on FFR are more robust.

A meta-analysis by Johnson et al indicated that FFR values should be viewed not only in the context of a cut point used in deciding whether to revascularize patients through PCI but also as part of a spectrum of values indicating which patients will receive the most benefit from PCI. ^[90]

The analysis, which utilized data from FFR trials (9173 lesions) and patient-level data (6961 lesions), supported the use of the 0.75-0.80 range, the same range employed in major FFR studies, as the optimal cut point for PCI; however, the results also indicated that the further beneath that range a patient’s FFR falls, the more benefit the patient will receive from PCI. ^[90] Johnson et al also found evidence that measuring the FFR after PCI can aid in determining a patient’s prognosis, with higher post-PCI numbers being associated with lower subsequent event rates.

Antithrombotic therapy

Aspirin and heparin have been the traditional adjunctive medical therapies for patients undergoing coronary angioplasty and have been shown to decrease complications after the procedure. Since 1994, several antithrombotic drugs have been developed that have advantages over standard heparin. Although heparin is an effective anticoagulant, it has several limitations, including variable pharmacokinetics requiring careful monitoring, inhibition by substances released from activated platelets, and inability to inhibit fibrin-bound thrombin.

To address these limitations, several direct thrombin inhibitors have been developed. Hirudin and bivalirudin were evaluated in multicenter trials, ^{[25, 91, 92, 93]} and both agents were found to be slightly better than heparin in preventing ischemic complications during balloon angioplasty, though they had no effect on restenosis rates.

At some centers, LMWHs are being substituted for standard heparin in the treatment of patients with acute coronary syndrome (ACS) and during coronary interventions. Factor IX and factor Xa inhibitors are being evaluated as potential alternative anticoagulants; however, trials have failed to show a significant difference in efficacy of factor Xa inhibition between these agents and UFH.

In the HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial, ^[94] 3602 patients presenting with STEMI and undergoing PCI were treated with bivalirudin and had substantially lower 30-day rates of major hemorrhagic complications and lower rates of net adverse clinical events (ie, major bleeding or composite major adverse cardiovascular events [death, reinfarction, target-vessel revascularization for ischemia, or stroke]) than patients treated with heparin plus a glycoprotein (GP) IIb/IIIa inhibitor.

The investigators continued to follow patients for 1 year. ^[94] Data were available for 1696 patients in the bivalirudin group and 1702 patients in the heparin plus GPIIb/IIIa inhibitor group. At 1 year, the bivalirudin group continued to have reduced rates for major bleeding and adverse events as compared with the heparin plus GPIIb/IIIa inhibitor group. Death, reinfarction, target-vessel revascularization for ischemia, and stroke rates were similar in the two groups.

The Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial, ^[95] which studied the impact of age on outcomes in moderate- and high-risk non–ST-segment elevation ACS (NSTE-ACS), found that patients aged 75 years or older who were treated with bivalirudin alone had similar ischemic outcomes but significantly lower bleeding rates than those who were treated with heparin plus GPIIb/IIIa inhibitors, both overall and in the PCI subset.

In this trial, outcomes were analyzed at 30 days and at 1 year in four age groups, overall, and in those undergoing PCI. ^[95] Of the 13,819 patients studied, 3655 (26.4%) were younger than 55 years, 3940 (28.5%) were aged 55-64 years, 3783 (27.4%) were aged 65-74 years, and 2441 (17.7%) were aged 75 years or older. Older patients had more cardiovascular risk factors and had a higher acuity at presentation.

In the NAPLES (Novel Approaches for Preventing or Limiting Events) trial, Tavano et al compared bivalirudin with UFH plus a GPIIb/IIIa inhibitor (ie, tirofiban) during PCI in 335 patients with diabetes mellitus and concluded that elective PCI with bivalirudin monotherapy is safe and feasible in patients with diabetes. ^[96]

The bivalirudin group experienced significantly less in-hospital bleeding (8.4% vs 20.8%). ^[96] Non–Q-wave MI rates were similar in the two groups (10.2% for bivalirudin vs 12.5% for UFH-tirofiban. In the early days of stenting, multiple antiplatelet agents and warfarin were used in an attempt to prevent stent thrombosis, but thrombosis continued to occur in approximately 6% of patients.

