The Impact of Age and Sex on In-Hospital Outcomes of Chronic Total Occlusion Percutaneous Coronary Intervention

Abstract: Objectives. We sought to determine the effect of age and sex on procedural outcomes and efficiency of chronic total occlusion (CTO) percutaneous coronary intervention (PCI). Methods. We examined the clinical and angiographic characteristics and outcomes of 1675 CTO-PCIs performed in 1644 patients between 2012 and 2016 at 15 United States centers. Results. Mean age was 65.3 ± 10 years and 1408 (86%) were men. Overall technical and procedural success rates were 88% and 87%, respectively. Increasing age was associated with more comorbidities (dyslipidemia, hypertension, prior coronary artery bypass graft surgery, prior stroke, peripheral arterial disease, and chronic lung disease) and more lesion calcification. As compared with the reference age of <65 years, age >75 years was independently associated with technical failure (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.20-4.28). Increasing age was also independently associated with the incidence of major adverse cardiovascular events (MACEs; OR, 2.93; 95% CI, 1.10-9.23 for 65-75 years and OR, 5.71; 95% CI, 1.89-19.60 for >75 years). Compared with men, women (n = 236; 14%) were older (66.8 ± 11.1 years vs 65.0 ± 9.8 years; P=.02), but had similar clinical characteristics and lower J-CTO scores (2.3 ± 1.3 vs 2.5 ± 1.2; P=.02). Although crude technical success rate was higher in women compared with men (92% vs 87%; P=.04), multivariable analysis did not show independent association between sex and technical failure (OR, men/women, 1.66; 95% CI, 0.86-3.50) or MACE (OR, 0.61; 95% CI, 0.25-1.73). Conclusions. Older age, but not sex, is associated with lower technical success and higher in-hospital complication rate for CTO-PCI. CTO-PCI is relatively infrequently attempted in women, despite high technical success and acceptable complication rates.

J INVASIVE CARDIOL 2017;29(4):116-122. Epub 2017 Jan 15.

Key words: chronic total occlusion, percutaneous coronary intervention, age, sex, outcomes, complications

Increasing age and female sex have been associated with worse outcomes after percutaneous coronary intervention (PCI).^1-4 The increasing life expectancy of the general population,⁵ combined with later presentation of coronary artery disease in women and the increase in prevalence of coronary chronic total occlusions (CTOs) with age, are likely to result in an increase in the number of older patients – especially women – who could potentially derive benefit from coronary CTO revascularization. However, women and elderly patients are currently underrepresented in most CTO-PCI series.^6-9 We therefore sought to examine the distribution of age and sex, as well as associated efficacy, efficiency, and safety of CTO-PCI in a large, contemporary multicenter United States registry.

Methods

We examined the clinical and angiographic records of patients who underwent CTO-PCI between May 2012 and May 2016 at 15 CTO-PCI centers in the United States (Appendix 1). The study was approved by the institutional review board of each site. Data collection was performed prospectively and retrospectively and recorded in a CTO database (PROGRESS CTO, Clinicaltrials.gov Identifier: NCT02061436).^10-18 Investigations were in accordance with the Declaration of Helsinki.

