Author + information
- Received September 2, 2014
- Revision received October 10, 2014
- Accepted October 24, 2014
- Published online February 1, 2015.
- Woo Jin Jang, MD∗,
- Jeong Hoon Yang, MD, PhD∗,
- Seung-Hyuk Choi, MD, PhD∗∗ (, )
- Young Bin Song, MD, PhD∗,
- Joo-Yong Hahn, MD, PhD∗,
- Jin-Ho Choi, MD, PhD∗,
- Wook Sung Kim, MD, PhD†,
- Young Tak Lee, MD, PhD† and
- Hyeon-Cheol Gwon, MD, PhD∗
- ∗Division of Cardiology, Department of Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- †Department of Thoracic and Cardiovascular Surgery, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
- ↵∗Reprint requests and correspondence:
Dr. Seung-Hyuk Choi, Division of Cardiology, Department of Medicine, Cardiac and Vascular Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, #50, Irwon-dong, Gangnam-gu, Seoul 135-710, Republic of Korea.
Objectives The purpose of this study was to compare the long-term clinical outcomes of patients with chronic total occlusion (CTO) and well-developed collateral circulation treated with revascularization versus medical therapy.
Background Little is known about the clinical outcomes and optimal treatment strategies of CTO with well-developed collateral circulation.
Methods We screened 2,024 consecutive patients with at least 1 CTO detected on coronary angiogram. Of these, we analyzed data from 738 patients with Rentrop 3 grade collateral circulation who were treated with medical therapy alone (n = 236), coronary artery bypass grafting (n = 170) or percutaneous coronary intervention (n = 332; 80.1% successful). Patients who underwent revascularization and medical therapy (revascularization group, n = 502) were compared with those who underwent medical therapy alone (medication group, n = 236) in terms of cardiac death and major adverse cardiac events (MACE), defined as the composite of cardiac death, myocardial infarction, and repeat revascularization.
Results During a median follow-up duration of 42 months, multivariate analysis revealed a significantly lower incidence of cardiac death (hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.15 to 0.58; p < 0.01) and MACE (HR: 0.32; 95% CI: 0.21 to 0.49; p < 0.01) in the revascularization group compared with the medication group. After propensity score matching, the incidence of cardiac death (HR: 0.27; 95% CI: 0.09 to 0.80; p = 0.02) and MACE (HR: 0.44; 95% CI: 0.23 to 0.82; p = 0.01) were still significantly lower in the revascularization group than in the medication group.
Conclusions In patients with coronary CTO and well-developed collateral circulation, aggressive revascularization may reduce the risk of cardiac mortality and MACE.
Several studies have reported the benefits of revascularization, percutaneous coronary intervention (PCI), and coronary artery bypass grafting (CABG) in patients with coronary chronic total occlusion (CTO) (1–3). CABG is widely performed in patients with multiple CTOs, multivessel coronary disease, or diabetes, and the surgical outcomes in patients with CTOs have improved, likely due to better perioperative management and the increased surgical experience (2,4). Similarly, the success rate of PCI in patients with CTO has also increased due to improvements in device technology such as drug-eluting stents, dedicated guidewires, and microcatheters (5,6). However, high frequencies of failed PCI, perioperative mortality, and potential lethal complications related to revascularization still exist in patients with CTO (5). For these reasons, some clinicians are more likely to treat patients who have CTO and abundant distal collateral flow with medical therapy alone. To date, no studies have compared the long-term clinical outcomes of patients with CTO and well-developed collateral circulation who undergo medical therapy versus those who undergo revascularization. Therefore, this study aimed to compare the long-term survival outcomes associated with revascularization versus medical therapy in patients with at least 1 CTO and well-developed collateral circulation.
