Long-Term Outcomes of Chronic Total Occlusion Recanalization Versus Percutaneous Coronary Intervention for Complex Non-Occlusive Coronary Artery Disease

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Long-Term Outcomes of Chronic Total Occlusion Recanalization Vs. Percutaneous Coronary Intervention for Complex Non-Occlusive Coronary Artery Disease Lorenzo Azzalini MD, PhD, MSc , Mauro Carlino MD , Barbara Bellini MD , Claudia Marini MD , Vittorio Pazzanese MD , Evelina Toscano MD , Mario Gramegna MD , Silvia Moscardelli MD , Ludovica Bognoni MD , Matteo Montorfano MD PII: DOI: Reference:

S0002-9149(19)31195-6 https://doi.org/10.1016/j.amjcard.2019.10.034 AJC 24263

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The American Journal of Cardiology

Received date: Revised date: Accepted date:

4 September 2019 14 October 2019 16 October 2019

Please cite this article as: Lorenzo Azzalini MD, PhD, MSc , Mauro Carlino MD , Barbara Bellini MD , Claudia Marini MD , Vittorio Pazzanese MD , Evelina Toscano MD , Mario Gramegna MD , Silvia Moscardelli MD , Ludovica Bognoni MD , Matteo Montorfano MD , Long-Term Outcomes of Chronic Total Occlusion Recanalization Vs. Percutaneous Coronary Intervention for Complex Non-Occlusive Coronary Artery Disease, The American Journal of Cardiology (2019), doi: https://doi.org/10.1016/j.amjcard.2019.10.034

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Long-Term Outcomes of Chronic Total Occlusion Recanalization Vs. Percutaneous Coronary Intervention for Complex NonOcclusive Coronary Artery Disease 1,2

Lorenzo Azzalini MD PhD MSc , Mauro Carlino MD1, Barbara Bellini MD1, Claudia Marini MD1, Vittorio Pazzanese MD1, Evelina Toscano MD1, Mario Gramegna MD1, Silvia Moscardelli MD1, Ludovica Bognoni MD1, Matteo Montorfano MD1.

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Interventional Cardiology Division, Cardio-Thoracic-Vascular Department, San Raffaele Scientific Institute, Milan, Italy. 2 Cardiac Catheterization Laboratory, The Mount Sinai Hospital, New York, NY, USA.

Corresponding author: Lorenzo Azzalini, MD PhD MSc Interventional Cardiology Division, Cardio-Thoracic-Vascular Department Via Olgettina 60, 20132 Milan, Italy Tel: +390226437331 – Fax: +390226437339 E-mail: [email protected]

Funding: none Disclosures: Dr. Azzalini received honoraria from Abbott Vascular, Guerbet, Terumo, and Sahajanand Medical Technologies; and research support from ACIST Medical Systems, Guerbet, and Terumo. The other authors have no disclosures.

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Short title: Long-term outcomes of CTO vs. non-CTO PCI

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Abstract The durability of chronic total occlusion (CTO) percutaneous coronary intervention (PCI) is uncertain. We aimed to compare the longterm outcomes of CTO PCI with those of complex non-CTO PCI. We built a single-center registry including all patients undergoing CTO and complex non-CTO PCI between 2012 and 2017. Complex non-CTO PCI was defined as: 3 vessels treated, ≥3 stents implanted, total stent length >60 mm, saphenous vein graft intervention, 2-stent bifurcation intervention, left main PCI, protected PCI, or rotational/laser atherectomy. The primary endpoint was target-lesion failure (TLF), a composite of cardiac death, myocardial infarction, and target-lesion revascularization. A total of 2,396 patients were included (n=609 CTO PCI, n=1,787 complex non-CTO PCI). Patients undergoing CTO PCI were younger and had higher prevalence of cardiovascular comorbidities. CTO PCI patients exhibited worse procedural metrics and success rate (74% vs. 98%, p<0.001). They also suffered a higher incidence of coronary perforation (3.5% vs. 2.0%, p=0.04) and cardiac tamponade (0.8% vs. 0.1%, p=0.001). However, there was no difference in the overall incidence of in-hospital major adverse cardiac and cerebrovascular events (4.1% vs. 5.0%, p=0.40). At 36 months, there were no differences in the incidence of TLF (10.1% vs. 9.9%, p=0.91) or its individual components, between the CTO and complex non-CTO group. This finding was confirmed on multivariable analysis. In conclusion, CTO PCI is associated with lower success rates and higher risk for coronary perforation and tamponade compared with complex non-CTO PCI. The incidence of other in-hospital and long-term adverse events is similar and reasonably low. Keywords: chronic total occlusion, percutaneous coronary intervention, complex PCI, long-term outcomes