The EUROMAX (European Ambulance Acute Coronary Syndrome Angiography) trial randomly assigned 2218 STEMI patients to receive either bivalirudin or UFH or LMWH with optional GP IIb/IIIa inhibitors. ^[97] The bivalirudin group had a lower risk of the primary outcome, which was a composite of death or major bleeding not associated with CABG (5.1% vs 8.5%). It also had a lower rate of the principal secondary outcome, a composite of death, reinfarction, or non-CABG major bleeding (6.6% vs 9.2%).

These differences reported in the EUROMAX trial were primarily driven by a reduced risk of major bleeding (2.6% vs 6%); there were no significant differences in the rates of death or reinfarction. ^[97] The bivalirudin group had higher rates of acute stent thrombosis (1.1% vs 0.2%).

The single-center HEAT PPCI (How Effective Are Antithrombotic Therapies in Primary PCI) trial randomly assigned 1812 STEMI patients to receive either bivalirudin or UFH and compared the two regimens with respect to primary efficacy outcome (composite of all-cause mortality, cerebrovascular accident, reinfarction, or unplanned target-lesion revascularization) and primary safety outcome (incidence of major bleeding). ^[98]

In this trial, heparin reduced the incidence of major adverse ischemic events as compared with bivalirudin (5.7% for heparin vs 8.7% for bivalirudin). ^[98] There was no increase in the rate of bleeding complications with heparin (3.5% vs 3.1% for bivalirudin).The results of the HEAT PPCI trial differed from those of previous trials and suggested that bleeding risk is not increased with heparin.

In concordance with the HEAT PPCI results were the results of the large MATRIX trial, which randomly assigned 7213 acute coronary syndrome patients undergoing PCI to receive either bivalrudin or UFH. ^[99] There was no significant difference in major adverse cardiovascular events (MACE; 10.3% vs 10.9%; relative risk [RR], 0.94; 95% confidence interval [CI], 0.81-1.09; P = 0.44) or net adverse clinical events (11.2% vs 12.4%; RR, 0.89; 95% CI, 0.78-1.03; P = 0.12).

Post-PCI bivalrudin infusion was given to a subgroup of patients but did not show significantly lower urgent target-vessel revascularization, definite stent thrombosis, or net adverse clinical events compared to patients who did not receive the post-PCI infusion. ^[99]

In summary, the early trials showed better outcomes with reduced bleeding in patients who received bivalrudin, but the two subsequent trials, HEAT PPCI and MATRIX, showed no such benefit. Heparin is significantly cheaper than bivalrudin, and the equivocal results in the more recent trials have led to another change in practice patterns, whereby bivalrudin use in PCI has decreased.

Antiplatelet therapy

The most feared complication of intracoronary stents has been thrombotic occlusion of a freshly deployed metallic endoprosthesis. Aggressive antiplatelet therapy has been shown to significantly reduce the risk of stent thrombosis and is required in all patients receiving a stent.

Patients receiving stents are now treated with a combination of aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel, ticagrelor, or cangrelor); with this DAPT, the development of less thrombogenic stents and improvements in stent deployment technology, the incidence of subacute thrombosis currently is less than 1%.

Today, DAPT is provided to all stent patients for a minimum of 4 weeks after a bare-metal stent (BMS) is placed and for a minimum of 6-12 months when a DES is used. Several trials have suggested that a shorter duration of P2Y12 inhibitor administration may be safe in patients with second-generation DESs, but the guidelines still recommend 12 months of DAPT in patients who present with acute coronary syndrome.

For patients who undergo PCI for stable ischemic heart disease (SIHD), the American College of Cardiology (ACC) and the American Heart Association (AHA) now recommend a shorter duration of DAPT. ^[100] Patients who receive DESs for SIHD should receive DAPT (with clopidogrel) for 6 months (class I recommendation). If such a patient is at high risk for severe bleeding (eg, is undergoing major intracranial surgery) or develops a high risk of bleeding (eg, needs treatment with oral anticoagulation), the P2Y12 inhibitor could be discontinued at 3 months after stent implantation (class II b recommendation).

