Outcomes of Intravascular Ultrasound-Guided Versus Angiography-Guided Percutaneous Coronary Interventions in Chronic Total Occlusions: A Systematic Review and Meta-Analysis

Abstract

Background. Percutaneous coronary interventions (PCI) with intravascular ultrasound (IVUS) guidance have been associated with better long-term outcomes, but adoption remains limited. There are limited data on the impact of IVUS on chronic total occlusion (CTO)-PCI. Objectives. To examine the impact of IVUS guidance on the outcomes of CTO-PCI. Methods. We performed a systematic review and study-level meta-analysis of IVUS vs angiography-guided CTO-PCI. Electronic databases were systematically searched for all pertinent studies from inception through January 2021. Randomized controlled trials (RCT), registry data, and abstracts published in peer-reviewed indexed journals were included. We examined the following in-hospital and long-term outcomes: major adverse cardiac events; all-cause mortality; cardiovascular mortality; myocardial infarction (MI); target-vessel revascularization (TVR); target-lesion revascularization (TLR); and stent thrombosis (ST). We also evaluated the following procedural metrics: procedure time; fluoroscopy time; contrast volume; total stent length; and total number of stents. Random-effects models were used to pool individual study results. Results. Four (2 observational, 2 randomized) studies including 1975 patients (IVUS-guided PCI, 861 patients; angiography-guided PCI, 1114 patients) were included in the analysis. IVUS-guided CTO-PCI had similar all-cause mortality, major adverse cardiac events, cardiovascular mortality, MI, TVR, and TLR compared with angiography-guided CTO-PCI, but lower risk of stent thrombosis (odds ratio, 0.24; 95% confidence interval, 0.08-0.76; P=.02; I²=0%), shorter procedure time (P<.001; I²=88%), shorter fluoroscopy time (P<.001; I²=63%), and less contrast volume use (P<.001; I²=59%). Total stent length (P<.001; I²=39%) and total number of stents (P<.001; I²=72%) were lower with IVUS-guided CTO-PCI. Conclusion. IVUS-guided CTO-PCI is associated with lower risk of ST.

J INVASIVE CARDIOL 2022;34(4):E310-E318.

Key words: chronic total occlusion, CTO, intravascular imaging, IVUS, PCI, percutaneous coronary intervention

Compared with angiography-guided percutaneous coronary intervention (PCI), intravascular ultrasound (IVUS) guidance has been associated with better clinical outcomes, including lower cardiovascular mortality when treating complex coronary lesions.^1-3 IVUS may be of particular benefit in chronic total occlusion (CTO)-PCI, both for crossing (for example, to clarify proximal cap ambiguity in cases of antegrade wiring and to identify guidewire position in cases of retrograde crossing) and for stent optimization.⁴ Meticulous attention to lesion preparation and stenting technique, often requiring intracoronary imaging, is required to ensure optimal stent expansion and is one of the global principles of CTO-PCI.⁵ We performed a systematic review and study-level meta-analysis to assess the impact of IVUS vs angiography-only guidance during CTO-PCI.

Methods

This systematic review and meta-analysis was performed in accordance with the PRISMA guidelines.⁶

Search strategy. A systematic search was performed using PubMed Central, Embase, Cochrane Library, Google Scholar, and the ClinicalTrials.gov databases from inception to January 2021, as well as the scientific session abstracts from Transcatheter Cardiovascular Therapeutics, Euro-PCR, the Society of Cardiovascular Angiography and Interventions, the American College of Cardiology, the American Heart Association, and the European Society of Cardiology, presented in the last 10 years. After the initial search yield, the references of pertinent studies and reviews were also manually searched for additional studies.

The search keywords included: “intravascular ultrasound or IVUS,” “chronic total occlusion or CTO,” “complex percutaneous coronary intervention,” “intra-coronary imaging,” “stent optimization,” “stent thrombosis,” “target-lesion revascularization,” “target-vessel revascularization,” and various combinations of these terms. There were no language restrictions. Two authors (YC and RB) independently and in duplicate performed the literature search. Disagreements were settled by consensus.

