Long‐Term Outcome of Percutaneous Coronary Intervention: The Significance of Native Coronary Artery Disease Progression

Abstract

The extensive use of stents during percutaneous coronary intervention (PCI) is associated with concerns about their potential adverse effects. In‐stent restenosis and stent thrombosis definitely significantly affect the PCI outcome. However, review of recent relevant studies suggests that stent‐related problems may have been somewhat overestimated when compared to coronary artery disease (CAD) progression at nonstented coronary segments as causative factors of adverse cardiac clinical events late (>30 days) post‐PCI. Both stent‐related problems and native CAD progression have to be equally addressed to optimize the PCI clinical benefit. © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Percutaneous coronary intervention (PCI) with stent implantation is the most commonly used myocardial revascularization procedure. Despite the proven safety and efficacy of PCI, adverse cardiovascular clinical events do occur after stent implantation, impairing its short‐ and long‐term outcome. Traditionally, events occurring within the 1st month following PCI are attributed to the intervention and considered as periprocedural, whereas those presenting later arise either from the stented (target) lesion or from disease progression at other sites in the coronary tree.1, 2 During the last decade, significant improvements of stent implantation techniques have been made. The introduction of drug‐eluting stents (DES) and their widespread application have led to significant amelioration of the restenosis problem. Continuous evolution of stent design, the drug eluted and its delivery systems as well as of the adjunctive antiplatelet pharmacotherapy, have occupied a great part of interventional cardiology literature, reflecting the attention paid to treatment at the stented site. In contrast, improvement of coronary artery disease (CAD) pharmacological treatment and intensive secondary prevention measures (eg, risk factors modification) seem to affect the coronary tree as a whole. In this review we discuss recent evidence on the significance of disease progression as a cause of events occurring late (>1 month) post‐PCI.2, 3, 4, 5, 6

Mechanisms Impairing the Outcome of PCI

Although PCI with stent implantation has improved long‐term patency rate compared to plain balloon angioplasty, the permanent placement of metallic prostheses inside the coronary artery can lead to complications at the stented segment (typically defined to include 5‐mm margins on either end of the stent), including in‐stent restenosis (ISR) and stent thrombosis (ST).

ISR is a major concern mainly for bare metal stents (BMS), with reported angiographic and clinical restenosis rates of 20% to 30%7 and 10% to 15%,8 respectively, depending mostly on patient comorbidities, vessel size, and lesion complexity.9 ISR can also occur with DES but with a significantly reduced frequency.3, 4 The proposed mechanism of ISR, namely neointimal hyperplasia with proliferation and migration of smooth muscle cells,10 suggested that ISR would manifest most commonly with a benign clinical presentation such as stable angina. However, macrophage accumulation and neovascularization have also been detected in neointimal tissue, and may serve as a nidus for thrombus formation and subsequent acute presentation with adverse outcomes.11

In the era of contemporary dual antiplatelet treatment, ST is a relatively infrequent complication post‐PCI, with an equal incidence among patients with DES and those with BMS in randomized clinical trials.12 In the Swedish Coronary Angiography and Angioplasty Registry a biphasic risk pattern has been described, with an initially high ST risk in the case of BMS, whereas DES present with an increased ST risk after the 1st month following implantation.13 However, the ST definition used in this study was different from the Academic Research Consortium Definitions, and the biphasic model observed may not be widely applicable. Although infrequent, ST is often associated with dramatic consequences including death and myocardial infarction (MI).14

Most importantly, however, stent implantation is a local treatment unlikely to influence coronary disease activity, which is a diffuse and continuous phenomenon. Although generally believed to evolve independently, there has been evidence that an association may exist between disease progression and ISR.15 Atherosclerotic disease progression outside the stented coronary segment may lead to localized plaque growth, resulting either in stenosis and clinical presentation as stable angina, or more dramatically in vulnerable plaque disruption and thrombus formation manifesting as acute coronary syndrome, including sudden cardiac death. It has been recognized that initially nonculprit coronary lesions discovered during PCI of the target lesion can evolve rapidly into clinically significant, requiring PCI in 6% of the patients by 1 year.16