Issues remain as to whether the duration of aspirin and P2Y12 inhibitor therapy should be longer in patients who received first-generation DESs. In the authors’ view, treatment with 81 mg of aspirin should be maintained for life in all DES patients, and lifetime P2Y12 inhibitor therapy should be considered unless bleeding contraindications restrict its use. Currently, there are multiple ongoing studies designed to evaluate the question of optimal DAPT duration for second-generation DESs.

Although pretreatment with P2Y12 inhibitors has been recommended by the guidelines for years, there has been no evidence supporting this strategy. The ACCOAST (Comparison of Prasugrel at the Time of Percutaneous Coronary Intervention or as Pretreatment at the Time of Diagnosis in Patients with Non-ST Elevation Myocardial Infarction) study was very important, in that it was the first, and to date the only, randomized controlled trial to have examined a pretreatment strategy. ^[101] The results, surprisingly to many, showed that pretreatment had no benefit in terms of MACE and was associated with an increase in bleeding.

The ACCOAST study compared pretreatment with prasugrel 30 mg and a further 30 mg dose before PCI with a regimen of prasugrel 60 mg after diagnostic angiography but before PCI among 4033 patients with NSTEMI who were scheduled for an early invasive strategy. ^[101] The median duration of pretreatment was 4.3 hours. Of the 4033 patients, 69% underwent PCI, 6% required surgical revascularization, and the remainder were treated conservatively.

At 7 days, patients randomized to the pretreatment arm experienced no reduction (hazard ratio [HR], 1.02; 95% CI, 0.84-1.25; P = 0.81) in the primary end point (ie, cardiovascular death, recurrent MI, stroke, urgent revascularization, and bailout use of GPIIb/IIIa inhibitors), and no benefits emerged at 30 days. ^[101] TIMI major bleeds were significantly increased in the pretreatment group at 7 days (2.6% for pretreatment vs 1.4% for no pretreatment; HR, 1.90; 95% CI, 1.19-3.02; P = 0.006).

As the 2015 ESC guidelines stated, ^[102] "Initiation of P2Y12 inhibitors soon after the diagnosis of NSTE-ACS irrespective of management strategy has been recommended. This implies pretreatment, defined as P2Y12 inhibitor administration before coronary angiography, in patients scheduled for an invasive approach.... As the optimal timing of ticagrelor or clopidogrel administration in NSTE-ACS patients scheduled for an invasive strategy has not been adequately investigated, no recommendation for or against pretreatment with these agents can be formulated.”

Concerns still exist regarding the risk of bleeding and platelet transfusion requirements in patients taking a P2Y12 inhibitor who require urgent CABG. Because emergency CABG is rare, there may be time to risk-stratify patients and to give a P2Y12 inhibitor before cardiac catheterization. If CABG is required, the effect of a P2Y12 inhibitor usually diminishes within 5 days.

Another important consideration is the clopidogrel loading dose. ACC/AHA guidelines recommend giving 600 mg within the 6 hours preceding PCI with stenting. ^[3]

Results of the HORIZONS-AMI study also indicated that a 600-mg loading dose of clopidogrel yielded better clinical outcomes than a 300-mg dose. ^[103] The 2158 patients in the 600-mg group had significantly lower unadjusted 30-day mortality than the 1153 in the 300-mg group (1.9% vs 3.1%), as well as lower rates of reinfarction (1.3% vs 2.3%) and stent thrombosis (1.7% vs 2.8%). Bleeding rates did not differ. Similar differences were shown in patients who received either bivalirudin or UFH plus a GP inhibitor.

The GRAVITAS (Gauging Responsiveness with A VerifyNow Assay—Impact on Thrombosis And Safety) study, which enrolled 2214 patients with high on-treatment reactivity 12-24 hours after PCI, found that high-dose clopidogrel (600 mg initially, 150 mg/day thereafter) provided a 22% absolute reduction in the rate of high on-treatment reactivity at 30 days in comparison with standard treatment (no additional loading dose, 75 mg/day). ^[104]

However, the GRAVITAS investigators noted no difference in the primary endpoint of 6-month incidence of death from cardiovascular causes, nonfatal MI, or stent thrombosis. ^[104] Severe or moderate bleeding according to the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) definition was lower in the standard group, but the decrease did not reach statistical significance.

