Author + information
- Received May 17, 2013
- Revision received September 11, 2013
- Accepted September 26, 2013
- Published online March 1, 2014.
- Jae-Sik Jang, MD, PhD∗∗ (, )
- Yeo-Jeong Song, MD∗,
- Wook Kang, MD∗,
- Han-Young Jin, MD∗,
- Jeong-Sook Seo, MD, PhD∗,
- Tae-Hyun Yang, MD, PhD∗,
- Dae-Kyeong Kim, MD, PhD∗,
- Kyoung-Im Cho, MD, PhD†,
- Bo-Hyun Kim, MD, PhD‡,
- Yong Hyun Park, MD, PhD§,
- Hyung-Gon Je, MD, PhD§ and
- Dong-Soo Kim, MD, PhD∗
- ∗Department of Cardiology, Busan Paik Hospital, University of Inje College of Medicine, Busan, South Korea
- †Department of Cardiology, Kosin University Medical Center, Busan, South Korea
- ‡Department of Cardiology, Pusan National University Hospital, Busan, South Korea
- §Department of Cardiology and Cardiovascular Surgery, Pusan National University Yangsan Hospital, Yangsan, South Korea
- ↵∗Reprint requests and correspondence:
Dr. Jae-Sik Jang, Department of Internal Medicine, Busan Paik Hospital, Inje University College of Medicine, 633-165 Gaegum-dong, Jin-gu, Busan 614-735, South Korea.
Objectives The aim of this study was to systematically review and perform a meta-analysis of randomized trials and observational studies of intravascular ultrasound (IVUS)-guided versus angiography-guided implantation of drug-eluting stents (DES).
Background Although studies in the bare-metal stents era suggested that there were clinical benefits to IVUS guidance, it is still controversial whether percutaneous coronary intervention (PCI) with DES guided by IVUS leads to better clinical outcomes.
Methods Relevant studies published through March 31, 2013, were searched for and identified in the electronic databases. Summary estimates were obtained using a random-effects model.
Results From 138 initial citations, 3 randomized trials and 12 observational studies with 24,849 patients (11,793 IVUS-guided and 13,056 angiography-guided) were included in this study. Comparison of IVUS- versus angiography-guided PCI disclosed odds ratios (ORs) for major adverse cardiac events of 0.79 (95% confidence interval [CI]: 0.69 to 0.91; p = 0.001). IVUS-guided PCI was also associated with significantly lower rates of all-cause mortality (OR: 0.64; 95% CI: 0.51 to 0.81; p < 0.001), myocardial infarction (OR: 0.57; 95% CI: 0.42 to 0.78; p < 0.001), target vessel revascularization (OR: 0.81; 95% CI: 0.68 to 0.95; p = 0.01), and stent thrombosis (OR: 0.59; 95% CI: 0.42 to 0.82; p = 0.002). A meta-analysis of propensity-matched studies demonstrated similar results in terms of clinical outcomes, but not repeat revascularization.
Conclusions IVUS-guided DES implantation is associated with significantly lower rates of adverse clinical events compared with angiography guidance. Further study is needed to clarify which subgroups of subjects with IVUS guidance will have greater benefit.
Intravascular ultrasound (IVUS) plays a substantial role in percutaneous coronary intervention (PCI) using coronary stents not only by providing more accurate information about the coronary artery and implanted stents but also by allowing earlier detection of procedure-related complications and suboptimal stent expansion. Previous studies and meta-analyses have demonstrated that IVUS-guided stent implantation may decrease restenosis and the adverse clinical outcomes after bare-metal stent (BMS) implantation (1–3).
It is still controversial whether implantation of drug-eluting stents (DES) guided by IVUS could reduce adverse clinical outcomes. Zhang et al. (4) recently performed a meta-analysis on this topic. They included 1 randomized trial and 10 observational studies comparing IVUS- and angiography-guided DES implantation in the DES era. However, they included a study (5) in which some of the patients received BMS. There has been the recent presentation (6) and publication of additional randomized trials (7,8) and an observational study (9) comparing IVUS and angiographic-guided DES implantation. This suggests the need for an updated meta-analysis to further support the efficacy of IVUS-guided DES implantation.
