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Optimal Antiplatelet Therapy: Intensity, Duration, and Bleeding Balance
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Antiplatelet therapy is the cornerstone of drug therapy to prevent recurrent ischemic events after coronary revascularization. DAPT, consisting of aspirin plus an inhibitor of the platelet P2Y12 receptor, is considered standard of care after PCI. Once uniform after DES implantation, decision making about DAPT has grown increasingly complex as stent technologies have improved,47,48 newer more-potent P2Y12 inhibitors have come to market,49,50 and a growing body of evidence has tested durations of therapy longer or shorter than the classic 12-month period.51,52,53 Central to this complexity is the judgment of an individual patient’s dynamic balance of ischemic and bleeding risks.
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Substantial overlap exists between risk factors for ischemic and bleeding events after PCI. Of note, acuity is an important determinant. Individuals undergoing PCI for unstable angina and acute myocardial infarction are, in general, at higher risk for both events. For the purposes of this review, we will restrict our discussion to patients with SIHD. The most important predictor of stent thrombosis, a sentinel ischemic event after PCI, is premature disruption of DAPT. Additional predictors of stent thrombosis include renal failure, diabetes mellitus, bifurcation lesions, calcified lesions, reduced left ventricular ejection fraction, small stent diameter and longer stent length, malignancy, prior stroke, dissection, and presence of intermediate coronary disease proximal and distal to a culprit lesion.54,55,56,57 Additional predictors of bleeding include age, female sex, heart failure, renal failure, and peripheral vascular disease.58 Predictors of post-discharge bleeding, in particular, include older age, lower baseline hemoglobin, lower platelet reactivity on clopidogrel, and use of chronic oral anticoagulant therapy.59
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Seminal trials establishing the anti-ischemic efficacy and supporting US Food and Drug Administration approval of the newer oral platelet P2Y12 inhibitors prasugrel and ticagrelor were conducted in patients with acute coronary syndromes. The utility of these more-potent agents in patients with SIHD is less certain. Promising data from the PEGASUS-TIMI 54 trial indicate that DAPT with aspirin and ticagrelor, initiated greater than 1 year after myocardial infarction, is associated with a 15% reduction in the primary composite end point of death, myocardial infarction, and stroke (P < .01).60
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The role of DAPT after CABG is less well established. It is uncertain whether DAPT improves graft patency. In a single-center study of 249 consecutive patients randomized to aspirin 100 mg or aspirin 100 mg plus clopidogrel 75 mg daily after elective CABG, DAPT was associated with improved venous graft patency at 3 months.37,61 In a second randomized study of aspirin 162 mg versus aspirin 162 mg plus clopidogrel 75 mg daily after CABG, there was no difference in the primary end point of intravascular ultrasound–determined saphenous vein graft intimal hyperplasia and no difference in freedom from major adverse cardiovascular events.38,62
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A separate potential benefit of DAPT may be added reduction in incidence of stroke after coronary revascularization.39,63 Larger trials are required to assess efficacy and safety of DAPT after CABG with particular attention to stroke outcomes.
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Bioresorbable Vascular Scaffolds: Successors to Stents?
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Ongoing investigation and intense interest are presently focused on bioresorbable vascular scaffolds (BVS) as a prospective successor to stents. Although risks of ischemic complications, and in particular stent thrombosis, have progressively declined with evolution of DES technology, the best available DESs continue to pose several putative disadvantages. Permanent metallic stents, with or without drug elution, can impede future coronary instrumentation and contribute to chronic inflammation,40,64 endothelial dysfunction,41,65 and adverse remodeling.42,66 In theory, a BVS might ameliorate these problems while providing a temporary period of radial support after PCI.
