Published online before print December 27, 2004, doi: 10.1161/01.CIR.0000150335.01285.12
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(Circulation. 2005;111:143-149.)
© 2005 American Heart Association, Inc.
Coronary Heart Disease |
Clinical Progression of Incidental, Asymptomatic Lesions Discovered During Culprit Vessel Coronary Intervention
From the University of Pennsylvania, Philadelphia (R.G., R.L.W.); University of Pittsburgh, Pittsburgh, Pa (F.S., H.A.C., K.M.D.); University of Chicago, Chicago, Ill (D.P.F.); Uniformed Services University of the Health Sciences, Bethesda, Md (W.K.L.); and New York University Medical Center, New York, NY (J.S.).
Correspondence to Robert L. Wilensky, MD, 9 Gates Pavilion Cardiology, University of Pennsylvania, 3400 Spruce St, Philadelphia, PA 19104.
Received April 23, 2004; revision received August 27, 2004; accepted September 8, 2004.
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Abstract |
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Background— With the reduction in restenosis rates by drug-eluting stents, there is new controversy concerning the optimal management of incidental, nontarget lesions identified during percutaneous coronary intervention (PCI). Such lesions have been treated conservatively because of risk of restenosis but now are being considered for PCI to prevent plaque instability. However, the impact of incidental stenoses on future cardiac events remains unknown.
Methods and Results— We performed a retrospective cohort study to determine the rate and features of clinical plaque progression using the National Heart, Lung, and Blood Institute Dynamic Registry of consecutive patients undergoing PCI at multiple centers in 1997 to 1998 and 1999. Of 3747 PCI patients, 216 (5.8%) required additional nontarget lesion PCI for clinical plaque progression at 1 year. Fifty-nine percent presented with new unstable angina, and 9.3% presented with nonfatal myocardial infarction. Patients with multivessel coronary artery disease during original PCI were more likely to require nontarget lesion PCI during follow-up (adjusted odds ratio, 1.72 [95% CI, 1.18 to 2.52] for 2 vessels; adjusted odds ratio, 3.37 [95% CI, 2.32 to 4.89] for 3 vessels). Angiographic review showed that the majority (86.9%) of lesions requiring subsequent PCI were 
60% in severity during original PCI, with the mean lesion stenosis 41.8±20.8% at the time of the initial PCI and 83.9±13.9% during the recurrent event.
Conclusions— Approximately 6% of PCI patients will have clinical plaque progression requiring nontarget lesion PCI by 1 year. Greater coronary artery disease burden confers a significantly higher risk for clinical plaque progression.
Key Words: atherosclerosis • angioplasty • plaque • coronary disease
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Introduction |
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Although the modification of systemic risk factors for further progression of atherosclerosis has reduced the incidence of death and myocardial infarction (MI) by
30%, a subset of patients continue to have recurrent symptoms related to coronary artery disease progression and lesion instability.1–3 Noninvasive imaging and coronary angiography have as yet not been able to identify those plaques with a higher propensity for future instability. Thus, focal prophylactic treatment of potentially vulnerable plaques is not performed because percutaneous coronary intervention (PCI) of intermediate lesions has been shown previously to have restenosis rates similar to those of PCI for symptom-causing lesions, thereby obviating the potential benefits of a prophylactic strategy.4 With the clinical introduction of drug-eluting stents, capable of reducing restenosis rates to <5%, targeting potentially unstable but nonculprit stenoses has been postulated as an approach to reduce death and MI. This has led to new debate about the optimal management of incidental, potentially unstable nontarget lesions noted during PCI.
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With the development of new modalities that may potentially identify thin-cap fibroatheromas, a prophylactic approach to "vulnerable" plaques may be possible.5,6 However, the incidence of clinical plaque progression in a large, contemporary cohort of patients treated with culprit vessel PCI and medical therapy for secondary prevention is unknown. Furthermore, the risk factors for clinical plaque progression in such a PCI population have not been examined. Knowledge of the incidence and risk factors of clinical plaque progression may serve as the basis for further research in screening and preventative modalities. Using the cohort of consecutive patients undergoing PCI in the National Heart, Lung, and Blood Institute (NHLBI) Dynamic Registry, we sought to determine the incidence, presentation, angiographic features, and risk factors associated with clinical plaque progression requiring nontarget lesion PCI during the year after culprit lesion PCI.
