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Periprocedural Myocardial Injury After Recanalization of Single Chronic Coronary Occlusion: A Propensity Score Analysis Comparing Long-Term Clinical Outcomes
Abstract: Background. Rates and importance of periprocedural myocardial injury (PMI) after crossing coronary chronic total occlusions (CTOs) is not well understood. This study sought to investigate long-term clinical implications of PMI in patients undergoing percutaneous coronary intervention (PCI) for single CTO utilizing antegrade technique. Methods. Out of 11,957 patients undergoing non-urgent PCI, a total of 1110 patients with symptomatic angina and single CTO were treated by antegrade PCI and observed for up to 10 years. The primary objective included cardiac death, while the secondary aim comprised all major adverse cardiovascular and cerebrovascular event (MACCE) rate. Results. Troponin-defined PMI occurred in 4.7% patients (n = 52). At 1 year, the cardiac death and MACCE rates were significantly higher in patients with vs without PMI (hazard ratio [HR], 5.72; 95% confidence interval [CI], 1.59-20.49; P=.01; HR, 1.84; 95% CI, 1.07-3.18; P=.03, respectively). At long-term follow-up, patients with PMI had a trend toward a higher incidence of cardiac death than patients without PMI (HR, 2.51; 95% CI, 0.99-6.33; P=.05) and no differences were demonstrated in terms of overall MACCE between both groups (HR, 1.19; 95% CI, 0.73-1.93; P=.49). After propensity score adjustment, no significant differences were observed regarding the short-term and long-term outcomes. Conclusion. CTO-PCI is a safe procedure if routinely performed in symptomatic patients at a high-volume center. PMI does not influence long-term outcomes after antegrade CTO-PCI.
J INVASIVE CARDIOL 2017;29(2):63-67. Epub 2016 November 15.
Key words: periprocedural myocardial injury, percutaneous coronary intervention, chronic total occlusion
Periprocedural myocardial injury (PMI) is one of the most common complications after percutaneous coronary intervention (PCI), with prognostic implications for the clinical outcome of the patients.1,2 The prognostic relevance of PMI, as defined by the sole elevation of cardiac markers with no other accompanying symptom or sign, however, is somewhat more debatable. It has been described that the occurrence of PMI increases mortality, even in asymptomatic patients with no changes in electrocardiogram (ECG).1,2 CTO-PCI remains one of the most challenging coronary procedures, requiring advanced techniques, specific materials, and an experienced team. Paralleling the complexity of the intervention, PMI is a frequent finding after CTO-PCI.3 This could be caused by the procedural techniques, devices used, and the extent of atherosclerosis processes, which are particularly pronounced in CTO patients.4 However, limited data exist on the clinical implication of PMI after CTO-PCI in a setting of stable angina. Thus, we investigated whether PMI after CTO-PCI influences long-term outcomes in patients with symptomatic single coronary occlusion.
Methods
Setting. Between January 1, 2003 and January 1, 2011, all patients with symptomatic angina and a single CTO who underwent PCI were prospectively included in the central CTO database of the Medical University of Gdansk, Poland. Patients with additional non-CTO lesions requiring PCI were excluded from the final analysis. The study was approved by the institutional review board. All patients were loaded with aspirin and clopidogrel prior to the procedure according to the recommendations. The use of dual-antiplatelet therapy after the procedure was recommended as per available guidelines.
Definitions and outcomes. PMI was defined as a postprocedure troponin I increase with a peak value exceeding 5x the upper reference limit (URL) alone or associated with chest pain or ST-segment or T-wave changes.5 Troponin I was measured before and 12-24 hours after CTO-PCIs. CTO was defined as a complete interruption of antegrade blood flow with Thrombolysis in Myocardial Infarction (TIMI) grade 0 flow (true CTO), or with minimal contrast penetration through the lesion without distal vessel opacification, TIMI grade 1 flow (functional CTO).6Procedural success was defined as the restoration of TIMI flow grade 3 with a residual stenosis of <20% in the target CTO. The primary objective included cardiac death, while the secondary objective comprised all major adverse cardiovascular and cerebrovascular events (MACCE), ie, death from any cause, non-fatal myocardial infarction, need for urgent revascularization in any coronary vessel, and stroke. Outcome records were obtained from the national administrative database and all patients were linked to the long-term follow-up.
Statistical analysis. The mean follow-up was 64.8 ± 29.6 months (PMI vs non-PMI: 59.0 ± 27.9 months vs 65.1 ± 29.7 months, respectively; P=.14). We used SPSS software (IBM SPSS Statistics, version 21.0) for all analyses. We expressed discrete and nominal variables as frequencies and continuous variables as mean ± standard deviation. The categorical variables were compared using the c2 test or Fisher’s exact test and continuous variables using two-sided Student’s t-test. Kaplan-Meier product limits were presented for cumulative probability of reaching primary and secondary objectives and compared using log-rank test. Since groups were not equal (Table 1), we performed a propensity score analysis to reduce potential biases. The propensity score analysis comprised the following: age, gender, hypertension, diabetes mellitus, hypercholesterolemia, smoking, prior myocardial infarction, prior PCI, location of CTO, procedure success, lab values (hemoglobin, platelet count, white blood count), Canadian Cardiovascular Society (CCS) score at admission, PCI attempt, TIMI flow before PCI, chronic obstructive pulmonary disease, chronic renal insufficiency, and malignancies. Logistic regression analysis including variables known to be associated with coronary artery disease and technical difficulties was performed to identify predictors of troponin-defined PMI. P<.05 was considered statistically significant.