Definitions. Coronary CTOs were defined as coronary lesions with Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow of at least 3-month duration. Estimation of the occlusion duration was based on first onset of anginal symptoms, prior history of MI in the target vessel territory, or comparison with a prior angiogram. Estimated glomerular filtration rate (eGFR) was calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. Calcification was assessed by angiography as mild (spots), moderate (involving ≤50% of the reference lesion diameter), or severe (involving >50% of the reference lesion diameter). Moderate proximal vessel tortuosity was defined as the presence of at least 2 bends >70° or 1 bend >90° and severe tortuosity as 2 bends >90° or 1 bend >120° in the CTO vessel. Interventional collaterals were defined as collaterals deemed amenable to crossing by a guidewire and a microcatheter by the operator. The J-CTO score was calculated as described by Morino et al.¹⁹Technical success of CTO-PCI was defined as successful CTO revascularization with achievement of <30% residual diameter stenosis within the treated segment and restoration of TIMI grade 3 antegrade flow. Procedural success was defined as achievement of technical success with no in-hospital major adverse cardiac event (MACE). In-hospital MACE included any of the following adverse events prior to hospital discharge: death, MI, recurrent symptoms requiring urgent repeat target-vessel revascularization with PCI or coronary artery bypass graft surgery (CABG), tamponade requiring either pericardiocentesis or surgery, and stroke. Periprocedural and late in-hospital MIs were defined according to the Third Universal Definition of Myocardial Infarction.²⁰Bleeding was defined according to the National Cardiovascular Data Registry (NCDR) CathPCI database, and included suspected/confirmed bleeding occurring within 72 hours of the procedure and associated with any of the following: (1) hemoglobin drop of ≥3 g/dL; (2) transfusion with whole blood or packed red blood cells; or (3) procedural intervention/surgery at bleeding site to reverse or correct the bleed. Procedure time was calculated from administration of local anesthetic for vascular access to removal of the last catheter. 

Statistical analysis. Categorical variables were described using percentages and compared between groups using Pearson’s Chi² test or Fisher’s exact test. Continuous variables were described as mean ± standard deviation or median with interquartile range and compared using the Student’s t-test, analysis of variance, Wilcoxon rank-sum test, or Kruskal-Wallis test, as appropriate. Age cut-offs of 65 years and 75 years were selected to create three age groups of adequate size. Multivariable logistic regression was performed to examine the independent effect of age and sex on technical success and MACE; variables with P<.10 on univariable analysis were inserted in the models, and included dyslipidemia, hypertension, smoking status, history of MI, congestive heart failure, CABG, stroke/transient ischemic attack, peripheral arterial disease, target vessel, occlusion length, proximal stump morphology, proximal vessel tortuosity, lesion calcification, presence of suitable collaterals, distal vessel quality, and utilization of a retrograde approach. Age <65 years was used as reference category. All statistical analyses were performed using JMP 12.0 (SAS institute). Two-sided P-values of .05 were considered statistically significant.

Results

Baseline clinical and angiographic characteristics. The study included 1644 patients who underwent 1675 CTO-PCIs. Mean age was 65.3 ± 10.0 years and 1408 (86%) were men (Figure 1). Baseline clinical characteristics according to age and sex are shown in Table 1. Older patients had a lower body mass index (BMI) and eGFR and had more comorbidities including dyslipidemia, hypertension, prior CABG, stroke, peripheral arterial disease, and chronic lung disease, but were less likely to be smokers. As compared with men, women (n = 236; 14%) were older (66.8 ± 11.1 years vs 65.0 ± 9.8 years; P=.02) and had a lower eGFR, but had otherwise similar baseline characteristics. Most patients presented with stable angina (62%), yet as compared with men, women were more likely to present with acute coronary syndromes (32% vs 24%; P=.02).

The most common target vessel was the right coronary artery (55%) followed by the left anterior descending artery (24%) and circumflex artery (21%) (Table 2). Older age was associated with more moderate/severe calcification and a higher J-CTO score. Compared with men, women had less moderate/severe tortuosity (28% vs 37%; P=.01) and a lower overall J-CTO score (2.3 ± 1.3 vs 2.5 ± 1.2; P=.02).