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Methods |
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Registry Design and Patient Population
The NHLBI-funded Dynamic Registry includes 17 clinical centers and a coordinating center. The Dynamic Registry has been described previously and is designed to evaluate cohorts of consecutive patients undergoing PCI in waves of recruitment.7 The protocol was approved by each center’s institutional review board, and informed consent to collect information after hospital discharge was obtained from all patients.
Data Collection and Management
All enrolled patients who provided informed consent for 1-year follow-up information after coronary intervention were eligible for analysis (n=4187). The following groups were excluded from analysis: (1) patients with in-hospital death after the primary procedure (n=69); (2) patients with a MI within 2 weeks of the primary procedure to exclude potential subacute stent thrombosis of the intervened arterial segment (n=1); (3) patients undergoing postdischarge CABG without sufficient supporting clinical or angiographic details, such as restenosis of the target lesion or clinical plaque progression of nontarget lesion (n=155); (4) patients without index or second PCI lesion data (n=60); and (5) patients without clinical follow-up (n=121). Patients with a MI during follow-up but without a catheterization or revascularization procedure (PCI or CABG) were also excluded (n=34) because it was not possible to determine whether the lesion that caused the MI was the original lesion or a progressing lesion. Patients who had a MI during follow-up with subsequent angiographic information were included. A total of 3747 patients were thus included in the analyses. Collected data included demographic information, medical history and risk factor status, detailed coronary angiographic information, and procedural strategy and success of each attempt at significant coronary artery lesion reduction (>50% in diameter reduction). Angiograms were initially interpreted at the clinical sites; however, angiograms of patients with progression of disease were retrieved from sites currently in the Dynamic Registry and evaluated independently by 2 investigators (R.G. and R.L.W.). The cineangiograms were evaluated in similar angiographic angles, and the percent stenosis was determined with the use of calipers with the stenosis compared with the proximal, angiographically normal segment. Procedural outcomes and major in-hospital complications were recorded. Lesion data with the use of the Ambrose criteria and clinical indication for any repeated PCI were also collected.8 At 1-year follow-up, information about vital status, presence and type of angina, medications and subsequent hospitalization for MI, and repeated PCI or CABG was collected.
Definitions
Death was defined as all-cause mortality. Patients were categorized as having nontarget lesion PCI, restenosis of target lesion, and no event. Nontarget lesion PCI was defined as clinically driven PCI of a previously untreated (no balloon angioplasty or stent) vessel segment. This was substantiated during angiographic review. Restenosis was defined as clinically driven PCI of a vessel segment had been treated either before or during the baseline procedure. In patients undergoing staged procedures, treated segments from both procedures were grouped together to prevent misclassification of repeated procedures as nontarget lesion PCI.
Data Analysis
The no event and nontarget lesion PCI groups were compared according to demographics, baseline history, risk factors, angiographic and procedural characteristics, initial success, complications, and in-hospital outcomes with the use of the 
2 test or Fisher exact test for categorical data and the Wilcoxon rank sum test for continuous data. Nontarget lesion PCI rates by vessel disease were calculated by the Kaplan-Meier approach and compared by means of the log-rank test for trend. Multivariable logistic regression was used to identify predictors of nontarget lesion PCI. For multivariable analyses, comparisons were limited to those patients presenting with only nontarget lesion PCI versus no event; patients undergoing both nontarget lesion PCI and target lesion PCI for restenosis were excluded to examine predictors of progression rather than restenosis. Explanatory variables considered for the models were baseline characteristics that either were clinically relevant to the outcome and/or differed significantly between groups. We also performed separate sensitivity analyses that classified previously excluded MI and CABG patients without supporting angiographic data into the nontarget lesion PCI group and no new event group.
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Results |
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A total of 3747 patients met criteria for further evaluation. During the 1-year follow-up, 216 patients underwent nontarget lesion PCI (5.8%) for new clinical symptoms, 276 patients underwent target lesion PCI for restenosis, and 3255 patients had no further clinical events. The mean time (±SD) from the initial PCI and the second PCI for progression of new disease was 163±99 days.