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There is now experience with use of one first-generation BVS, the everolimus-eluting Absorb BVS (Abbott Vascular, Redwood City, CA), in over 100,000 patients worldwide. In ABSORB III, a large, multicenter randomized comparison of the Absorb BVS versus the everolimus-eluting Xience (Abbott Vascular) stent,43,67 rates of target lesion failure (cardiac death, target vessel myocardial infarction, and ischemia-driven target lesion revascularization) were higher at 1 year in patients randomized to receive a BVS (7.8% vs 6.1%). Subjects randomized to receive a BVS also experienced a nonsignificantly higher rate of device thrombosis (1.5% vs 0.7%). The studied BVS platform satisfied prespecified criteria for noninferiority. Observed excesses in ischemic events may stem from a learning curve in optimal deployment of BVS, which appears to rely on meticulous lesion preparation. Validation of the proposed long-term benefits of a BVS for angina and late ischemic events awaits results of the ongoing ABSORB IV trial.68
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Hybrid Revascularization
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The use of a hybrid approach to coronary revascularization is gaining popularity and may be an appropriate alternative for a carefully selected subset of patients with limited CAD involving the proximal or mid LAD and at least one other non-LAD coronary artery. In hybrid coronary revascularization (HCR), a minimally invasive surgical approach is used to bypass the LAD with a LIMA graft in combination with stenting of non-LAD targets. This is believed to leverage the advantages of surgical arterial revascularization of the LAD and substitution of advanced stent technology for saphenous vein grafts for the other targets. In a recent analysis from the STS Adult Cardiac Surgery Database, HCR is offered in about one-third of hospitals but represents less than 1% of CABG procedures in the United States.69 The current body of evidence is limited to observational studies and a small pilot randomized trial (Fig. 44–5). Overall, pooling of the studies shows a trend for fewer MACCE (odds ratio, 0.69; 95% CI, 0.41-0.92; P = .18) in favor of HCR over conventional CABG. Although stroke was reduced by 80% (P = .039) in the HCR group, there was an excess of repeat revascularization (odds ratio, 4.05; P < .001).
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The current ACC/AHA guidelines on coronary revascularization consider HCR only when PCI of the LAD is considered suboptimal, and therefore, it is given a Class IIa recommendation.4 A large prospective randomized trial may be necessary to define the benefit of this new alternative technique.
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High-Risk Percutaneous Coronary Intervention
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Advances in technique and technology have dramatically improved the safety of elective PCI. For a subset of patients, however, elective PCI continues to pose substantial risk of morbidity and mortality. Candidates for so-called “high-risk PCI” are typified by advanced age, multiple comorbidities, severe left ventricular dysfunction, unsuitability for surgery, and little room for error in the catheterization laboratory. Lesions are frequently complex and may be characterized by multivessel disease, unprotected left main disease, or involvement of a last remaining coronary vessel.
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Assessment of a proposed PCI as high risk is a clinical judgment made by an experienced heart team. Risk models developed from analysis of large registries can help in predicting likelihood of in-hospital mortality after elective PCI. One such model is the Mayo Clinic Risk Score (MCRS), derived from a cohort of 7640 patients undergoing PCI between 2000 and 2005,3,70 and subsequently validated in a data set of over 300,000 patients as a predictor of in-hospital mortality after PCI.71 The MCRS (Fig. 44–6) incorporates seven variables: age, serum creatinine, left ventricular ejection fraction, preprocedural shock, myocardial infarction within 24 hours, heart failure on presentation, and peripheral vascular disease. Patients at high risk for elective PCI are often also at high risk for surgery, and indeed, the MCRS correlates strongly with the STS score for risk of death after CABG.72
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Selected cases of high-risk PCI may benefit from adjunctive use of mechanical circulatory support. An expanding armamentarium of percutaneous devices for this purpose today includes intra-aortic balloon pump (IABP), centrifugal flow (TandemHeart; CardiacAssist, Pittsburgh, PA) and axial flow (Impella; Abiomed, Danvers, MA) ventricular assist devices, and extracorporeal membrane oxygenation (CardioHelp; Maquet, Wayne, NJ). Recent studies of device support have helped to define current concepts of high-risk elective PCI.