Use of newer intravenous (IV) antiplatelet agents such as cangrelor may help overcome these issues. In June 2015, cangrelor was approved by the US Food and Drug Administration (FDA) for use in adults undergoing PCI. Aspirin 325 mg should be given before all PCIs and then maintained at a dosage of 81 mg/day.

Clopidogrel is the most frequently utilized P2Y12 inhibitor. Numerous studies have shown the inconsistency in the metabolism of this drug as a result of variations in the CYP2C19 pathway. Clopidogrel is a prodrug that is metabolized to an active form by the cytochrome (CYP) 450 enzyme system in the liver. Research has demonstrated that genetic variation at the CYP450 2C19 locus results in decreased metabolic activation of clopidogrel and increased risk of stent thrombosis and ischemic events. Patients with two or three abnormal alleles in their CYP2C19 genotype are at higher risk for MACE when treated with clopidogrel. ^[105]

This finding led to an update to the package insert for clopidogrel, which now includes a “black box” warning for use in patients who are “poor metabolizers” (ie, those who have two abnormal alleles at the CYP 2C19 locus; approximately 2-4% of white patients fall into this category).

Individuals with a single abnormal allele have intermediate metabolism of clopidogrel to the active metabolite. In a meta-analysis of nine studies and almost 10,000 patients, Mega et al found that the presence of even one reduced-function CYP2C19 allele in patients treated with clopidogrel after PCI was associated with a significantly increased risk of MACE, particularly stent thrombosis. ^[106]

Studies of platelet function testing have shown variability in the pharmacodynamic response to clopidogrel, and studies of genetic testing have identified genetic polymorphisms that affect its absorption (ABCB1), metabolism (eg, CYP2C19) and ultimately its pharmacodynamic effects. Genetic testing for CYP2C19 polymorphisms has potentially important prognostic implications.

In population-based studies, patients with high on-treatment platelet reactivity have had an increased risk of MACE. Unfortunately, studies have not shown that measuring platelet reactivity in an individual patient (primarily with the VerifyNow assay) is useful for identifying those at risk. Currently, measurement of platelet reactivity is still reserved for use as a research tool. ^{[107, 108]}

Besides genetic polymorphisms, there are clinical factors to consider, such as obesity and diabetes mellitus, as well as potential drug interactions, such as those with calcium-channel blockers and proton pump inhibitors (PPIs). In particular, omeprazole was implicated in clopidogrel hyporesponsiveness. However, the COGENT trial demonstrated that there was no increase in MACE in patients who took clopidogrel plus a PPI as compared with clopidogrel alone. ^[109]

Prasugrel is a thienopyridine adenosine diphosphate (ADP) receptor inhibitor that inhibits platelet aggregation. It has been shown to reduce new and recurrent MIs. ^[110] The loading dose is 60 mg orally given once, and the maintenance dosage is 10 mg/day orally (given with aspirin 75-325 mg/day).

Prasugrel is indicated for reducing thrombotic cardiovascular events (including stent thrombosis) in patients with an ACS that is managed with PCI. It is used specifically for unstable angina or NSTEMI or for acute STEMI that is managed with primary or delayed PCI.

TRITON TIMI (Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel—Thrombolysis in Myocardial Infarction) 38 analyzed whether the type, size, and timing of MI affected prasugrel’s ability to reduce new or recurrent MI. ^[110] Compared with clopidogrel, prasugrel significantly reduced the overall risk of any type of MI (eg, procedure-related, nonprocedural, and consistently across MI size). Significant, sometimes fatal, bleeding occurred more often with prasugrel than with clopidogrel.