Between March 2003 and February 2012, 2,024 consecutive patients were enrolled in the retrospective Samsung Medical Center CTO registry. The inclusion criteria for the registry were: 1) at least 1 CTO detected on diagnostic coronary angiography; and 2) symptomatic angina and/or a positive functional ischemia study. Exclusion criteria included: 1) previous CABG; 2) history of cardiogenic shock or cardiopulmonary resuscitation; and 3) ST-segment elevation acute myocardial infarction (MI) during the preceding 48 h. A CTO lesion was defined as the obstruction of a native coronary artery with a Thrombolysis In Myocardial Infarction (TIMI) flow grade 0 with an estimated duration longer than 3 months. Duration was estimated based on the interval from the last episode of acute coronary syndrome (ACS), or in patients with no history of ACS, from the first episode of exertional angina consistent with the location of the occlusion or previous coronary angiogram (7–9).
Of the 2,024 patients included in the registry, 738 patients had Rentrop grade 3 collateral flow (10) and were included in the final analysis. The institutional review board of Samsung Medical Center approved this study and waived the requirement for informed consent.
Well-developed collateral circulation
Coronary angiography was reviewed by experienced interventional cardiologists blinded to patient data, and the extent of collateral flow was assessed according to the validated Rentrop classification scale (10). The grades of collateral filling from the contralateral vessel were: 0 = none; 1 = filling of side branches of the artery to be dilated via collateral channels without visualization of the epicardial segment; 2 = partial filling of the epicardial segment via collateral channels; and 3 = complete filling of the epicardial segment of the artery to be dilated via collateral channels. We considered patients with well-developed collateral circulation to have Rentrop grade 3 collateral flow. After selection of these patients, we confirmed the Rentrop grades by reviewing the associated angiograms in all cases.
All patients received antiplatelet therapy with aspirin at a dose of 81 to 325 mg/day, or clopidogrel at 75 mg/day if aspirin intolerance was reported. All patients were taking 1 or more antianginal medications, including a long-acting beta-blocker, calcium-channel blocker, and isosorbide mononitrate, alone or in combination, along with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as standard secondary prevention. All patients received a high-dose statin alone or in combination with ezetimibe in order to reduce the low-density lipoprotein cholesterol level to a target level of 60 to 85 mg/dl (1.55 to 2.20 mmol/l). The dosages of all medications were maximized as allowed by heart rate, blood pressure, and side effects in the absence of justifiable relative contraindications.
Revascularization of CTOs was accomplished by CABG or PCI with drug-eluting stent, and each revascularization strategy was selected as a treatment option based on the patient’s and physician’s preference. In a case of CABG for CTOs, arterial grafting with off-pump coronary artery bypass was the preferred technique. The surgical risk was assessed using the EuroSCORE (mean ± SD), and high surgical risk was defined as a EuroSCORE of ≥6 (11). PCI was performed using contemporary techniques such as bilateral injections; a specialized stiff, hydrophilic wire with a tapered tip; microcatheters; and a retrograde approach when available. The decision to pursue invasive treatment, the access site, type of drug-eluting stent, use of intravascular ultrasound, and use of glycoprotein IIb/IIIa receptor inhibitor were all left to the operator’s discretion. All interventions and procedural anticoagulation were performed according to current standard guidelines. All patients received loading doses of aspirin (300 mg) and clopidogrel (300 to 600 mg) before PCI unless they had previously received these antiplatelet medications. Aspirin treatment was continued indefinitely, and the duration of clopidogrel treatment was also left to the discretion of the individual physician. Successful revascularization was defined as final residual stenosis <20% of the vessel diameter, with TIMI flow grade ≥2 after revascularization, as assessed by visual estimation of the angiograms (7).
Clinical, angiographic, procedural, and outcome data were collected using a web-based reporting system. Additional information was obtained by reviewing the medical records or by telephone contact, if necessary. All baseline and procedural cine coronary angiograms were reviewed and analyzed quantitatively at the angiographic core laboratory (Cardiac and Vascular Center, Samsung Medical Center, Seoul, Korea) with an automated edge-detection system (Centricity CA 1000, GE, Waukesha, Wisconsin) using standard definitions (12). The minimum luminal diameters (MLDs) were measured in matched views before and after main vessel stenting if applicable. For the main vessel, the reference diameter (RD) was the average of the proximal and distal reference lumen diameters. For the side branch, the RD was the distal reference lumen diameter. Diameter stenosis was calculated as: 100 × (RD − MLD)/RD.