Study selection criteria. Studies were included if they met the following criteria: (1) randomized controlled trials (RCTs) or observational studies comparing the use of IVUS guidance with angiography guidance in CTO-PCI; and (2) studies reporting clinical and procedural outcomes after CTO-PCI. We excluded studies that did not report the use of IVUS for stent optimization following CTO-PCI and studies that only reported the use of IVUS for CTO crossing.

Two reviewers (YC and RB) independently reviewed studies and collected data. Data were extracted using a standard protocol based on the above inclusion/exclusion criteria. The following variables were collected: first author; year of publication; design of study; sample size for both IVUS-guided and angiography-guided CTO-PCI groups; patient demographics; lesion characteristics; type of stents used; number of stents used per patient; and total stented length.

For RCTs, quality and assessment of risk of trial bias was evaluated per the Cochrane Collaboration criteria,⁷ specifically emphasizing sequence generation, allocation concealment, blinding, outcomes assessment, and selective reporting. The quality of observational studies was assessed using the Newcastle-Ottawa scale.⁸

Study outcomes. The following clinical outcomes were assessed: all-cause mortality; stent thrombosis (ST); target-lesion revascularization (TLR); myocardial infarction (MI); target-vessel revascularization (TVR); major adverse cardiac event (MACE) rate; and cardiovascular mortality. The following procedural metrics were evaluated: number of stents used; procedure time (minutes); fluoroscopy time (minutes); contrast volume (mL), and total stent length (mm).

The CTO-IVUS (Chronic Total Occlusion Intervention With Drug-eluting Stents) trial and the study by Vemmou et al reported 12-month outcomes, whereas the AIR-CTO (Angiographic and clinical comparisons of Intravascular ultrasound vs angiography-guided drug-eluting stent implantation for patients with Chronic Total Occlusion lesions) study and the K-CTO (Korean-Chronic Total Occlusion) registry reported 2-year outcomes.^9-12

We used the definitions of MACE, all-cause mortality, MI, TLR, and TVR used in each study. Stent thrombosis was defined as definite or probable according to the Academic Research Consortium criteria across all studies (Table 1).¹³

Statistical analysis. Due to methodological and statistical heterogeneity between studies, the random-effects model was utilized to pool effect estimates. Heterogeneity was assessed using Higgins and Thompson’s I² statistics. I² is the proportion of total variation observed between the trials attributable to differences between trials rather than sampling error (chance), with I² values of <25%, 25% to 75%, and >75% correspond to low, moderate, and high levels of heterogeneity, respectively.⁷ The results were confirmed by a fixed-effects model to avoid small studies being overly weighted. Meta-influence analysis (sensitivity analysis, using the leave-1-study method) was also performed, whereby each study was sequentially removed from the pooled analysis to assess whether any study had a significant influence on the overall pooled analysis. Publication bias was estimated visually by funnel plots and validated using the Begg-Mazumdar test and Egger’s weighted regression test.¹⁴ In case of any publication bias, Duval and Tweedie’s trim-and fill method was used to adjust for publication bias.¹⁵ A 2-tailed P<.05 was considered statistically significant for all analyses. Statistical analyses were performed using RevMan, version 5.02 (Copenhagen: The Nordic Cochrane Center, The Cochrane Collaboration, 2014) and Comprehensive Meta-Analysis Software, version 2.0 (Biostat, Inc).

Results

Study selection and characteristics. The search strategy, after removing duplicates, identified 99 potential articles (Figure 1), 4 of which were included in the final analysis (2 RCTs and 2 observational studies).^9-12 The characteristics of the included studies are presented in Table 1. The studies included 1975 patients, 861 of whom underwent IVUS-guided CTO-PCI and 1114 of whom underwent angiography-guided CTO-PCI.