Data sources and searches
We identified relevant studies through electronic searches of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 2001 through March 2013. Medical subject headings and keyword searches included intravascular ultrasound, coronary angiography, stents, drug-eluting stents, coronary angioplasty, and percutaneous coronary intervention. Reference lists of selected articles were reviewed for other potentially relevant citations. In addition, we manually searched the content pages of issues published from 2011 through 2012 by the American College of Cardiology, the European Society of Cardiology, the Transcatheter Cardiovascular Therapeutics, and the American Heart Association to retrieve further potential publications.
Two investigators (J.-S.J. and H.-Y.J.) independently conducted the literature search, data extraction, and quality assessment by using a standardized approach. Selected publications were reviewed by the same investigators to assess whether studies met the inclusion criteria: comparison of IVUS- and angiography-guided PCI with DES implantation in which follow-up angiographic and/or clinical outcome data were reported. Final inclusion of studies was based on the agreement of both reviewers.
Data extraction and quality assessment
Two reviewers (J.-S.J. and T.-H.Y.) extracted relevant information from the papers including study design, follow-up duration, patient characteristics (mean age, sex distribution, risk factors), and angiographic/procedural characteristics. To reduce the effect of treatment-selection bias and potential confounding in nonrandomized observational studies, we also abstracted adjusted risk estimates from observational studies. If additional information was needed, the authors of the studies were contacted.
The endpoints of this study were major adverse cardiac events (MACE), all-cause mortality, myocardial infarction (MI), target vessel revascularization (TVR), target lesion revascularization (TLR), stent thrombosis, and postintervention minimal lumen diameter. The definition of MACE was slightly different across studies, and we used the trial-specific definitions of MACE. Most of the included studies defined MACE as a composite of all-cause death, MI, and TVR. Four studies (7,8,10,11) included cardiovascular death instead of all-cause death, and the other 2 studies (12,13) included TLR instead of TVR. MI included Q-wave MI and non–Q-wave MI. Stent thrombosis was definite or probable according to the definition of the Academic Research Consortium (14).
Data synthesis and analysis
We used random-effects models to produce across-study summary odds ratios (ORs) with 95% confidence intervals (CIs). A crude OR with 95% CI was used to assess the efficacy of IVUS guidance on adverse clinical events in study populations. Continuous data were expressed as mean (SD) and weighted mean differences. All p values were 2 tailed, with statistical significance set at 0.05. For comparison of registry studies with matched pairs by propensity score analysis, adjusted risk estimates were pooled after logarithmic transformation according to random-effects models with generic inverse variance method.
We assessed statistical heterogeneity between trials with the I2 statistic, which is derived from Cochran's Q and the degree of freedom [100 × (Q–df)/Q)] (15). I2 values >25%, 50%, and 75% were considered evidence of low, moderate, and severe statistical heterogeneity, respectively. In case of heterogeneity across the studies, we performed sensitivity analyses, serially excluding studies to determine the source of heterogeneity. Additionally, sensitivity analyses were conducted to examine the heterogeneity on the basis of coronary anatomy (bifurcation vs. nonbifurcation and left main vs. non–left main), the study design (randomized vs. nonrandomized studies), and the publication period (previous vs. new studies). Publication bias was examined by visual inspection of constructed funnel plots for clinical outcomes and mathematically by means of the Egger test (p for significant asymmetry <0.1) (16). All statistical analyses were performed using Review Manager version 5.1 (The Nordic Cochrane Center, Copenhagen, Denmark) and MIX version 2.0 (BiostatXL, Sunnyvale, California).
This meta-analysis was performed according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analysis) statements (17).
A total of 138 publications were reviewed, and 35 studies were selected for inclusion and further evaluated. Three studies were excluded because DES data could not be extracted from the database (5,18,19). Subsequently, 15 clinical studies were included in the final analysis (Fig. 1) (6–13,20–26). Characteristics of the included studies are summarized in Table 1. Of the 24,849 patients, 11,793 patients underwent IVUS-guided PCI and 13,056 underwent angiography-guided PCI.