Results
Out of 11,957 patients undergoing non-urgent PCI, a total of 1110 displayed single CTO and were enrolled in the central CTO registry database. Patients with other lesions treated in the same setting or after acute coronary syndromes within the last 3 months were excluded from the final analysis.
Troponin-defined PMI occurred in 52 patients (4.7%). CTO-PCI was successful in 77% of patients with PMI and 66% of patients with no PMI (P=.09). Baseline and angiographic characteristics are shown in Table 1 and Table 2. Compared with patients without PMI, those with PMI had a higher incidence of 1-year cardiac death (hazard ratio [HR], 5.72; 95% confidence interval [CI] ratio, 1.59-20.49; P=.01) and 1-year overall MACCE rate (HR, 1.84; 95% CI, 1.07-3.18; P=.03). At long-term follow-up, patients with PMI had a trend toward a higher incidence of cardiac death than patients without PMI (HR, 2.51; 95% CI, 0.99-6.33; P=.05). However, the overall MACCE rate during long-term follow-up was similar between both groups with and without PMI (HR, 1.19; 95% CI, 0.73-1.93; P=.49) (Table 3 and Figure 1). After propensity score adjustment, no significant differences were observed regarding the short-term and long-term outcomes (Table 4 and Figure 1). The results for survival and overall MACCE outcomes persisted after 10 years of follow-up.
In multivariate analysis, age (odds ratio [OR], 1.04; 95% CI, 1.01-1.07; P=.01) and PCI of right coronary artery (OR, 1.8; 95% CI, 1.02-3.19; P=.04) were identified asindependent predictors of troponin-defined PMI. Interestingly, the procedural success did not predict PMI in our study (OR, 1.83; 95% CI, 0.94-3.55; P=.07).
Discussion
This study demonstrates that despite the higher mortality at 1 year, the presence of PMI in patients undergoing CTO-PCI was not associated with long-term clinical outcomes. To the best of our knowledge, this is the largest single-center cohort of patients undergoing PCI for a single CTO and the first study investigating whether troponin-defined PMI 
influences long-term outcomes in symptomatic patients undergoing recanalization of single CTO.
Recent reports on mortality improvement after successful CTO-PCI7 still have not answered the question of whether all symptomatic patients with known coronary occlusion should undergo this complex intervention. The broader indications for this procedure comprising, ie, myocardial ischemia of >10%, multivessel disease (MVD), and left ventricular systolic dysfunction, remain a matter of permanent debate.8,9 However, MVD patients are still likely scheduled for coronary artery bypass grafting (CABG).10 Indeed, the prolonged PCI procedure may increase myocardial injury and provoke troponin release. Most PMIs after CTO-PCI are diagnosed by the asymptomatic elevation of cardiac 
enzymes and range between 0.0%-19.4%.11 Although successful CTO revascularization was associated with a better clinical outcome vs patients in whom it failed, regardless of the occurrence of PMI, long-term prognostic significance of PMI after PCI for single CTO has not been well investigated to date.12 In a study published by Lo et al, PMI after CTO-PCI occurred in 8.6% of cases and was more often observed after the retrograde approach. In line with this observation, our study, which was based on an essentially larger and more selective CTO subset, demonstrated that PMI was associated with worse mid-term overall outcome measures.3 However, at 10 years, we noticed only a trend toward higher cardiac mortality and no difference regarding overall MACCE rates in patients with PMI vs without PMI. Interestingly, the PMI rate during the index hospitalization after CTO-PCI using antegrade approach was relatively low. PMI could be essentially driven by vessel complications such as side-branch occlusion and dissections.13,14 A large body of evidence exists demonstrating that PMI remains more frequently after retrograde attempt as compared with the antegrade technique.3,11,15,16 The retrograde approach requires insertion of microcatheters or guidewires in the distal portion of the coronary artery via collaterals.17 PMI during this procedure could be caused by the myocardial injury during the collateral crossing or by dissection strategies disrupting small side branches,18 obstruction of the collateral pathway, and by the increased plaque burden of complex lesions.14,19 The obstruction of the main supply to the collateralized area could not be compensated by the rest of the parallel collaterals.20 On the other hand, the retrograde approach is used in complex CTOs, usually as the consequence of an antegrade crossing failure. Interestingly, CTO in the right coronary artery, which is more likely to be crossed utilizing a retrograde technique, remained an independent factor of PMI in our study where all procedures were attempted with antegrade approach. This finding suggests that vessel-dependent factors might be acting as confounders and contributing to overestimate the myocardial insult attributable to the retrograde approach. Although no exclusion criteria for CTO complexity have been defined in the study, the use of antegrade-alone approach at our center could have relatively influenced the final low PMI rate.
Conclusion
The results presented herein, which are based on a large, single-center cohort, suggest that antegrade CTO-PCI is a safe procedure if performed in a high-volume center where recanalization of chronically occluded coronaries is routinely performed in symptomatic patients. We were able to demonstrate for the first time that PMI after antegrade CTO-PCI does not influence outcomes at long-term observation.
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*Joint first authors.
From the 1First Department of Cardiology, Medical University of Gdansk, Poland; 2Department of Invasive Cardiology, Klinikum Frankfurt/Oder, Germany; and 3Department of Invasive Cardiology, Pomeranian Cardiology Centres, Gdansk, Poland.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.
Manuscript submitted June 23, 2016, provisional acceptance given July 1, 2016, final version accepted July 6, 2016.
Address for correspondence: Milosz Jaguszewski, MD, PhD, FESC, First Department of Cardiology, Medical University of Gdansk, Debinki 7, 80-210 Gdansk, Poland. Email: mjaguszewski@escardio.com.pl