Data for MACE, MI, number of stents used, total stented length, TVR, and cardiovascular mortality were pooled from the 4 studies.^9-12 Data on fluoroscopy time,^9-11 procedure time,^9-11 contrast volume,^9-11 all-cause mortality,^9,11,12 ST,^9,11,12 and TLR^9,11,12 were pooled from 3 studies.

The detailed inclusion and exclusion criteria for the 4 studies are presented in Table 1. The included observational studies were of good quality and both RCTs were of fair quality (Supplemental Table S1 and Supplemental Table S2). Patient characteristics are presented in Table 2.

Across included studies, 77%-88.7% of patients were men and 27%-51.6% had diabetes mellitus. Two studies used second-generation drug-eluting stents^,12 and 1 study used both first- and second-generation drug-eluting stents.¹¹ The lesion length in both study arms varied from 26.7 ± 12.9 mm to 36.3 ± 17.1 mm.

Procedural outcomes. Compared with angiography-guided CTO-PCI, IVUS-guided CTO-PCI was associated with significantly shorter procedure time (P<.001; I²=88%), fluoroscopy time (P<.001; I²=63%), and contrast volume (P<.001; I²=59%). The total stented length (P<.001; I²=39%) and number of stents used (P<.001, I²=72%) were significantly lower with IVUS-guided PCI (Figure 2).

Clinical outcomes. During a mean follow-up of 1.5 years, IVUS-guided CTO-PCI was associated with a 76% lower risk of ST when compared with angiography-guided CTO-PCI (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.07-0.76; P=.02; I²=0%). There was no significant difference in the incidence of MACE (OR, 0.84; 95% CI, 0.73-1.22; P=.67; I²=44%), MI (OR, 0.73; 95% CI, 0.50-1.06; P=.10; I²=63%), TVR (OR, 0.79; 95% CI, 0.48-1.52; P=.13; I²=57%), TLR (OR, 0.75; 95% CI, 0.47-1.20; P=.24; I²=0%), all-cause mortality (OR, 0.74; 95% CI, 0.34-1.51; P=.44; I²=0%), and cardiovascular mortality (OR, 0.73; 95% CI, 0.38-1.60; P=.44; I²=0%) (Figure 3 and Figure 4).

Publication bias. Visual inspection of funnel plots showed asymmetry suggesting bias for the outcomes of contrast volume and procedure time (Supplemental Figures S1, S2, S3). However, subsequent testing with Begg-Mazumdar test and Egger’s test showed no evidence of publication bias for any outcome (P>.05) (Supplemental Table S3).

Subgroup analyses. For the outcomes of all-cause mortality, cardiovascular mortality, MACE, MI, TLR, ST, and TVR (Supplemental Figures S4, S5, S6), subgroup analysis for RCTs and observational studies showed similar treatment effects, with no evidence of interaction by study type (P>.05).

Fluoroscopy time, procedure time, contrast volume, number of stents used, and total stented length were lower in observational studies (interaction P<.05), favoring IVUS-guided CTO-PCI; however, there was no significant difference in RCTs (P>.05).

Sensitivity analysis. Sensitivity analysis (Supplemental Figure S7) demonstrated no variation in the outcomes of total stent length and total number of stents when any of the included studies were removed. The removal of the study by Vemmou et al influenced the outcomes of fluoroscopy time, procedure time, and contrast volume, making the overall results not significant.¹⁰

Discussion

Our meta-analysis of 4 studies involving 1975 patients found IVUS-guided CTO-PCI to be associated with shorter procedure and fluoroscopy time, shorter total stent length, and lower ST rates compared with angiography-guided CTO-PCI.