The HOME DES IVUS (Long-Term Health Outcome and Mortality Evaluation After Invasive Coronary Treatment Using Drug Eluting Stents with or without the IVUS Guidance) study (12), the AVIO (Angiography Vs. IVUS Optimization) trial (7), and the RESET (Real Safety and Efficacy of a 3-Month Dual Antiplatelet Therapy Following Zotarolimus-Eluting Stents Implantation) trial (8) were prospective, randomized trials that assessed the routine use of IVUS guidance during DES deployment. The other 12 studies were observational cohort studies with matched cohorts or consecutive patients (6,9–11,13,20–26). To identify possible differences between groups, prevalence of risk factors (diabetes, hypertension, hyperlipidemia, current smoking, history of PCI or MI), American College of Cardiology/American Heart Association B2/C lesion, left ventricular ejection fraction, and proportion of patients with acute coronary syndrome were extracted and compared (Table 1). Of the 15 studies, 3 studies (21,23,25) had routine angiographic follow-up data available at 6 or 12 months, and 2 studies (7,25) reported rates of restenosis. Four recent studies included zotarolimus- (24) or everolimus-eluting stents (8,9,24,25), whereas most earlier studies used sirolimus- and paclitaxel-eluting stents (10,12,13,20–23,26). Three studies (6,7,11) did not report the type of DES used. Angiographic and procedural characteristics are shown in Table 2. Quantitative coronary angiography results of included studies were compared in detail between IVUS- and angiography-guided PCI groups (Online Table 1).
Major adverse cardiac events
Eleven studies reported the incidence of MACE at follow-up. The summary OR was 0.79 (95% CI: 0.69 to 0.91; p = 0.001) (Fig. 2) in favor of IVUS-guided PCI. No evidence of statistical heterogeneity was noted among the included studies (heterogeneity chi-square = 11.13, I2 =10%, p = 0.35).
Stratified analysis by the study design demonstrated a significantly lower incidence of MACE with IVUS-guided PCI in nonrandomized studies (OR: 0.81; 95% CI: 0.68 to 0.96; p = 0.02) compared with randomized trials that failed to show significant benefit of IVUS- over angiography-guided PCI (OR: 0.69; 95% CI: 0.46 to 1.04; p = 0.07) (7,8,12). Sensitivity analyses were performed for MACE according to coronary anatomy. Performing a meta-analysis after exclusion of studies with predominantly bifurcation lesion did not offset the benefit of IVUS guidance (OR: 0.78; 95% CI: 0.65 to 0.94; p = 0.009) (11,13). Also, sensitivity analysis of left main coronary disease did not change the overall results favoring IVUS-guided PCI over angiography-guided PCI (OR: 0.80; 95% CI: 0.69 to 0.92; p = 0.002) (20).
All-cause mortality, MI, TVR, and TLR
IVUS-guided PCI was associated with significantly lower rates of all-cause mortality (OR: 0.64; 95% CI: 0.51 to 0.81; p < 0.001), MI (OR: 0.57; 95% CI: 0.42 to 0.78; p < 0.001), and TVR (OR: 0.81; 95% CI: 0.68 to 0.95; p = 0.01) (Fig. 3). Evidence of statistical heterogeneity was noted among studies with all-cause mortality (heterogeneity chi-square = 18.67, I2 = 36%, p = 0.10), MI (heterogeneity chi-square = 17.32, I2 = 37%, p = 0.10), and TVR (heterogeneity chi-square = 16.23, I2 = 38%, p = 0.09).
Of the 15 studies, 7 were included for the analysis of TLR (7,9,11–13,21,25). The risk of TLR was significantly lower in patients with IVUS guidance (OR: 0.76; 95% CI: 0.62 to 0.94; p = 0.01). There was no statistically significant evidence of heterogeneity (heterogeneity chi-square = 2.06, I2 = 0%, p = 0.91).