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The recent advances in technical developments and algorithmic approaches to chronic total occlusion (CTO) percutaneous coronary intervention (PCI) have allowed a remarkable increase in success rates of this challenging lesion subset, while reducing the incidence of complications and improving procedural efficiency1–4. While most of the available literature in this field has focused on the technical aspects and immediate clinical benefit of CTO recanalization, few studies have investigated the durability of this intervention, showing moderately high rates of adverse events on long-term follow-up5–7. Whether this finding should be considered suboptimal is however unclear, as no study has so far compared the long-term outcomes of CTO vs. complex non-CTO PCI. In particular, it is unknown if specific (patient-, lesion- or procedure-related) characteristics of CTO intervention expose these patients to a differential risk of adverse outcomes, compared to well-known features of complexity observed in subjects undergoing percutaneous recanalization of non-occlusive lesions. The aim of this study was to compare the long-term clinical outcomes of patients undergoing CTO intervention with those of subjects undergoing other types of complex PCI.

Methods This single-center multi-operator retrospective registry included all patients who underwent complex PCI (as defined below) at our institution between January 2012 and December 2017. CTO PCI was indicated according to the presence of angina, ischemia or both, and was performed electively (ad hoc PCI was discouraged)3. Baseline, procedural and hospitalization data were recorded. All patients signed an informed consent, approved by the local ethics committee, for procedural data collection and for the anonymous use of data for retrospective evaluation.

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Complex PCI was defined utilizing a modified definition of Giustino et al.8,9: CTO PCI, 3 vessels treated, ≥3 stents implanted, total stent length >60 mm, saphenous vein graft intervention, bifurcation intervention with 2 stents excluding left main, left main PCI with 1 or 2 stents, protected PCI (use of a mechanical circulatory support device in non-emergency settings, namely ST-elevation myocardial infarction, cardiogenic shock, or cardiac arrest), or use of rotational or laser atherectomy. In this study, patients undergoing CTO PCI were compared with patients undergoing the other types of complex PCI. In case of multiple PCIs in the same patient, only the last intervention in the planned sequence of revascularization procedures was considered for analysis. CTO was defined as a 100% stenosis with Thrombolysis In Myocardial Infarction (TIMI) 0 flow for >3 months10 (occlusion duration was estimated on the basis of clinical history and angiographic appearance, and on the presence of an occluded target vessel on a prior angiogram, when available). Technical success was defined as a residual stenosis <30% with antegrade TIMI flow grade 3 in the CTO vessel 10. In-hospital major adverse cardiac and cardiovascular events (MACCE)9 were defined as a composite of contrast-induced nephropathy requiring dialysis, tamponade, major bleeding (bleeding causing hemodynamic instability with need for vasopressors or requiring transfusion, percutaneous or surgical intervention), stroke, periprocedural myocardial infarction (MI)11, and death. Follow-up was performed by means of phone interview, review of hospital records or outpatient visit. The primary endpoint of this study was target-lesion failure (TLF), defined as a composite of cardiac death, any MI, and ischemia-driven target-lesion revascularization (TLR). Continuous variables are presented as mean ± standard deviation and t-test was used for comparisons. Categorical variables are presented as frequency (percentages) and compared using chi-square test. Kaplan-Meier curves of TLF-free survival were plotted and