Study outcomes and definitions
The primary outcome was cardiac death during follow-up. The secondary outcomes were all-cause death, MI, repeat revascularization, and major adverse cardiac event (MACE). Repeat revascularization was a composite of target vessel revascularization (TVR) and non-TVR treated with PCI or CABG. MACE was defined as a composite of cardiac death, MI, and repeat revascularization. All deaths were considered to be of cardiac origin unless a definite noncardiac cause could be established. MI was defined as an elevation of creatine kinase-MB fraction or troponin-T/troponin-I greater than the upper limit of normal with concomitant ischemic symptoms or electrocardiographic findings indicative of ischemia (13). Perioperative enzyme elevation was not included in this definition of MI. TVR indicates the repeated revascularization of the target vessel by PCI or CABG; non-TVR indicates repeated revascularization of any vessel other that the target vessel by PCI or CABG.
All statistical analyses were performed using the intent-to-treat principle. Continuous variables were compared using the Student t test or the Wilcoxon rank-sum test where applicable and were presented as mean ± SD or median with interquartile range. Categorical data were tested using the Fisher exact test or the chi-square test as appropriate. Cumulative event rates were estimated by the Kaplan-Meier method, and treatment effects were assessed using stratified log-rank statistics. Covariates that were either statistically significant on univariate analysis or clinically relevant were included in multivariate models. Adjusted hazard rates were compared by Cox regression based on age, history of ACS, CTO of the left anterior descending coronary artery, multiple CTOs, previous PCI, and proximal to mid CTO. To reduce selection bias for treatment and any other related potential confounding factor, we performed a baseline characteristic adjustment for patients using propensity scores. Propensity scores were estimated using multiple logistic regression analysis. A full nonparsimonious model was developed that included all variables listed in Tables 1 and 2⇓⇓. The discrimination and calibration abilities of this propensity score model were assessed using c-statistics. Pairs were matched 1:1 by an optimal balance based on a genetic algorithm. We assessed the balance in baseline covariates between the 2 groups in a propensity score-matched cohort through the standardized mean difference and hypothesis test using the stratified analyses considering matched pairs (2-way analysis of variance or Friedman test) for continuous variables and the Mantel-Haenszel method for categorical variables. In the propensity score-matched population, risk reductions were compared using a conditional Cox regression model (14). All tests were 2-tailed, and p < 0.05 was considered to be statistically significant. All analyses were performed with the Statistical Analysis Software package, version 9.2, (SAS Institute, Cary, North Carolina).
Of the 2,024 patients in the registry, 738 patients had at least 1 CTO and well-developed collateral circulation, of whom 236 patients were treated with medical therapy alone (32%, medication group) and 502 patients were treated with PCI or CABG (68%, revascularization group). Of the 502 patients who underwent revascularization, 170 patients underwent CABG and 332 patients underwent PCI. Of the 332 patients who underwent PCI, 266 patients (80.1%) were successfully revascularized. The extent of coronary disease did not vary between the 2 groups (2.2 ± 0.8 in the revascularization group vs. 2.1 ± 0.7 in the medication group, p = 0.73), but the number of treated vessels was significantly greater in the revascularization group than in the medication group (1.5 ± 1.0 vs. 0.5 ± 0.7, p < 0.01). The EuroSCORE of patients treated with medical therapy, PCI, or CABG was 4.9 ± 3.6, 3.6 ± 2.9, or 4.5 ± 3.3, respectively. Baseline characteristics of the 2 groups are shown in Table 1. Compared with the medication group, the revascularization group was younger and had significantly lower prevalence of previous PCI but higher prevalence of dyslipidemia and ACS. The left ventricular ejection fraction was higher in the revascularization group. Angiographic analysis showed that CTO of the left anterior descending coronary artery, multiple CTOs, and proximal to mid CTO were noted more frequently in the revascularization group. The SYNTAX score (15) was higher in the revascularization group (Table 2). Complicated revascularization occurred in 26 patients (5.2% of the revascularization group). There were no deaths associated with the revascularization therapy, but cerebrovascular accidents including stroke occurred in 18 patients (3.6%), cardiac tamponade in 4 patients (0.8%), and cardiogenic shock in 2 patients (0.4%). Periprocedural MI (16) occurred in 70 patients (15.0%) in the revascularization group. A total of 35 patients (20.6%) treated with CABG and 35 patients (11.7%) treated with PCI suffered from this periprocedural complication.