Procedural characteristics and outcomes. Overall technical and procedural success rates were 88% and 87%, respectively (Table 3). Male sex was associated with higher use of antegrade dissection/reentry and retrograde CTO crossing. As compared with men, women had higher crude overall technical success rates (92% vs 87%; P=.04), but similar procedural success rates (89% vs 86%; P=.25); older age was associated with decreasing technical and procedural success rates but only in men (Figure 2). In multivariable analysis, age >75 years was an independent predictor of technical failure (odds ratio [OR], 2.28; 95% confidence interval [CI], 1.20-4.28; P=.01). Age 65-75 years (OR, 1.42; 95% CI, 0.89-2.28; P=.14) and sex (OR for men/women, 1.66; 95% CI, 0.86-3.50; P=.14) were not independently associated with angiographic result. Compared to procedures performed in women, procedures performed in men required more contrast volume (275 mL [200-375 mL] vs 250 mL [175-335 ml]; P<.001) and a higher air-kerma radiation dose (3.3 Gy [2.0-5.3 Gy] vs 2.4 Gy [1.4-4.2 Gy]; P<.001).

In-hospital adverse events. Overall, 44 patients (2.7%) experienced in-hospital MACE in our study. Increasing age was an independent predictor of MACE (OR, 2.93; 95% CI, 1.10-9.23; P=.03 and OR, 5.71; 95% CI, 1.89-19.60; P<.01 for patients aged 65-75 years and >75 years, respectively). This effect was largely due to a graded increase in in-hospital MI, emergent pericardiocentesis, and death with older age (Table 3). Women underwent emergency pericardiocentesis more often than men (2.1% vs 0.6%; P=.04), but the overall incidence of MACE remained similar between the two groups (crude rate, 3.4% vs 2.6%; P=.46; adjusted OR for men/women, 0.61; 95% CI, 0.25-1.73; P=.33). Coronary perforation and clinically significant bleeding occurred more frequently with increasing age; bleeding also tended to occur more frequently in women (2.1% vs 0.9%; P=.08).

Discussion

The main findings of this contemporary multicenter United States study are: (1) women represent only a small proportion (14%) of patients undergoing CTO-PCI; (2) sex is not an independent predictor of technical success for CTO-PCI or in-hospital MACE; and (3) older age is independently associated with lower CTO-PCI technical success and higher in-hospital MACE.

Sex-based differences in the uptake of diagnostic testing, revascularization procedures, and their outcome for coronary artery disease have long been identified.^21-25 Women are considered to have worse outcomes as compared with men, a finding that has been attributed to various reasons, such as: (1) later presentation, often in the context of more advanced disease and more comorbidities; (2) anatomic differences in body and vessel size, leading to more vascular access complications and coronary artery injury;^2,3,26 and (3) a higher incidence of bleeding in women, which may also be in part linked to body and vessel size, as well as heterogeneity in anticoagulation and antiplatelet pharmacotherapy.²⁷ 

Consistent with reports from other large CTO-PCI registries, women represented only 14% of patients in our study;^6,7 even after exclusion of the three Veterans Affairs hospitals participating in the registry, the proportion of women remained low at 17%. Furthermore, although women were older than men, baseline clinical characteristics (including BMI) were similar in the two groups and women displayed slightly lower angiographic complexity. Finally, overall technical success in women was high (92%), with an acceptable rate of in-hospital MACE (3.4%), and only a trend toward more bleeding events when compared with men. The above findings considered in combination could be related to selection bias toward healthy women with less angiographic complexity for CTO-PCI, and may imply that potentially equally good results could be achieved in younger women with more complex disease and more comorbidities. Indeed, Wolff et al analyzed the Canadian Multicenter CTO Registry and showed that women diagnosed with CTO on angiography (19%) were significantly more likely to undergo management with medical therapy as compared with men (71% vs 63%; P<.01); notably, CTO-PCI success was similar between the two groups (81% vs 75%; P=.81).²⁸ Similarly, a large analysis from the NCDR showed that women represented 22% of CTO-PCI volume (vs 31% of non-CTO PCIs; P<.001) in the United States between 2009 and 2013, despite the fact that sex was not significantly associated with technical success (adjusted OR for women/men, 1.03; 95% CI, 0.99-1.08) or MACE (adjusted OR, 0.89; 95% CI, 0.69-1.16).²⁹ In an analysis by Claessen et al, from the Multinational CTO registry, women represented 14% of CTO-PCIs; similar to our findings, despite older age, women displayed fewer markers of angiographic complexity, and sex was not found to be associated with CTO-PCI procedural outcome (adjusted OR for failure, women/men, 0.80; 95% CI, 0.58-1.11; P=.18).³⁰ 