Table 1 compares demographic information between the patients with nontarget lesion PCI and those without further clinical events. Patients with nontarget lesion PCI were more likely to have a history of prior coronary revascularization and more likely to present with unstable angina than those without subsequent events. The use of statins and thienopyridines was similar at discharge in the 2 groups. At 1-year follow-up, however, a significantly higher percentage of patients with nontarget lesion PCI were taking digitalis, long-acting nitrates, calcium channel blockers, and statins.
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An acute coronary syndrome was the clinical presentation on repeated presentation in 68.5% of patients requiring nontarget lesion PCI, with 59.2% presenting with unstable angina pectoris and 9.3% presenting with nonfatal MI. Stable angina was the presentation in 24.1%, whereas atypical symptoms were rare presentations (6.8%).
Table 2 compares angiographic and procedural characteristics of the 2 groups during baseline PCI. The degree of significant coronary artery disease during initial angiography was significantly higher in those patients who required subsequent nontarget lesion PCI. The presence of only minimal luminal irregularities was also somewhat higher in patients requiring nontarget lesion PCI (61.4% versus 55.0% in patients with nontarget lesion PCI versus no event). There were no differences in angiographic characteristics of the original lesion in those patients returning for nontarget lesion PCI compared with those without events. Kaplan-Meier analyses showed that the rate of nontarget lesion PCI during 1 year of follow-up was significantly higher by degree of significant coronary artery disease (Figure 1).
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Of the 216 patients requiring nontarget lesion PCI, angiograms from 157 (72.7%) were available for independent evaluation. The lesion requiring nontarget PCI was observed in a different coronary artery in 95 patients (61%), whereas 62 patients (39%) had progression in the same artery but in a separate segment (>5 mm) from the original PCI. Of the newly clinically significant lesions within the same artery, the lesions were evenly divided between proximal and distal locations (Table 3). The mean stenosis of the progressed lesion was 41.8±20.8% at the initial angiogram and 83.9±13.9% at the time of the second angiogram, with a mean increase in stenosis severity of 42.1±21.9%. The majority of lesions requiring subsequent PCI were <50% in severity at the time of the initial PCI (95/157, 60.5%), whereas only 21 of 157 (13.4%) lesions were >70% in severity at the time of the initial angiogram. Furthermore, 120 of the 157 patients (76.4%) had multivessel disease (defined as stenosis >50% in severity) at the time of initial PCI. Of these 120 patients, 104 underwent initial culprit vessel PCI only, whereas the remaining 16 patients underwent multivessel PCI. The majority of patients with multivessel disease did not require subsequent, unplanned PCI of lesions that appeared angiographically significant during original PCI; only 24 patients with multivessel disease required subsequent PCI of a lesion that was >50% in severity during initial angiogram. The remaining 80 patients with multivessel disease required subsequent PCI of a lesion that was originally 50% in severity.
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According to Ambrose criteria,8 the majority of lesions requiring subsequent PCI were concentric lesions on initial angiogram (57%), whereas 22.9% were eccentric type I, 7.6% were eccentric type II, and 12.5% had multiple irregularities. At repeated angiography, 20.1% were concentric lesions, 22.0% were eccentric type 1, 18.1% were eccentric type II, and 28.5% were with multiple luminal irregularities. At the time of lesion progression requiring subsequent PCI, the majority of concentric lesions had changed to either eccentric (42.6%) or with multiple luminal irregularities (22.0%). Those concentric lesions that did not change had the least mean change in severity of stenosis (34.4±19.5%), whereas those that changed to eccentric configuration had a mean change of 58.6±14.2% in severity of stenosis, and those that progressed to multiple luminal irregularities had the highest mean change in stenosis severity (63.9±17.4%). Examples of lesions exhibiting progression are seen in Figure 2.