Native CAD Progression Leading to Adverse Events

Early studies of PCI with 1st generation stents focused on adverse events attributed to stent related problems (ISR, ST) with a clinical follow‐up period limited to 1 year, whereas those with longer follow‐up mainly described the late stability of the target lesion.1 Although outcomes related to target lesions are important for the assessment of the biologic effect of the stent, a patient‐oriented evaluation including all‐cause mortality, any MI, and any revascularization has been suggested as a more important measure of device influence on PCI outcomes.17, 18

Recent studies of PCI outcomes with long‐term follow‐up periods have evaluated the relative contribution of stent‐related complications and disease progression at nonstented sites, to adverse clinical events post‐PCI (Table 1).

Table 1.

The Contribution of Stent Related Problems and CAD Progression in Late Post‐PCI Clinical Events

Study	Population	N	Follow‐Up Period (Years)				Results
Cutlip et al2	Stent implantation as part of pivotal second‐generation stent trials	1228	5	HR, %	Target Lesion Events, %a		Non‐Target Lesion Events, %
				Year 1	18.3		12.4
				Years 2–5	6.5		25
				HR, %	BMS			PES
Leon et al3	TAXUS I, II, IV, and V trials with BMS or DES implantation	BMS, 1397; PES, 1400	4.8		TVR	TLR	Non‐TL TVR	TVR	TLR	Non‐TL TVR
				Year 1	20.4	17.6	4.5	11.2	7.5	4.3
				Years 2–5	15.2	8.0	8.4	13.2	6.4	7.2
Chacko et al4	SIRIUS Study	BMS, 524; SES, 533	5	Cumulative Incidence, %			BMS	SES
				TLR			28.8	12.5
				TVR remote			15.0	11.7
				Non‐TVR			22.9	22.3
Alexopoulos et al5	Nonfatal AMI at least 1 month after stent implantation	91	2 (median)	AMI Mechanism			Relative Incidence (%)
				Progression			42 (46.2%)
				Stent restenosis			35 (38.4)
				Stent thrombosis			10 (11.0)
				Unidentifiable			4 (4.4)
Stone et al6	PROSPECT Study, ACS/NSTEMI/ STEMI with PCI	700	3	MACEb			Incidence (%)
				Composite			132 (20.4)
				Culprit lesion related			83 (12.9)
				Non‐culprit lesion related			85 (13.3)

Abbreviations: ACS, acute coronary syndromes; AMI, acute myocardial infarction; BMS, bare metal stent; DES, drug‐eluting stent; MACE, major adverse cardiac events; NSTEMI, non–ST‐segment elevation myocardial infarction; PCI, percutaneous coronary intervention; PES, paclitaxel‐eluting stents; SES, sirolimus eluting stents; STEMI, ST‐segment elevation myocardial infarction; TL, target lesion; TLR, target lesion revascularization; TVR, target vessel revascularization.

^aEvents: repeat TLR, death, myocardial infarction, ACS, and congestive heart failure.

^bMACE: cardiac death/arrest, myocardial infarction, unstable angina, increasing angina.

In a low‐risk clinical trial population of 1228 patients who underwent BMS implantation, Cutlip et al2 demonstrated that target lesion events prevailed during the 1st year post‐PCI. Thereafter, the stented lesion was clinically stable, and new adverse clinical events during years 2 to 5 of the study mostly originated from disease progression at other segments of the coronary tree with an annual hazard rate of 6.3% for non‐target lesion events vs 1.7% for target lesion events. Over the 5‐year follow‐up period, non‐target lesion events contributed remarkably to a 46.4% combined cumulative event rate.

In the paclitaxel‐eluting stent and BMS cohorts of the TAXUS randomized clinical trial program, Leon et al3 indicated that during a median follow‐up of 4.8 years, target vessel revascularization after the 1st year involved equal numbers of target lesion revascularization and non‐target lesion events. Interestingly, although DES significantly lowered the target lesion revascularization hazard rate during the 1st year post‐PCI, a late ongoing 2% to 4% annual rate of target vessel revascularization was observed, suggestive of disease progression outside the stented segment.