Complete follow-up data were obtained in the overall study population. During follow-up (median 42 months, interquartile range: 22 to 68 months), 40 cardiac deaths occurred (23 in the medication group [9.7%] vs. 17 in the revascularization group [3.4%], p < 0.01). In multivariate analysis, the revascularization group was found to have significantly lower risk of cardiac death (hazard ratio [HR]: 0.29; 95% confidence interval [CI]: 0.15 to 0.58; p < 0.01), all-cause death (HR: 0.44; 95% CI: 0.27 to 0.71; p < 0.01), repeat revascularization (HR: 0.38; 95% CI: 0.23 to 0.63; p < 0.01), and MACE (HR: 0.32; 95% CI: 0.21 to 0.49; p < 0.01). The incidence of MI (HR: 1.04; 95% CI: 0.16 to 6.80; p = 0.97) were similar between 2 groups (Table 3, Figures 1A and 1B).
Propensity score-matched analysis
After performing propensity score matching, a total of 215 pairs were generated. The c-statistic for the propensity score model was 0.75, indicating good discrimination. There were no significant differences in baseline clinical or angiographic characteristics for the propensity score-matched subjects (Tables 1 and 2). A total of 29 cardiac deaths occurred during follow-up in the matched patients. Compared with the medication group, the revascularization group had a lower prevalence of cardiac death (20 in the medication group [9.3%] vs. 9 in the revascularization group [4.2%], HR: 0.27; 95% CI: 0.09 to 0.80; p = 0.02), all-cause death (18.1% vs. 7.4%, HR: 0.23; 95% CI: 0.10 to 0.53; p < 0.01) and MACE (24.7% vs. 10.7%, HR: 0.44; 95% CI: 0.23 to 0.82; p = 0.01). However, there were no significant differences in incidence of MI (0.5% vs. 0.9%, HR: 2.00; 95% CI: 0.18 to 22.06; p = 0.57) or repeat revascularization (15.3% vs. 6.5%, HR: 0.59; 95% CI: 0.27 to 1.29; p = 0.18) between the 2 groups (Table 4, Figures 2A and 2B).
Subgroup analysis of the revascularization group
The revascularization group was composed of the CABG subgroup (n = 170, 34% of the revascularization group) and the PCI subgroup (n = 332, 66%); there were no significant differences in clinical outcomes between the 2 subgroups with the exception of MACE, which was primarily driven by repeat revascularization. In multivariate analysis adjusted for diabetes mellitus, the left ventricular ejection fraction (%), and SYNTAX score, the PCI subgroup had a significantly higher prevalence of repeat revascularization (HR: 7.30; 95% CI: 2.09 to 25.46; p < 0.01) and MACE (HR: 2.23; 95% CI: 1.11 to 4.49; p = 0.03) compared with the CABG subgroup. However, the incidence of cardiac death (HR: 0.54; 95% CI: 0.19 to 1.56; p = 0.25), all-cause death (HR: 1.05; 95% CI: 0.51 to 2.14; p = 0.90) and MI (HR: 3.83; 95% CI: 0.31 to 47.02; p = 0.29) were not significantly different between the 2 subgroups (Table 5).
Subgroup analysis of the failed CTO-PCI group
Of 66 patients with failed CTO-PCI, 33 patients (50% of patients with failed CTO-PCI) were treated with medical therapy, 9 patients (13.6%) with CABG, and 24 patients (36.4%) with a reattempt at PCI. A total of 6 failed CTO-PCI patients (25% of the reattempted CTO-PCI patients) were successfully treated with reattempt PCI. Among 9 failed CTO-PCI patients treated with CABG, 4 patients emergently underwent CABG because of hypotension or sustained chest pain, and 5 patients electively underwent CABG several weeks later (Figure 3). In the failed CTO-PCI patients, 4 all-cause deaths (6.1% of failed CTO-PCI patients), 2 cardiac deaths (3.0%), and no MIs occurred during follow-up duration.