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The degree of significant coronary artery disease at initial PCI remained an important predictor of clinical plaque progression in multivariable logistic regression analyses (Table 4). The only other independent predictors of nontarget lesion PCI were prior PCI, female gender, and age <65 years. Medications were not predictive of nontarget lesion PCI, with the exception of statin use at 1-year follow-up. Sensitivity analyses involving statin use, whereby we assumed both "yes" and "no" for patients missing statin use at follow-up, yielded similar results for the multivariable analysis, although the strength of the statin use variable decreased (nonsignificant for the model for no statin use). Sensitivity analyses for patients with nonfatal MI without angiographic follow-up were also performed with patients included in each of the 2 categories, and there was no significant effect in the results of the multivariable analyses. Similarly, sensitivity analyses for patients with CABG without angiographic follow-up with patients included in the nontarget lesion PCI group did not significantly alter the primary results.
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Discussion |
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Our analysis of a large cohort of patients undergoing PCI for various clinical indications demonstrates that at least 5.8% of these patients will have clinical plaque progression requiring nontarget lesion PCI within the first postprocedural year. In addition, a total of 6.6% of patients without restenosis will have clinical plaque progression requiring new PCI. Furthermore, a significant proportion (68.5%) of these patients will present with new acute coronary syndromes. Our results likely underestimate the number of patients with plaque progression because we excluded from analysis patients who died or suffered a MI (possibly of new lesion instability) without angiographic information, and we included only patients who had a clinically driven new procedure. Importantly, our cohort of patients reflects practices in the United States and Canada, with contemporary rates of postprocedural antiplatelet therapy, ß-blocker use, and statin medication use.
An increasing number of studies suggest that a subset of patients presenting with acute coronary syndromes may have higher risk of a second ischemic event caused by a stenosis that is anatomically unrelated to the initial event.9,10 Inflammation may play a central role in these patients.11–17 For example, higher C-reactive protein levels in patients with unstable angina predict poor in-hospital and 14-day outcomes, even in the setting of normal troponin levels.18,19 Moreover, coronary artery inflammation in patients with unstable angina may be widespread rather than associated only with the culprit lesion.20 Although there is thus considerable evidence that subgroups of patients have a potentially widespread coronary artery inflammatory process, the actual incidence of clinical plaque progression of nontarget lesions after percutaneous treatment of a culprit lesion has not been assessed previously.
Early angiographic evaluation of the incidence of progression in medically managed coronary artery disease was initially performed in the 1980s, an era with less aggressive secondary prevention measures. Mock et al21 showed an 8% incidence of MI during 3 years of follow-up of non-CABG patients in the Coronary Artery Surgery Study (CASS). Progression of nonbypassed segments was 18.6% at 5 years.22 More recently, in a study of patients awaiting first PCI after diagnostic angiography, Kaski et al23 found angiographic progression in 24% of patients at a median follow-up of 8 months and a 57% incidence of acute coronary events in those patients with lesion progression. Of those patients with stenoses >50%, culprit lesions progressed to a greater extent (28% of culprit lesions intended for angioplasty progressed) than did nonculprit lesions (9% progressed).24 However, many patients in these studies had poorly controlled risk factors, including a high percentage of active tobacco smokers (62%) and high mean cholesterol levels. In contrast, the NHLBI Dynamic Registry cohort had higher rates of secondary prevention measures and, importantly, is the first cohort examined for second events in patients who have already undergone PCI for a presumed culprit stenosis. The higher use of statin medications in patients with subsequent PCI in our study may be a reflection of prescribing habits of those patients with symptomatic coronary artery disease rather than a true risk factor for lesion progression.
The presence of multiple complex coronary lesions in a MI population has been found previously to be associated with a higher incidence of subsequent cardiac events; these studies suggest that it may be possible by angiography or intravascular ultrasound to determine which lesions have a higher likelihood of subsequent rupture and instability.25–31 Multiple fissured plaques, potentially vulnerable to instability, have been identified in patients with acute coronary syndromes by intravascular ultrasound or necropsy.26–28 In a retrospective study by Goldstein et al,25 the presence of multiple complex lesions by angiography was associated with a 19.0% rate of acute coronary syndrome and a 6.0% rate of death. The finding that multiple plaques increase the risk of recurrent events is similar to that shown in our study. However, although these authors found an association between plaque complexity and future events, we did not find any association between plaque complexity, defined as the presence of thrombus or ulceration, and clinical plaque progression elsewhere. This may be secondary to the more general population studied in the present study compared with the selected MI population studied by Goldstein et al and thus may support the notion that plaque vulnerability is a dynamic process not limited to morphological plaque characteristics.32–34
The present study demonstrates that small but not insignificant numbers of patients return to the cardiac catheterization laboratory requiring PCI of a newly stenotic lesion. In the great majority of cases, the lesions were hemodynamically insignificant at the time of initial angiography, with only 13.1% of patients demonstrating lesions worse than 70% on the initial angiogram that then progressed. As a result, it is difficult by either clinical or angiographic means to determine a priori which stenoses will subsequently demonstrate clinical instability. Furthermore, our angiographic data suggest that the presence of more severe disease is associated with the higher need for additional revascularization; however, which lesion will cause the future instability cannot be predicted by either clinical or angiographic criteria.