Chacko et al4 reported results from the SIRIUS (Sirolimus‐Eluting Stent in De Novo Native Coronary Lesions) double‐blind, randomized, controlled trial regarding the origin of cardiac events in patients followed clinically for 5 years after sirolimus eluting stent or BMS implantation. Over the follow‐up period, patients in the DES group had lower rates of all‐cause mortality, MI, and revascularization mainly due to a reduction in target lesion revascularization that was maintained for 5 years. More specifically, the cumulative incidence of revascularization was 32.3% in the DES vs 45.0% in the BMS group. Target lesion revascularization cumulative incidence was 12.5% and 28.8%, respectively, a finding demonstrating that remote coronary segments are a significant source of future adverse events in patients with implanted DES or BMS.

The relative impact of disease progression, restenosis, and stent thrombosis as responsible mechanisms of nonfatal late MI following stent implantation was described by our group in a real‐world population consisting of post‐stenting MI survivors who underwent coronary angiography.5 The comparison between post‐MI and initial angiogram revealed that almost half of the late MIs were attributed to disease progression at nonstented sites. MIs originating from disease progression at nonstented coronary sites occurred later post‐PCI (mean time from PCI was 27 months) in comparison to stent related MIs, which had an earlier presentation (mean time was 9 months in cases of ST and 19 months for MIs attributed to ISR). Furthermore, MIs resulting from disease progression presented as ST‐segment elevation myocardial infarction (STEMI) in 38.1% of patients, whereas in ST and ISR related MIs the percentages of STEMI occurrence were 60% and 20%, respectively.

The recently published PROSPECT (Providing Regional Observations to Study Predictors of Events in the Coronary Tree) study6 represents the only available prospective assessment of the clinical event rate attributable to progression of vulnerable plaque using in vivo coronary atherosclerosis imaging (intravascular ultrasound [IVUS] virtual histology). In 700 patients with acute coronary syndrome enrolled in the study and followed up for at least 3 years, adverse events were equally attributable to recurrence at originally treated culprit lesions (12.9%) and to disease progression at nonculprit coronary segments (11.6%). It is estimated that approximately 12% of patients developed major adverse cardiac event during the 3‐year follow‐up period from the nonstented lesions.

Prognostic Factors of CAD Progression at Nonstented Coronary Segments

The understanding of native CAD progression significance—as a major cause of post‐PCI adverse cardiovascular events—poses the challenge of determining the factors that promote and/or predict this phenomenon.

It is reasonably expected that traditional risk factors of CAD are associated with disease progression at nonstented segments. Using IVUS monitoring of changes in atheroma burden in 3473 patients, Chhatriwalla et al demonstrated that patients with very low low‐density lipoprotein (LDL) (≤70 mg/dL) and normal systolic blood pressure (≤120 mm Hg) showed the slowest CAD progression.19 Additionally, in patients managed to achieve LDL levels ≤70 mg/dL, progression of native coronary atherosclerotic disease was associated with the presence of residual risk factors including high baseline glucose levels, increased level of triglycerides, and small decrease of apolipoprotein B.20 The SWISSI II (Swiss Interventional Study on Silent Ischemia II) study highlighted baseline diabetes as the strongest significant cardiovascular disease factor for disease progression.21

C‐reactive protein (CRP) is not only an inflammatory marker but also a mediator of endothelial dysfunction and atherosclerosis, with controversial results from various studies regarding its prognostic value after PCI.22 In a recent, large, retrospective analysis of 8834 patients who underwent PCI, Razzouk et al indicated that elevated preprocedural high‐sensitivity C‐reactive protein (hsCRP) levels are associated with all‐cause mortality rate in long‐term follow‐up, even independent of LDL cholesterol.23 It is likely that preprocedural hsCRP predominantly represents post‐PCI global cardiovascular risk due to disease progression rather than stent‐related complications.24