To our knowledge, this is the first meta-analysis to examine the impact of IVUS guidance in CTO-PCI. A recent meta-analysis by Malik et al, which included 10 RCTs comparing the effect of IVUS in patients undergoing PCI for a spectrum of coronary artery disease including stable ischemia heart disease, acute coronary syndrome, and CTOs, reported a significant reduction in TLR, TVR, MACE, and cardiovascular mortality with the use of IVUS.¹ The largest RCT to date on IVUS-guided PCI in 1448 all-comer patients showed lower incidence of TLR and definite ST at 12 months in the IVUS-guided group.³

IVUS use in CTO-PCI has had low adoption—as low as one-third of all cases reported in a recent publication—despite published studies.¹⁰ There is wide variability in IVUS use for CTO-PCI even at experienced centers.¹⁶ CTO-PCI is often complex and associated with longer procedural duration and higher operator radiation dose. CTO lesions often have severe calcification and are long, requiring implantation of multiple stents. Different IVUS trials have used varied criteria for guidance before stent placement and for stent optimization. Conventional criteria for IVUS-guided drug-eluting stent implantation may not be applicable to CTOs, which are often associated with negative remodeling.²

Barriers to IVUS use in PCI include the cost of the device and the time added to the procedure. Earlier studies, however, have suggested cost effectiveness with the use of IVUS. Despite a higher upfront cost with initial IVUS use, the cumulative costs were lower over long-term follow-up.^17,18

Study limitations. This meta-analysis has several inherent limitations. First, the study design, treatment exposure, and outcome definitions varied across the different studies; however, where available, standard definitions were used. These limitations may at least partly explain the observed heterogeneity for the different outcomes. Second, we did not have patient-level and lesion-level data, which prevents the evaluation of important determinants of stent failure (such as dual-antiplatelet therapy compliance, etc). Third, the inclusion of observational studies may introduce selection bias (based on operator preferences and experiences with either IVUS or angiography interpretation). The inherent bias and unmeasured confounding elements of observational studies may influence the study results despite multiple sensitivity analyses. Fourth, some studies utilized rotational IVUS and others phased-array IVUS, which may have influenced image interpretation. Fifth, the study by Tian et al used both first- and second-generation drug-eluting stents, whereas all other studies used second-generation drug-eluting stents.¹¹ Finally, the IVUS optimization criteria differed across all studies.

Conclusion

IVUS guidance during CTO-PCI was associated with lower rates of ST during follow-up, highlighting the potential benefits of IVUS use in this complex lesion subgroup.

Affiliations and Disclosures

From the ¹Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, Minneapolis, Minnesota; ²Rochester Regional Health, Rochester, New York; and ³Mount Sinai Heart at Mount Sinai St Luke’s, New York, New York.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Garcia reports consulting for Medtronic, Edwards Lifesciences, Neochord, and Abbott Vascular; institutional research grants from Edwards Lifesciences, Abbott Vascular, Gore, and Boston Scientific; proctoring for Edwards Lifesciences. Dr Goessl reports consulting for Livanova; consulting and speakers’ bureau for Abbott Vascular. Dr Burke reports stock in Egg Medical and MHI Ventures. Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, American Heart Association (Associate Editor, Circulation), Amgen, Asahi Intecc, Biotronik, Boston Scientific, Cardiovascular Innovations Foundation (Board of Directors), ControlRad, CSI, Elsevier, GE Healthcare, InfraRedx, Medtronic, Siemens, and Teleflex; research support from Regeneron; owner, Hippocrates LLC; shareholder in MHI Ventures, Cleerly Health. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript accepted June 26, 2021.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute and Minneapolis Heart Institute Foundation, Abbott Northwestern Hospital, 920 East 28th Street, #300, Minneapolis, MN 55407. Email: esbrilakis@gmail.com

References

1. Malik AH, Yandrapalli S, Aronow WS, Panza JA, Cooper HA. Intravascular ultrasound-guided stent implantation reduces cardiovascular mortality — updated meta-analysis of randomized controlled trials. Int J Cardiol. 2020 Jan 15;299:100-105. doi:10.1016/j.ijcard.2019.07.033