The fact that we observed progression within the instrumented artery in 45% of the arteries is not unexpected because recent data suggest that a generalized arterial inflammatory pattern may exist. Hence, acute instability causing clinical symptoms may herald the initial event, and although treatment for the culprit lesion is successful, continued arterial inflammation may result in progressive instability in other areas of the coronary artery. It is possible that the initial PCI played a role in the accelerated clinical instability; however, this scenario is unlikely because patients requiring additional PCI in identical segments were classified as having restenosis rather than nontarget lesion PCI, and further angiographic evaluation also classified patients with possible PCI-induced injury as experiencing restenosis.
Our study has limitations. Given the uncertainty about whether patients dying or undergoing CABG without available angiograms had progression of disease or restenosis, these patients were excluded from analysis, and thus the incidence of clinical progression of disease might be underestimated. If all MI patients without angiograms were included as clinically significant progressors, the incidence of clinically apparent progression would potentially be as high as 6.7%, and if all patients undergoing CABG were additionally included as progressors, the incidence would potentially be as high as 10.8%. We did not obtain biomarkers at the time of the original or second PCI procedure. Newer markers of potential clinical instability may prove helpful in predicting those patients with a higher likelihood of future progression of disease.
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Conclusion |
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TopAbstractIntroductionMethodsResultsDiscussionConclusionReferences |
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In a large, contemporary cohort of patients undergoing PCI, the incidence of clinical plaque progression requiring additional nontarget lesion PCI is
6%. Clinical plaque progression presents in the majority of cases as an acute coronary syndrome. Overall coronary artery disease burden during initial angiography confers significant risk for subsequent clinical plaque progression requiring nontarget lesion PCI, but the majority of lesions are <50% in severity during initial angiography. In addition, current angiographic and clinical predictors are relatively poor surrogates to predict future events in a not insignificant portion of the PCI population. This highlights the need for further study to refine our ability to identify potentially vulnerable, but clinically silent, plaques. |
Acknowledgments |
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This study was supported in part by NHLBI grant HL 33292-14. For their diligent efforts to provide angiograms for additional independent review, we gratefully acknowledge the following: Madhi Al-Bassam, MD; Carole Farrell, RN; Terry Chaffee, RN; Betsy Block, RN; Mary Murphy, RN, MS; Denise Fine, BS; Lise Robillard; Dana Beach, RN; Susie Brevig, RN; Lenore Roach, RN, BSN; Deborah Tormey, RN, MPH; and Fred Steele, CCRC.
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J. E. Muller, A. Tawakol, S. Kathiresan, and J. Narula New opportunities for identification and reduction of coronary risk treatment of vulnerable patients, arteries, and plaques. J. Am. Coll. Cardiol., April 18, 2006; 47(8 Suppl): C2 - C6. [Abstract] [Full Text] [PDF]
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K. Sano, M. Kawasaki, Y. Ishihara, M. Okubo, K. Tsuchiya, K. Nishigaki, X. Zhou, S. Minatoguchi, H. Fujita, and H. Fujiwara Assessment of Vulnerable Plaques Causing Acute Coronary Syndrome Using Integrated Backscatter Intravascular Ultrasound J. Am. Coll. Cardiol., February 21, 2006; 47(4): 734 - 741. [Abstract] [Full Text] [PDF]
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L. W. Klein Are Drug-Eluting Stents the Preferred Treatment for Multivessel Coronary Artery Disease? J. Am. Coll. Cardiol., January 3, 2006; 47(1): 22 - 26. [Abstract] [Full Text] [PDF]
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