Ticagrelor, a cyclopentyl-triazolo-pyrimidine, is an oral P2Y12 receptor antagonist that reversibly inhibits platelets. It does not require hepatic bioactivation, because it is an active drug. The PLATO (Platelet Inhibition and Patient Outcomes) trial, looking at 18,264 patients with ACS (35% STEMI), showed that ticagrelor reduced the composite primary efficacy event (death, MI, or stroke) in comparison with clopidogrel (9.8% vs 11.7%) but increased non–CABG-related major bleeding (2.8% vs 2.2%) and fatal intracranial hemorrhage. ^[111]

Potential disadvantages of ticagrelor include side effects such as dyspnea, ventricular pauses, significantly greater cost than generic clopidogrel, and increased concentration of uric acid and creatinine.

On the basis of the benefit observed in these trials, current NSTE-ACS guidelines state that it is reasonable to use ticagrelor in preference to clopidogrel for DAPT in patients with NSTE-ACS who undergo an early invasive or ischemia-guided strategy. Prasugrel (at the time of PCI) may be chosen over clopidogrel for DAPT in patients with NSTE-ACS who undergo PCI and are not at high risk for bleeding complications.

In mid-2015, the FDA approved the IV antiplatelet drug cangrelor. It is indicated as an adjunct to PCI to reduce stent thrombosis, periprocedural MI, and repeat coronary revascularization in patients who were not treated with an oral P2Y12 inhibitor for any reason (eg, vomiting or intubation). It is a direct-acting P2Y12 platelet receptor inhibitor that blocks ADP-induced platelet activation and aggregation. It is rapidly distributed and metabolized and reaches C_max in 2 minutes of infusion. Its effect rapidly clears once the infusion is stopped, and platelet function returns to normal in 60 minutes.

An oral P2Y12 platelet inhibitor should be administered in order to maintain platelet inhibition after discontinuance of the cangrelor infusion. Whereas ticagrelor 180 mg could be initiated at any time during the cangrelor infusion, prasugrel 60 mg and clopidogrel 600 mg should only be given immediately after discontinuance of cangrelor.

Glycoprotein inhibitor therapy

PCI results in disruption of the coronary endothelium, which leads to platelet activation. Activated platelets bind to the vessel wall (adhesion) and to each other (aggregation) and release numerous vasoactive compounds.

Aspirin blocks the cyclooxygenase pathway and reduces thrombotic complications after balloon angioplasty. However, despite heparin and aspirin therapy, thrombotic complications are not eliminated. Studies identified the importance of the GPIIb/IIIa receptor, which binds fibrinogen and mediates platelet cross-linking and aggregation. The introduction of GP IIb/IIIa inhibitors had a major influence on PCI treatment strategies in the 1990s, but these drugs are now used much less frequently than they once were.

Early studies of GPIIb/IIIa inhibitors showed the following:

• Abciximab, tirofiban, and eptifibatide are capable of reducing ischemic complications in patients undergoing balloon angioplasty and coronary stenting
• In primary PCI, GPIIb/IIIa inhibitors can improve flow and perfusion and reduce adverse events
• Abciximab may improve outcomes in patients when given before arrival in the catheterization laboratory for primary PCI ^[112]
• A meta-analysis of GPIIb/IIIa inhibitor trials showed a significant reduction in early mortality when these agents are used during coronary intervention; the combined endpoint of death or MI was also reduced significantly at 30 days
• The EVA-AMI (Eptifibatide vs Abciximab in Primary PCI for Acute ST Elevation Myocardial Infarction) trial, which compared the efficacy of two GPIIb/IIIa inhibitors as adjuncts to PCI in 427 patients with STEMI, showed that double-bolus eptifibatide followed by a 24-hour infusion was as effective as single-bolus abciximab followed by a 12-hour infusion for ST-segment resolution ^[113]
• These agents are effective at reducing ischemic complications of PCI; however, they have not been shown to improve outcome in saphenous vein graft PCI
• A meta-analysis of 22 studies including 10,123 patients evaluated the use of GPIIb/IIIa inhibitors during elective PCI in patients pretreated with clopidogrel determined that GPIIb/IIIa inhibitors had no effect on mortality or major bleeding but were associated with a decrease in the incidence of nonfatal MI and an increase in the rate of minor bleeding ^[114]

The evidence supporting the use of GPIIb/IIIa inhibitors derives largely from the time before the widespread use of oral P2Y12 inhibitors. Several studies failed to show a benefit with upstream administration of GPIIb/IIIa inhibitors. In view of these findings, coupled with the increased risk of bleeding, routine use of these agents is no longer recommended. GPIIb/IIIa inhibitors may be used as an adjunctive therapy at the time of PCI, on an individual basis, for large thrombus burden or inadequate P2Y12 receptor antagonist loading.