A challenging issue is the determination of specific plaque characteristics predictive of future angiographic and clinical progression. Morphological studies, mostly from autopsy, suggest that thin cap fibroatheroma (TCFA) constitutes the precursor of ruptured plaque. TCFAs are histopathologically defined by the presence of large necrotic cores containing numerous cholesterol clefts and a thin (<65μm) overlying fibrous cap infiltrated by macrophages. Additionally, smooth muscle cells are rare and vasa vasorum are present within the adventitia and plaque.25

In vivo imaging of the vulnerable plaque has been described mainly with invasive methods. Angioscopy offers a direct visualization of the plaque allowing assessment of its surface and detection of tears and thrombi. However, it is difficult to perform and its application is limited to the proximal part of the vessels.26 IVUS virtual histology is a promising modality in the detection of vulnerable plaque that is highly accurate—according to comparison to in vitro histopathology—in the classification of different types of atherosclerotic plaque components.27 Optical coherence tomography, one of the most novel invasive imaging techniques, is capable of accurate tissue characterization and fibrous cap thickness assessment, providing high‐resolution cross‐sectional coronary imaging.28 Recently, noninvasive assessment of thin‐cap fibroatheroma has been attempted by multidetector computed tomography, indicating the potential applicability of this technique in the noninvasive assessment of the vulnerable plaque.29 The PROSPECT study, using multimodality imaging, described the combination of large plaque burden and a large necrotic core with thin‐cap fibroatheroma as lesion characteristics indicative of especially high risk for future adverse cardiovascular events.6 It has also been demonstrated that complex angiographic morphology, according to the American College of Cardiology/American Heart Association classification constitutes an independent variable for the progression of a non‐culprit lesion.30

The Pivotal Role of Secondary Prevention and Future Directions

As previously highlighted,19, 20, 21 intensive global risk modification in patients with CAD is of paramount importance for deceleration of disease progression or even regression of atherosclerotic lesions. The efficacy of secondary prevention has been demonstrated by many large randomized clinical trials, and the significance of lifestyle and pharmacological interventions post‐PCI—including cessation of smoking, appropriate nutrition, regular exercise, diabetes management, LDL cholesterol lowering, and blood pressure control–is underscored in current secondary prevention guidelines for CAD.31 Statin therapy appears to have an effect on plaque size and composition; in patients treated with statin, IVUS studies have demonstrated regression or no progression of coronary plaques,32, 33 whereas serial volumetric virtual histology‐IVUS analysis showed significant changes in necrotic core and fibrofatty plaque volume.34 Statins have been described to improve the clinical outcome after PCI among patients presenting with stable CAD35 and acute coronary syndromes.36 Dual antiplatelet treatment is routinely given post‐PCI mainly to avoid stent thrombosis. In the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, however, administration of clopidogrel and aspirin proved to benefit patients with documented prior MI, ischemic stroke, or symptomatic peripheral artery disease as well, suggestive of a beneficial effect of this treatment on native atherosclerosis progression.37

A remarkable example of successfully performed multifactorial intervention for secondary prevention is the contemporary COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) trial, where patients with chronic stable angina were randomly assigned to an initial treatment with either PCI in conjunction with optimal medical therapy or optimal medical therapy alone. In both treatment arms, significant lifestyle change was observed, medical compliance was high, and therapeutic targets were achieved in large proportions of patients.38 However, it is important to mention that implementation of secondary prevention measures post‐PCI is often disappointing in real‐world clinical practice,39 an issue requiring greater attention and further investigation from the medical and cardiological community.

CAD often progresses over time despite adequate risk modification and current pharmacological treatment with antiplatelets, β‐blocker, angiotensin‐converting enzyme inhibitor, and statin.21 Further research is needed for the possible determination of other potentially modifiable risk factors of CAD progression and development of more effective therapy post‐PCI, possibly with novel agents.40

Conclusion

Although most attention has been paid to stent‐related problems, progression of native vessels' atherosclerosis constitutes an equally significant mechanism impacting on PCI outcome. Improvements in PCI techniques, stent technology, and adjunctive pharmacotherapy should be accompanied by equal research efforts concerning CAD progression deceleration, stabilization/regression of the atherosclerotic plaque and optimization of secondary prevention post‐PCI.