Data on stent thrombosis was reported in 14 studies. IVUS-guided PCI was associated with a significantly lower rate of definite or probable stent thrombosis compared with patients treated without IVUS guidance (OR: 0.59; 95% CI: 0.42 to 0.82; p = 0.002) (Fig. 4). Statistical heterogeneity was noted among the included studies (heterogeneity chi-square = 17.52, I2 = 26%, p = 0.18). None of the studies influenced the results to an extent that the conclusion would have changed: the sensitivity analysis of the stent thrombosis risk with IVUS-guided PCI after exclusion of 1 study at a time yielded effect sizes similar in magnitude and direction to the overall estimates.
Post-intervention minimal lumen diameter
Nine studies including 4,703 patients were applied to the analysis of post-intervention minimal lumen diameter. The mean post-intervention minimal lumen diameter ranged from 2.50 to 3.00 mm in the IVUS-guided PCI group and from 2.40 to 2.87 mm in the angiography-guided PCI group. The pooled weighted mean difference of post-intervention minimal lumen diameter was 0.12 mm (95% CI: 0.08 to 0.16 mm; p < 0.001) (Fig. 5). Statistical heterogeneity was noted among the included studies (heterogeneity chi-square = 20.22, I2 = 60%, p = 0.01).
Propensity score–matched pairs analysis
Propensity score–matched adjusted estimates for IVUS- versus angiography-guided PCI could be analyzed in 9 studies (Online Fig. 1) (9–11,13,21–23,25,26). Adjusted risk estimates for MACE (hazard ratio [HR]: 0.79; 95% CI: 0.66 to 0.95; p = 0.01), all-cause death (HR: 0.58; 95% CI: 0.42 to 0.81; p = 0.001), MI (HR: 0.56; 95% CI: 0.33 to 0.97; p = 0.04), and stent thrombosis (HR: 0.52; 95% CI: 0.34 to 0.82; p = 0.004) were significantly lower in the IVUS-guided PCI group. However, no significant differences were observed for the risk of TVR and TLR between the 2 groups (HR: 0.93; 95% CI: 0.79 to 1.09; p = 0.34 and HR: 0.85; 95% CI: 0.64 to 1.13; p = 0.26). Statistical heterogeneity was noted among studies reporting MACE, all-cause death, MI, and stent thrombosis.
Assessment of publication bias using the ORs of clinical outcomes of the included studies demonstrated a symmetrical funnel plot with no evidence of publication bias for the primary analysis by the Egger regression-based test (p = 0.55 for MACE, p = 0.86 for all-cause death, p = 0.76 for MI, p = 0.39 for TVR, p = 0.31 for TLR, and p = 0.73 for stent thrombosis) (Fig. 6).
In the present meta-analysis of 3 randomized trials and 12 observational studies consisting of 24,849 patients, we found that IVUS-guided DES implantation is associated with a 21% reduction in the risk of MACE and a 36% reduction in the risk of mortality compared with angiography-guided PCI. This is in agreement with the previous meta-analysis of 11 studies including 19,619 patients with PCI (4), which demonstrated a 41% reduction in mortality with IVUS guidance. In addition, IVUS-guided PCI reduced MI, TVR, TLR, and stent thrombosis compared with angiography-guided PCI. Analysis of 9 propensity score–matched studies including 13,545 patients demonstrated broadly similar results in terms of clinical outcomes, but no statistically significant difference in repeat revascularization.
It is still controversial whether routine IVUS guidance improves clinical outcomes after PCI with coronary stents. Although earlier studies demonstrated a significant benefit in reducing repeat revascularization after BMS implantation (1,2), several other studies have failed to prove the beneficial effects of IVUS-guided stent implantation (12,27). Among 15 studies included in our meta-analysis, only the EXCELLENT (Efficacy of Xience/Promus versus Cypher in Reducing Late Loss after Stenting) study reported data on binary angiographic restenosis (25), which were not significantly different between IVUS guidance and angiography guidance (1.7% vs. 1.1%, p = 0.373). Moreover, they showed an increased incidence of MACE at 1 year (HR: 2.40; 95% CI: 1.15 to 5.02; p = 0.02), mainly due to an increased risk of periprocedural MI with IVUS guidance. According to a meta-analysis performed in the pre-DES era (3), IVUS guidance was associated with a larger postprocedure angiographic minimal lumen diameter with significantly lower rates of angiographic restenosis (OR: 0.64; 95% CI: 0.42 to 0.96; p = 0.02) and repeat revascularization (OR: 0.66; 95% CI: 0.48 to 0.91; p = 0.004). However, the advantage of IVUS-guided DES implantation seems to be related to achievement of a lower incidence of MI or risk of death rather than a decreased rate of angiographic restenosis or need for repeat revascularization. The mechanism of beneficial effects of IVUS guidance in the DES era might be the capability to identify factors associated with periprocedural complications, such as side branch occlusion, stent edge dissections and hematoma, stent underexpansion, and incomplete stent apposition (28,29).