The common complications of PCI are bleeding, hematoma, and pseudoaneurysm at the access site. To minimize the risk of these complications, extreme care must be taken in obtaining access at the beginning of the procedure.

Bleeding avoidance strategies (eg, bivalirudin and the radial approach) appear to lower the risk of post-PCI bleeding for both men and women; however, such strategies may be of particular significance in female patients, in that the absolute differences in risk are substantially greater in women. ^[115]

A retrospective cohort analysis of data on 2,820,874 PCI procedures from the CathPCI registry demonstrated that the use of radial access for PCI (r-PCI) was on the increase and that the procedure was associated with a lower risk of bleeding and vascular complications than traditional transfemoral PCI, even after age, sex, and clinical presentation were accounted for. ^[116]

Anaphylaxis caused by the contrast agent can occur; therefore, a careful preprocedural history must be obtained. Patients with a prior anaphylactoid reaction to the contrast media should receive appropriate steroid prophylaxis before repeat contrast administration. Contrast administration is one of the leading causes of hospital-acquired acute kidney injury (AKI). The only strategies that have been shown to minimize the risk of AKI are hydration and minimizing the use of contrast.

Early registries of balloon angioplasty results showed complication rates that were much higher than those typically observed today. Reductions in the complication rate have been complemented by improvements in the acute success rate. Previously, registries such as the National Heart, Lung, and Blood Institute (NHLBI) Coronary Angioplasty Registry reported primary success rates of 61%. Today, with the use of stents and adjunctive pharmacotherapy, success rates range from 95% to 99%.

The mechanism by which balloon angioplasty or stenting improves luminal diameter is associated with significant local trauma to the vessel wall, which can, in turn, lead to occlusive complications in a minority of patients. Coronary artery dissection typically results from the vessel injury secondary to balloon expansion. Animal and postmortem human studies have shown that localized dissection at the site of balloon expansion is detected angiographically in as many as 50% of patients immediately after balloon angioplasty.

Such small dissections probably are necessary to obtain adequate lumen expansion; they rarely interfere with antegrade blood flow and are usually unimportant. Angiographic follow-up typically shows no residual evidence of a dissection as early as 6 weeks after angioplasty in most of the cases studied. However, larger dissections can lead to complications.

Often, these dissections are treated with a stent to cover the dissection flap. Coronary perforation or rupture is very rare (occurring in fewer than 1% of cases) and is typically associated with the use of ablative devices or oversized balloons. It can occur from the wire tip or at the culprit lesion. Wire perforations are typically small and usually do not warrant further intervention; perforations from balloon inflation or stent implantation can occasionally necessitate treatment with a covered stent graft.

Abrupt vessel closure may occur in as many as 5% of balloon angioplasty cases, usually developing when the true lumen is compressed by a large dissection flap, thrombus formation, superimposed coronary vasospasm, or a combination of these processes. The presence of large coronary dissections immediately after balloon angioplasty is associated with a fivefold increase in the risk of abrupt closure.

Since the introduction and implementation of intracoronary stents and newer antiplatelet drugs, the incidence of abrupt closure has decreased significantly, to less than 1%. Microembolization of plaque debris or adherent thrombus may also cause acute complications during angioplasty and may contribute to postprocedural cardiac enzyme elevation and chest pain in some patients.

In fewer than 1% of angioplasty patients, microembolization of the platelet-rich thrombus may cause diffuse distal arteriolar vasospasm secondary to release of vasoactive agents, resulting in no-reflow. This complication is difficult to treat but may respond to intracoronary calcium channel antagonists, adenosine, or nitroprusside. Patients undergoing balloon angioplasty of saphenous vein graft lesions and primary angioplasty in the setting of acute MI with a large amount of adherent thrombus are at greatest risk for distal embolization.