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compared using the log-rank test. Multivariate Cox regression analysis with backward stepwise selection of variables (p-entry=0.05, pexit=0.10) was performed to identify independent predictors of TLF on follow-up. The model included the following prespecified candidate predictors: CTO vs. complex non-CTO PCI, age, sex, diabetes mellitus, prior MI, prior PCI, prior coronary artery bypass graft surgery, estimated glomerular filtration rate (eGFR), left ventricular ejection fraction (LVEF), number of diseased vessels, acute coronary syndrome, use of intravascular imaging, total stent length, and technical success. Results of these analyses are presented as hazard ratios (HR) with 95% confidence intervals (CI). For all tests, a p<0.05 was considered significant. Statistical analysis was performed using SPSS 24 (IBM Corp., Armonk, NY).

Results During study period, 5,436 patients underwent PCI at our institution. Of those, 2,396 subjects (44%) underwent complex PCI: n=609 CTO PCI (11%) and 1,787 complex non-CTO PCI (33%). Figure 1A shows the features of complexity in the study population. Implantation of ≥3 stents and total stent length >60 mm were the most common complexity features in both groups. Patients undergoing complex non-CTO PCI had a higher prevalence of all complexity features, except total stent length >60 mm, which had similar prevalence in the 2 groups. Most procedures in both groups had only 1 complexity feature, although this tended to be more frequent in CTO PCI patients. While 2 complexity features were more often observed in the complex non-CTO group, patients undergoing CTO PCI had higher prevalence of 3 or ≥4 complexity features (Figure 1B).

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Table 1 presents the clinical characteristics of the study population. Patients undergoing CTO PCI were younger than those undergoing complex non-CTO PCI (65.3±10.7 vs. 68.5±12.3 years, p<0.001), had higher body mass index (27.3±3.7 vs. 26.6±3.9 kg/m2, p=0.001), and higher prevalence of men (88% vs. 83%, p=0.005), dyslipidemia (74% vs. 67%, p=0.002), prior MI (52% vs. 36%, p<0.001), and prior PCI (69% vs. 49%, p<0.001). Patients undergoing complex non-CTO PCI had worse renal function and higher prevalence of chronic kidney disease (26% vs. 20%, p=0.003). While stable coronary artery disease was the most frequent indication for revascularization in both groups, patients undergoing complex non-CTO PCI more frequently exhibited an unstable presentation (p<0.001). In the CTO group, the mean J-CTO score was 1.7±1.2. A retrograde approach was used in 33% of cases. As shown in Table 2, patients undergoing CTO PCI exhibited worse procedural metrics (contrast volume, radiation dose, fluoroscopy time; p<0.001 for all) and technical success rate (74% vs. 98%, p<0.001). Subjects treated with complex non-CTO PCI had a higher number of diseased vessels (2.4±0.7 vs. 2.2±0.8, p<0.001), higher use of the radial access (69% vs. 50%, p<0.001) and intravascular imaging (16% vs. 6%, p<0.001). Patients in the complex non-CTO PCI group were treated more often for a left main lesion (23% vs. 3%), while subjects undergoing CTO PCI had a higher prevalence of right coronary artery as target vessel (43% vs. 22%, p<0.001). Table 3 compares the incidence of in-hospital adverse events in the 2 groups. Patients undergoing CTO PCI suffered a higher incidence of coronary perforation (3.5% vs. 2.0%, p=0.04) and cardiac tamponade (0.8% vs. 0.1%, p=0.001). However, there were no differences in the overall incidence of MACCE (4.1% vs. 5.0%, p=0.40), including death (1.2% vs. 1.5%, p=0.51).

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Follow-up was available for 2,145/2,396 patients (90%) for a median of 786 (interquartile range: 431-1,350) days. At 36 months, there were no differences in the incidence of TLF (10.1% vs. 9.9%, p=0.91) or its individual components, between the CTO and complex non-CTO group (Table 4). This finding was confirmed by the Kaplan-Meier analysis of 36-month TLF-free survival (log-rank p=0.85; Figure 2). Table 5 presents the multivariable analysis for the prediction of TLF on follow-up. The type of PCI (CTO vs. complex non-CTO) was not a predictor of TLF. A lower eGFR (HR 0.93, p=0.02), lower LVEF (HR 0.81, p=0.002), higher number of diseased vessels (HR 1.32, p=0.03), and presentation as acute coronary syndrome (HR 1.61, p=0.009) were identified as independent predictors of the primary endpoint, whereas a borderline association was found for prior PCI (HR 1.38, p=0.06).