With respect to age, our results indicate that age >75 years is independently associated with technical failure as well as in-hospital MACE after CTO-PCI, even after multivariable adjustment for several comorbidities and angiographic characteristics. This may be explained by several factors, such as: (1) residual confounding from examined variables; (2) variables unexamined in the present registry, such as frailty;³¹ and (3) operator-dependent bias with respect to “aggressiveness” in achieving revascularization (although this is unlikely, given the high utilization of the retrograde approach and long procedure times in older patients observed in our study). In the aforementioned report from the NCDR, age was also identified as an independent predictor of technical failure (OR for success/failure per 10-year increase in age, 0.95; 95% CI, 0.93-0.97); however, the same report did not reveal an association between age and in-hospital MACE. Similarly, Galassi et al recently published a prediction rule for CTO-PCI technical success, according to which age ≥75 years was one of three factors predictive of technical failure (along with ostial lesion location and collateral Rentrop grade <2).³² In a prospective analysis of 356 patients by André et al, patients ≥75 years undergoing CTO-PCI showed a higher incidence of in-hospital major adverse cardiac and cardiovascular events (MACCE), defined as death, MI, or stroke (5.4% vs 0.4% for patients <75 years; P<.01).³³ Nevertheless, patients aged ≥75 years derived significant benefit from a successful procedure, with more freedom from MACE at median follow-up of 20 months (hazard ratio [HR], 0.43; 95% CI, 0.19-0.96; P=.04). Hoebers et al investigated the effect of age on procedural and long-term outcomes in the Multinational CTO Registry: compared to patients <75 years old (n= 1578; 88.1%), those ≥75 years old (n = 213; 11.9%) had numerically lower procedural success rates (63.8% vs 69.1%; P=.12); at a median follow-up of 890 days, greater age at the time of procedure was a significant predictor of MACE (HR per year increase, 1.03; 95% CI, 1.003-1.03; P=.01).³⁴

Study limitations. This was a retrospective, observational analysis and is thus subject to selection bias. Some potential confounding factors, such as frailty, were not assessed as part of the study. Only procedural outcomes were available for analysis. Our analysis included procedures performed by highly skilled and experienced CTO operators, and thus our results may not apply to less experienced operators. Some of the participating centers enrolled patients during parts of the study period due to participation in other studies. There was no local monitoring or core laboratory adjudication of the angiograms or centralized clinical event adjudication.

Conclusion

In conclusion, older age, but not sex, is a non-modifiable independent predictor of lower technical success and higher in-hospital complication rate for CTO-PCI. While infrequently performed, CTO-PCI in women has good procedural outcomes and an acceptable rate of in-hospital MACE.

Acknowledgment. Study data were collected and managed using REDCap electronic data capture tools hosted at University of Texas Southwestern Medical Center.³⁵ REDCap (Research Electronic Data Capture) is a secure, web-based application designed to support data capture for research studies, providing: (1) an intuitive interface for validated data entry; (2) audit trails for tracking data manipulation and export procedures; (3) automated export procedures for seamless data downloads to common statistical packages; and (4) procedures for importing data from external sources.