Restenosis after balloon angioplasty necessitating a second revascularization procedure is a major limitation that occurs in about 15-30% of patients, depending on the definition of restenosis applied. With the advent of DESs, restenosis rates have fallen to less than 10%.

Some of the very rare but serious complications of PCI are stroke, MI, and death. With advances in technique, technology, and adjuvant medical therapy, PCI is now associated with mortality and emergency bypass rates lower than 1%. The rate of nonfatal MI after coronary angioplasty ranges from 5% to 15%, whereas the rate after stent placement ranges from 2% to 5%.

Restenosis

After balloon angioplasty or stent implantation, the vessel wall undergoes a number of changes. Platelets and fibrin adhere to the site within minutes of vessel injury. Within hours to days, inflammatory cells infiltrate the site, and vascular smooth muscle cells begin to migrate toward the lumen.

The vascular smooth muscle cells then undergo hypertrophy and excrete an extensive extracellular matrix. During this period of vascular smooth muscle cell proliferation, endothelial cells colonize the surface of the lumen and regain their normal function.

Over the course of several weeks to months, multiple forces interact to cause remodeling of the vessel wall with either a decrease in lumen diameter (negative remodeling) or an increase in lumen diameter (positive remodeling). The amount of late loss in lumen diameter is dependent on the amount of neointimal proliferation and the degree of remodeling after intervention (see the image below). After 6 months, the repair process stabilizes and the risk of restenosis decreases significantly.

Several studies have shown that the lumen diameter or area after treatment is one of the major predictors of restenosis. The use of coronary artery stents has decreased the rate of restenosis by improving the acute gain achieved and by minimizing negative remodeling.

Depending on the definition used, angiographic restenosis has been reported in as many as 50% of patients within 6 months after balloon angioplasty, necessitating repeat target-vessel revascularization in approximately 20-30% of patients. As noted (see above), DESs have reduced restenosis rates to less than 10%. Poststenting lumen diameter and lesion complexity are still the major predictors of restenosis with these newer stents.

Stent thrombosis

Although DESs have significantly reduced the incidence of restenosis, early generations of these devices were linked with concerns regarding stent thrombosis. Currently, the thrombosis rate for a DES is virtually identical to that for a BMS at 1 year (0.5-0.7%). The NORSTENT study reported that the rates of definite stent thrombosis were 0.8% with DESs and 1.2% with BMSs (P = 0.05) over 6 years of follow-up. ^[117] Late stent thrombosis (>1 year), which occurred with early-generation DESs, is rarely seen with current DESs.

The factor that makes the greatest contribution to stent thrombosis is interruption of antiplatelet therapy. Current guidelines recommend a minimum of 1 year of DAPT for DES patients with acute coronary syndrome, 6 months of DAPT for stable DES patients, and 1 month of DAPT for BMS patients. ^[7] DESs take longer to endothelialize on the coronary vessel wall than BMSs do, and discontinuing DAPT may expose patients to an increased risk for stent thrombosis over time.

In some clinical situations (eg, before urgent noncardiac surgery in which antiplatelet therapy may have to be discontinued and when known or potential medicine compliance issues are present), implanting a bare-metal stent during PCI may be preferred to implanting a DES. Another important factor is final stent diameter and area.

Underdeployment or incomplete apposition of any stent increases the risk of stent thrombosis. Stone et al found that although stent thrombosis is infrequent, it results in higher rates of MI and death. ^[118]

An analysis of data from 7090 consecutive PCI-treated patients in the ISAR-ASPI (Intracoronary Stenting and Antithrombotic Regimen-ASpirin and Platelet Inhibition) registry suggested that high platelet reactivity in patients on aspirin (HAPR) at the time of PCI was associated with a greater risk of death or stent thrombosis (6.2% vs 3.7% for non-HAPR) during the first year after PCI. ^[119] Moreover, HAPR independently predicted death or stent thrombosis at 1 year. These findings may support use of HAPR as a prognostic biomarker in PCI-treated patients.