Discussion Our study provides a snapshot of the current patterns of utilization and outcomes of complex PCI at a large tertiary-care institution. The main findings of our study are as follows: 1) patients undergoing CTO PCI have a different clinical and angiographic profile compared with subjects undergoing complex non-CTO PCI; 2) CTO PCI is associated with worse procedural metrics and success rate; 3) although patients undergoing CTO PCI suffer a higher incidence of perforation and tamponade, the overall rate of in-hospital MACCE is similar between groups; 4) CTO PCI is not associated with worse clinical outcomes at 36-month follow-up; 5) CTO PCI is not an independent predictor of TLF on follow-up.

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Recently, the benefit of CTO PCI over medical therapy has been questioned6,12. In particular, the recently-published “Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients With Chronic Total Occlusion” (DECISION-CTO) trial6 showed that CTO-PCI, compared with medical therapy, was not associated with lower rates of a composite endpoint of death, MI, stroke, or any revascularization (22.3% vs. 22.4%; HR 1.03; 95% CI 0.77 to 1.37, p=0.86), at a median follow-up of 4.0 years. Moreover, this study, similar to the “Evaluation of the XIENCE Coronary Stent, Performance, and Technique in Chronic Total Occlusions” (EXPERT-CTO)5 and the “Evaluating Xience and left ventricular function in PCI on occlusiOns afteR STEMI” (EXPLORE)7 trials, found moderately high rates of adverse events in patients undergoing CTO PCI on long-term follow-up. In EXPERT-CTO5, the composite endpoint of death, MI, and TLR was observed in 18.5% of patients at 1 year. In EXPLORE7, the combined endpoint of cardiac death, coronary artery bypass grafting and MI was observed in 13.5% of the CTO PCI cohort at a median of 3.9 years. Therefore, the long-term durability of CTO PCI, compared to that of other types of complex coronary intervention, is uncertain. Prior to the present study, very little evidence existed on this topic. Brilakis et al. 13 reported on the clinical and procedural characteristics as well as the acute outcomes of CTO PCI vs. non-CTO PCI (all-comers) in 594,510 patients from the National Cardiovascular Data Registry (NCDR) CathPCI Registry, between 2009 and 2013. Similar to our study, they found that CTO patients were younger, more often men, and had a higher cardiovascular comorbidity burden, compared with subjects undergoing non-CTO PCI. Contrast volume and fluoroscopy time were higher and success rate was lower (59% vs. 96%, p<0.001) in CTO PCI patients, which again mirrors our findings. Patients undergoing CTO PCI suffered a higher incidence of tamponade (0.3% vs. 0.1%, p<0.001), similar to our study. However, unlike our report, the incidence of other in-hospital adverse events (death 0.4% vs. 0.3%, need for urgent surgical

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revascularization 0.8% vs. 0.4%, MI 2.7% vs. 1.9%, and need for transfusion 2.7% vs. 1.9%; p<0.001 for all) was also significantly higher in the CTO group in the study by Brilakis et al., which might be explained by the much larger sample size, differences in institutional practices, and/or earlier experience with CTO PCI in their study. Follow-up after hospital discharge was not available in the study by Brilakis et al. To the best of our knowledge, no study so far investigated the long-term outcomes of CTO vs. complex non-CTO PCI. Our report provides reassuring data to this regard, as we found no differences in the primary endpoint of TLF or any of its individual components between CTO and complex non-CTO PCI, at 36-month follow-up. These findings were confirmed on multivariable analysis, which identified renal and left ventricular function, as well as coronary disease burden and presentation with acute coronary syndrome, as independent predictors of TLF on follow-up. These observations had previously been reported in the literature 10,14,15, which confers external validity to our findings. Our study has some limitations. First, it is an observational study, and is therefore susceptible to the bias usually ascribed to this kind of design. However, the neutral study findings in unadjusted analyses were confirmed upon multivariable adjustment. Moreover, the prevalence of CTO PCI in our cohort (11%) was similar to the figures reported by others (9-11%)16,17, which contributes to the external validity of our report. Second, follow-up was not available for all patients, although it is unlikely that the findings in the small proportion of subjects lost to follow-up (10%) would have changed the overall study conclusions. Third, the relatively long study inclusion period might have introduced historical bias with regard to operator experience and introduction of newer devices (particularly in the CTO PCI group; this fact could also explain the modest technical success rate in such group). Fourth, intravascular imaging use was low in both groups,