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From the ¹VA North Texas Healthcare System and University of Texas Southwestern, Dallas, Texas; ²Center for Interventional Vascular Therapy at New York-Presbyterian Hospital/Columbia University Medical Center, New York, New York; ³Henry Ford Hospital, Detroit, Michigan; ⁴Massachusetts General Hospital, Boston, Massachusetts; ⁵Beth Israel Deaconess Medical Center, Boston, Massachusetts; ⁶Piedmont Heart Institute, Atlanta, Georgia; ⁷VA San Diego Healthcare System and University of California San Diego, La Jolla, California; ⁸University of Washington, Seattle, Washington; ⁹Torrance Memorial Medical Center, Torrance, California; ¹⁰St. Luke’s Mid America Heart Institute, Kansas City, Missouri; ¹¹Medical Center of the Rockies, Loveland, Colorado; ¹²University of Pittsburgh Medical Center Presbyterian, Pittsburgh, Pennsylvania; ¹³Baylor Heart and Vascular Hospital, Dallas, Texas; ¹⁴Central Arkansas VA Healthcare System, Little Rock, Arkansas; ¹⁵Boston Scientific, Natick, Massachusetts; and ¹⁶Minneapolis Heart Institute, Minneapolis, Minnesota.

Funding. Research reported in this publication was supported by the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under award number UL1TR001105. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.

Disclosure. The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Karmpaliotis reports speakers’ bureau for Abbott Vascular, Medtronic, and Boston Scientific; consultant to Bridgepoint Medical. Dr Alaswad reports consulting fees from Terumo, Asahi Intecc, and Boston Scientific; consultant, no financial support, Abbott Laboratories. Dr Jaffer is a  consultant to Boston Scientific, Siemens, and Merck; he reports non-financial research support from Abbott Vascular, research grants from the NIH (HL-R01-108229), Siemens, and Kowa. Dr Yeh received the Career Development Award (1K23HL118138) from the National Heart, Lung, and Blood Institute. He is a consultant for Abbott Vascular, Gilead Sciences, and Boston Scientific; advisory board of Abbott Vascular; salary support from Harvard Clinical Research Institute. Dr Patel is on the speakers’ bureau for Astra Zeneca. Dr Mahmud receives clinical trial support from Boston Scientific, Cordis, Abbott Vascular, Corindus, and Gilead Pharmaceuticals; speakers bureau for Medtronic, the Medicines Company, Corindus, and St. Jude. Dr Wyman receives honoraria/consulting/speaking fees from Boston Scientific, Abbott Vascular, and Asahi Intecc. Dr Lombardi reports equity with Bridgepoint Medical; consultant to Boston Scientific, Abiomed, and Abbott Vascular. Dr Grantham reports speaking fees, consulting, and honoraria from Abbott Vascular, Boston Scientific, Asahi Intecc; research grants from Boston Scientific, Asahi Intecc, Abbott Vascular, Medtronic; member of Boston Scientific Executive Physician Leadership Committee; advisory board for Boston Scientific; CTO advisory board for Abbott Vascular. Dr Kandzari reports research/grant support and consulting honoraria from Boston Scientific and Medtronic Cardiovascular, and research/grant support from Abbott. Dr Lembo reports speakers’ bureau fees from Medtronic; advisory board fees from Abbott Vascular and Medtronic. Dr Moses is a consultant for Boston Scientific and Abiomed. Dr Kirtane reports institutional research grants to Columbia University from Boston Scientific, Medtronic, Abbott Vascular, Abiomed, St. Jude Medical, Vascular Dynamics, Glaxo SmithKline, and Eli Lilly. Dr Ali reports grant support/consultant fees from St. Jude Medical. Dr Thompson is an employee of Boston Scientific. Dr Banerjee reports research grants from Gilead and the Medicines Company; consultant/speaker honoraria from Covidien, Merck, and Medtronic; ownership in MDCare Global (spouse); intellectual property in HygeiaTel; educational grant from Boston Scientific (spouse).  Dr Brilakis reports consulting/speaker honoraria from Abbott Vascular, Asahi Intecc, Boston Scientific, Elsevier, Somahlution, St Jude Medical, and Terumo; research support from Boston Scientific and InfraRedx; spouse is employee of Medtronic. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted September 1, 2016, provisional acceptance given September 6, 2016, final version accepted September 19, 2016.

Address for correspondence: Emmanouil S. Brilakis, MD, PhD, Minneapolis Heart Institute, 920 E. 28th Street #300, Minneapolis, MN 55407. Email: esbrilakis@gmail.com