Zhang et al. (4) reported in their recent meta-analysis that IVUS guidance was associated with significantly lower rates of mortality (HR: 0.59; 95% CI: 0.48 to 0.73; p < 0.001), MACE (HR: 0.87; 95% CI: 0.78 to 0.96; p = 0.008), and stent thrombosis (HR: 0.58; 95% CI: 0.44 to 0.77; p < 0.001) compared with angiography-guided PCI, but it did not reduce MI, TLR, or TVR. Recently, the ADAPT-DES (Assessment of Dual AntiPlatelet Therapy with Drug-Eluting Stents) study was published (6). Witzenbichler et al. (6) showed that IVUS guidance during DES PCI was associated with a significantly reduced incidence of stent thrombosis (0.6% vs. 1.0%, p = 0.02), MI (2.5% vs. 3.7%, p = 0.002), and ischemia-driven TVR (2.4% vs. 4.0%, p < 0.001) compared with PCI without IVUS. The results of the present study correspond with the previous studies. However, analyses of 3 randomized trials and 12 observation studies from the present work, including >24,000 patients, further support the efficacy of IVUS-guided PCI with DES implantation, with an OR of 0.79 for MACE in favor of IVUS guidance compared with angiography-guided PCI without significant heterogeneity or evidence of publication bias. In addition, we extracted DES data exclusively from the included studies and tried not to include studies mixed with BMS data.
Our study corresponds to several previous studies proposing a possibility that IVUS-guided PCI may reduce DES-related stent thrombosis. With IVUS, assessment of suboptimal results of coronary stenting associated with the occurrence of stent thrombosis is possible. IVUS evaluations of stent underexpansion, malapposition, incomplete lesion coverage, and residual plaque have been found to predict stent thrombosis after DES implantation (30–33). Also, selection of appropriate stenting strategy according to the IVUS findings might be important in reducing adverse outcomes. The finding of reduced definite or probable stent thrombosis in the IVUS guidance group of our study is in keeping with these findings.
First, most studies included in our meta-analysis were observational studies from different cohorts or consecutive patients. Therefore, we abstracted propensity score–matched adjusted risk estimates from observational studies with generic inverse variance weighting. Second, the definition of endpoints differed among the included studies. Third, there was wide variability in risk profile and lesion complexity of the included patients. In addition, we could not have access to patient-level data to determine whether specific lesion subsets (e.g., left main and bifurcation lesions) or other risk factors (e.g., diabetes and advanced age) would influence the effect of IVUS guidance on the adverse clinical outcomes. Fourth, some results of our meta-analysis have significant heterogeneity, which is frequent in meta-analyses performed on global data. Thus, we tried to overcome heterogeneity by sensitivity analyses of the lesion subsets and according to study design. Finally, the types of DES used were different among the included studies.
Our meta-analysis demonstrates that IVUS-guided DES implantation significantly reduces adverse clinical outcomes compared with angiography-guided PCI. These data should provide further support for IVUS use in the modern DES era, but adequately powered trials that measure patient-oriented outcomes in participants with different risk profiles and lesion subsets are needed.
This work was supported by a 2013 Inje University research grant. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bare-metal stent(s)
- confidence interval
- drug-eluting stent(s)
- hazard ratio
- intravascular ultrasound
- major adverse cardiac events
- myocardial infarction
- odds ratio
- percutaneous coronary intervention
- target lesion revascularization
- target vessel revascularization
- Received May 17, 2013.
- Revision received September 11, 2013.
- Accepted September 26, 2013.
- American College of Cardiology Foundation
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