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particularly in CTO PCI (6%), which has also been reported by others (19%)18 and can be explained by operator reluctance in prolonging these already lengthy procedures. Fifth, the fact that several operators performed the interventions in both groups might have introduced a certain degree of bias with regard to procedural choices and outcomes, although this very condition at the same time extends the reproducibility of our findings to different practice patterns. Finally, the results reported in this study might not be applicable to other institutions, where limited experience with complex PCI and CTO recanalization exists.

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Figure 1. (A) Prevalence of specific complexity features and (B) total number of complexity features in patients undergoing CTO vs. complex non-CTO PCI.

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Figure 2. Kaplan-Meier curves of 36-month target-lesion failure (TLF)-free survival in patients undergoing CTO vs. complex non-CTO PCI.

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Table 1. Baseline clinical characteristics. Variable Age (years) Men 2

Body mass index (kg/m ) Diabetes mellitus

Overall

CTO

Complex non-

(n=2,396)

(n=609)

CTO (n=1,787)

p-value

67.7±12.0

65.3±10.7

68.5±12.3

<0.001

2,019 (84%)

535 (88%)

1,484 (83%)

0.005

26.8±3.8

27.3±3.7

26.6±3.9

0.001

774 (33%)

190 (32%)

584 (33%)

0.48

Dyslipidemia

1,629 (69%)

446 (74%)

1,183 (67%)

0.002

Hypertension

1,856 (79%)

478 (79%)

1,378 (79%)

0.22

Current smoker

350 (15%)

105 (18%)

245 (14%)

0.03

Prior myocardial infarction

943 (40%)

313 (52%)

630 (36%)

<0.001

Prior percutaneous coronary intervention

1,282 (54%)

414 (69%)

868 (49%)

<0.001

Prior coronary artery bypass graft surgery

474 (20%)

116 (19%)

358 (20%)

0.56

eGFR (ml/min/1.73 m2)

78.3±26.7

81.9±25.9

77.0±26.9

<0.001

eGFR <60 ml/min/1.73 m2

569 (25%)

120 (20%)

449 (26%)

0.003

LVEF (%)

51.5±11.0

51.3±10.3

51.6±11.2

0.54

LVEF <50%

616 (30%)

165 (31%)

451 (29%)

0.39

1,303 (55%)

395 (65%)

908 (51%)

UAP/NSTEMI

411 (17%)

52 (9%)

359 (20%)

STEMI

102 (4%)

12 (2%)

90 (5%)

Shock/cardiac arrest

39 (2%)

2 (0.3%)

37 (2%)

Indication of PCI Stable coronary artery disease

<0.001

20

Heart failure/low ejection fraction

75 (3%)

16 (3%)

59 (3%)

Complete revascularization

345 (15%)

110 (18%)

235 (13%)

Other

101 (4%)

17 (3%)

84 (5%)

Abbreviations: eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; STEMI, ST-elevation myocardial infarction; UAP/NSTEMI, unstable angina pectoris/non-ST-elevation myocardial infarction.