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The Balloon Pump-Assisted Coronary Intervention Study (BCIS-1) randomized 301 patients with multivessel CAD and left ventricular ejection fraction ≤ 30% to PCI with or without IABP support. MACCE were equally common in the hospital (15.2% vs 16.0%; P = .85).73 Mortality in this cohort was high at 5-year follow-up (33%) and, surprisingly, significantly lower in IABP-treated patients (hazard ratio, 0.66; 95% CI, 0.44-0.98; P = .039).74
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The PROTECT II trial, which was underpowered due to early termination, randomized 452 symptomatic patients with complex three-vessel CAD or unprotected left main CAD and left ventricular ejection fraction ≤ 30% to PCI with IABP or Impella support.75 Both IABP and Impella-supported patients experienced significant improvements in functional status and left ventricular ejection fraction after PCI. At 30 days, there was no difference in a broad primary composite end point of major adverse events (40.1% vs 35.1%; P = .23). After discharge, however, there was a lower rate of death, stroke, myocardial infarction, and repeat revascularization in patients randomized to Impella.
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In considering these data, a few salient points emerge. First, patients with ischemic cardiomyopathy and severe left ventricular dysfunction are indeed at high risk, with substantial short-term jeopardy of morbidity and mortality. Second, these patients benefit from revascularization, with improvement in symptoms and left ventricular function. Third, and perhaps most interestingly, the benefits of adjunctive mechanical circulatory support may not appear in the hospital but rather accrue with passage of time. The explanation for this final observation remains uncertain but may relate to differences in completeness or quality of PCI under conditions of mechanical circulatory support.
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The Impact of Fractional Flow Reserve
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Major trials10,11,12,13 informing current management of multivessel CAD have relied predominantly on angiographic criteria for study inclusion and lesion selection. Yet recent studies of physiologic lesion assessment using fractional flow reserve (FFR) have underscored the limitations of anatomy-guided PCI.
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FFR is a lesion-specific index of stenosis severity defined as the ratio of maximum flow in the presence of stenosis to normal maximum flow.76 In practice, FFR is estimated as the ratio of coronary artery pressure distal to a lesion of interest to aortic pressure, averaged over the entire cardiac cycle, with variation in microvascular resistance minimized by pharmacologic induction of maximal hyperemia. Dedicated fiberoptic pressure wire systems have helped make FFR measurement simple, safe, and widely available in clinical practice.
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FFR is useful to reclassify the functional severity of angiographically indeterminate coronary lesions77 and to define the utility of PCI. When a lesion is functionally insignificant, as defined in the DEFER trial by an FFR ≥ 0.75, PCI may be safely deferred without excess risk of cardiac death or myocardial infarction.78 Use of FFR guidance improves both efficacy and appropriateness of PCI. In the FAME study, which randomized 1005 patients with multivessel CAD to PCI guided by angiography alone or angiography plus FFR, a strategy of FFR guidance was associated with a reduced rate of death, nonfatal myocardial infarction, and repeat revascularization at 1 year (13.2% vs 18.3%; P = .02) as well as a reduced usage of stents per patient (1.9 ± 1.3 vs 2.7 ± 1.2; P < .001).79 Indeed, when a lesion is functionally significant, as defined by an FFR ≤ 0.80, revascularization is beneficial. In the FAME 2 trial, which randomized 888 patients with at least one functionally significant stenosis to PCI plus medical therapy or medical therapy alone, PCI conferred a significant reduction in death, nonfatal myocardial infarction, and urgent revascularization at 2 years.80
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Whether the advantages of FFR guidance for PCI may be extrapolated to CABG remains uncertain. Physiologic differences in the mechanism of CABG invoke separate considerations, including risk of conduit failure and potential for lesion progression. Furthermore, the standard of care for CABG has been founded on a principle of complete anatomic revascularization, rendering the notion of omitting bypass of FFR-negative intermediate stenosis as exploratory. In a retrospective study of 627 patients undergoing CABG, of whom 198 underwent grafting or deferral of grafting of at least one intermediate stenosis based on an FFR cut point of 0.80, the use of FFR guidance was associated with a lower number of graft anastomoses, a lower rate of angina, and no excess of death, myocardial infarction, or target vessel revascularization at 36 months.81 Results are awaited from randomized clinical trials currently under way to evaluate the role of FFR guidance for CABG planning.
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Based on presently available data, the authors advocate a central role for FFR guidance in determining appropriateness for PCI (Fig. 44–7).
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