2. Hong SJ, Mintz GS, Ahn CM, et al. Effect of intravascular ultrasound–guided drug-eluting stent implantation. JACC Cardiovasc Interv. 2020;13(1):62-71. doi:10.1016/j.jcin.2019.09.033

3. Zhang J, Gao X, Kan J et al. Intravascular ultrasound versus angiography-guided drug-eluting stent implantation: the ULTIMATE trial. J Am Coll Cardiol. 2018;72(24):3126-3137. doi:10.1016/j.jacc.2018.09.013

4. Galassi AR, Sumitsuji S, Boukhris M, et al. Utility of intravascular ultrasound in percutaneous revascularization of chronic total occlusions: an overview. JACC Cardiovasc Interv. 2016;9(19):1979-1991. doi:10.1016/j.jcin.2016.06.057

5. Brilakis ES, Mashayekhi K, Tsuchikane E, et al. Guiding principles for chronic total occlusion percutaneous coronary intervention. Circulation. 2019;140(5):420-433. doi:10.1161/CIRCULATIONAHA.119.039797

6. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med. 2009;151(4):W65-W94. doi:10.7326/0003-4819-151-4-200908180-00136

7. Higgins JP, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med. 2002;21(11):1539-1558. doi:10.1002/sim.1186

8. Stang A. Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses. Eur J Epidemiol. 2010;25(9):603-605. doi:10.1007/s10654-010-9491-z

9. Kim BK, Shin DH, Hong MK, et al. Clinical impact of intravascular ultrasound-guided chronic total occlusion intervention with zotarolimus-eluting versus biolimus-eluting stent implantation: randomized study. Circ Cardiovasc Interv. 2015;8(7):e002592. doi:10.1161/CIRCINTERVENTIONS.115.002592

10. Vemmou E, Khatri J, Doing AH, et al. Impact of intravascular ultrasound utilization for stent optimization on 1-year outcomes after chronic total occlusion percutaneous coronary intervention. J Invasive Cardiol. 2020;32(10):392-399. Epub 2020 Jul 22.

11. Tian NL, Gami SK, Ye F, et al. Angiographic and clinical comparisons of intravascular ultrasound- versus angiography-guided drug-eluting stent implantation for patients with chronic total occlusion lesions: two-year results from a randomised AIR-CTO study. EuroIntervention. 2015;10(12):1409-1417. doi:10.4244/EIJV10I12A245

12. Hong SJ, Kim BK, Shin DH, et al. Usefulness of intravascular ultrasound guidance in percutaneous coronary intervention with second-generation drug-eluting stents for chronic total occlusions (from the Multicenter Korean-Chronic Total Occlusion Registry). Am J Cardiol. 2014;114(4):534-540. doi:10.1016/j.amjcard.2014.05.027

13. Cutlip DE, Windecker S, Mehran R, et al. Clinical endpoints in coronary stent trials: a case for standardized definitions. Circulation. 2007;115(17):2344-2351. doi:10.1161/CIRCULATIONAHA.106.685313

14. Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088-1101.

15. Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000;56(2):455-463. doi:10.1111/j.0006-341x.2000.00455.x

16. Karacsonyi J, Alaswad K, Jaffer FA, et al. Use of intravascular imaging during chronic total occlusion percutaneous coronary intervention: insights from a contemporary multicenter registry. J Am Heart Assoc. 2016;5(8):e003890. doi:10.1161/JAHA.116.003890

17. Alberti A, Giudice P, Gelera A, et al. Understanding the economic impact of intravascular ultrasound (IVUS). Eur J Health Econ. 2016;17(2):185-193. doi:10.1007/s10198-015-0670-4

18. Gaster AL, Slothuus Skjoldborg U, Larsen J, et al. Continued improvement of clinical outcome and cost effectiveness following intravascular ultrasound guided PCI: insights from a prospective, randomised study. Heart. 2003;89(9):1043-1049. doi:10.1136/heart.89.9.1043