Table 2. Angiographic characteristics and procedural data. Overall

CTO

Complex non-

(n=2,396)

(n=609)

CTO (n=1,787)

2.3±0.7

2.2±0.8

2.4±0.7

Left main

419 (18%)

16 (3%)

403 (23%)

Left anterior descending

856 (36%)

207 (34%)

649 (36%)

Circumflex

356 (15%)

120 (20%)

236 (13%)

Right coronary artery

646 (27%)

260 (43%)

386 (22%)

Variable Number of diseased vessels

p-value <0.001

Target vessel

Bypass graft

<0.001

119 (5%)

6 (1%)

113 (6%)

Radial access

1328 (64%)

258 (50%)

1,070 (69%)

<0.001

Complex lesion (B2/C type)

1,952 (82%)

609 (100%)

1,343 (75%)

<0.001

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Drug-eluting stents

2,094 (92%)

454 (90%)

1,640 (92%)

0.14

329 (14%)

39 (6%)

290 (16%)

<0.001

61±33

60±38

61±32

0.55

Contrast volume (ml)

272±124

323±144

254±111

<0.001

Radiation dose (Gy·cm2)

171±130

229±168

151±107

<0.001

33±24

46±34

28±17

<0.001

2,196 (92%)

447 (74%)

1,749 (98%)

<0.001

Intravascular imaging Total stent length (mm)

Fluoroscopy time (min) Technical success

Table 3. In-hospital adverse events. Overall

CTO

Complex non-

(n=2,396)

(n=609)

CTO (n=1,787)

113 (4.8%)

25 (4.1%)

88 (5.0%)

Coronary perforation

56 (2.4%)

21 (3.5%)

35 (2.0%)

0.04

Cardiac tamponade

6 (0.3%)

5 (0.8%)

1 (0.1%)

0.001

Major bleeding

18 (0.8%)

4 (0.7%)

14 (0.8%)

0.74

Variable Major adverse cardiac and cerebrovascular events (MACCE)

p-value

0.40

New need for dialysis

9 (0.4%)

1 (0.2%)

8 (0.5%)

0.32

Periprocedural myocardial infarction

51 (2.2%)

12 (2.0%)

39 (2.2%)

0.73

Stroke

4 (0.2%)

2 (0.3%)

2 (0.1%)

0.26

In-hospital death

34 (1.4%)

7 (1.2%)

27 (1.5%)

0.51

22

Table 4. Clinical outcomes at 36-month follow-up. Overall

CTO

Complex non-

(n=2,145)

(n=528)

CTO (n=1,617)

Target-lesion failure

212 (9.9%)

53 (10.1%)

159 (9.9%)

0.91

Cardiac death

81 (3.8%)

15 (2.8%)

66 (4.1%)

0.20

Any myocardial infarction

46 (2.2%)

8 (1.5%)

38 (2.4%)

0.25

Ischemia-driven target-lesion revascularization

130 (6.1%)

39 (7.5%)

91 (5.7%)

0.15

Variable

23

p-value

Table 5. Independent predictors of target-lesion failure on follow-up.

CTO vs. complex non-CTO PCI

HR 1.03

Univariate 95% CI 0.76-1.41

p 0.85

Age (per 10 years)

1.07

0.93-1.22

0.35

Male sex

0.79

0.56-1.11

0.18

Diabetes mellitus

1.68

1.27-2.23

<0.001

Prior myocardial infarction

1.23

0.93-1.63

0.15

Prior percutaneous coronary intervention

1.04

0.79-1.37

0.80

Prior coronary artery bypass graft

1.14

0.82-1.59

0.43

eGFR (per 10 ml/min/1.73 m )

0.88

0.84-0.93

Left ventricular ejection fraction (per 10%)

0.76

0.67-0.86

Number of diseased vessels (per one vessel)

1.41

Acute coronary syndrome

1.80

Intravascular imaging Total stent length (per 10 mm) Technical success

Variable

2

HR

Multivariate 95% CI

1.38

0.98-1.94

<0.001

0.93

0.87-0.99

0.02

<0.001

0.81

0.71-0.92

0.002

1.15-1.73

0.001

1.32

1.03-1.69

0.03

1.35-2.41

<0.001

1.61

1.13-2.30

0.009

0.70

0.45-1.10

0.12

1.01

0.97-1.06

0.63

0.62

0.40-0.95

0.03

Abbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; HR, hazard ratio.

24

p

0.06