We investigated the long-term clinical outcomes of coronary revascularization versus medical therapy in patients with CTO and well-developed collateral circulation using a large dedicated registry. The primary finding of our study was that patients with CTO and well-developed collateral circulation who underwent revascularization had significantly lower risk of cardiac death, all-cause death, and MACE compared with those treated with medical therapy alone. Although this study was limited by its observational design, this is the first report specifically addressing the issue of revascularization and collateral circulation, and it evaluated the potential survival benefit related with the revascularization in those CTO patients.
Several studies have shown a survival benefit in patients with CTO who undergo successful PCI compared with those who undergo failed procedures, suggesting that survival depends on procedural success (17,18). However, these results are limited in their application, as it is difficult to predict the success of an intervention. In contrast to previous studies, we evaluated the clinical outcomes of overall treatment strategies (including medical therapy, CABG, successful PCI, or failed PCI, and so on) using an intent-to-treat analysis of a large, dedicated registry. Therefore, our results would be helpful when making a clinical decision in real-world practice.
Persistent myocardial ischemia despite abundant collateral circulation
Distal coronary collateral is frequently present in patients with CTO, with a catheterization-documented incidence of 80% to 90% (19). Hansen (20) reported that distal collateralization led to greatly improved survival and freedom from MI in patients with ischemic heart disease. Theoretically, well-developed collateral circulation may also improve survival and be a protector in patients with CTO. On the basis of this theoretical protective effect of distal collateral circulation in patients with ischemic heart disease, many clinicians recommend medical therapy alone in order to avoid procedural complications. However, this clinical decision is based on data generated from patients with stable nonocclusive coronary disease rather than on patients with CTO. Moreover, several published studies have reported a weak relationship between visualized collaterals and cardiac events (21,22). In addition, it has been reported that coronary steal, the phenomenon of decreased collateral flow due to microvascular dilation, causes poor myocardial oxygen supply through the collaterals and can gradually damage the myocardium (23). Therefore, even well-developed collateral circulation may not protect the myocardium. In our study, patients with CTO and abundant collateral circulation who underwent revascularization had significantly better outcomes compared with those treated with medical therapy alone. In line with previous studies, our findings suggest that the recovery of anterograde coronary artery flow, even in patients with CTO and abundant collateral circulation, may reduce myocardial ischemia and, thus, adverse cardiac events.
Protection of viable myocardium by collateral flow
Previous experimental and clinical data suggest that collateral blood flow protects the myocardium in patients with CTO. For example, our group reported that the transmural extent of myocardial injury and the presence of regional left ventricular dysfunction were inversely related to the degree of collaterals as determined by angiography (24). Similarly, Steg et al. (25) reported that well-developed collaterals may reduce transmural myocardial ischemia and allow the tissue to maintain a more viable myocardium if anterograde flow is severely reduced or absent. If abundant collateral flow maintains the viability of a larger amount of myocardial tissue, revascularization may allow for complete recovery of this myocardium and improve overall heart function, reduce ventricular remodeling, and prevent fatal arrhythmia (26,27).
Potential benefits of late patency of the infarct-related artery
Kim and Braunwald (28) suggested that late myocardial reperfusion confers several benefits, including recovered left ventricular function and improved survival resulting from myocardial salvage, which has given rise to what has been called the “open-artery hypothesis.” Erne et al. (29) also reported that, among patients with silent ischemia after MI, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. They reported that open infarct-related artery conferred improved healing of infarcted tissue, prevention of infarct expansion, and prevention of ventricular remodeling.
First, the design of this study was nonrandomized, retrospective, and observational, which may have significantly affected the results due to confounding factors. Second, because of the retrospective nature of our registry, we could not thoroughly identify the alteration of medical therapy in all study patients during follow-up duration. Third, the Rentrop classification of coronary collateral circulation only reflects collaterals visualized by angiography and may not reflect their functional capabilities or physiologic consequences. Fourth, our study population had a high prevalence of multivessel disease, and our results may not be generalizable to populations with less severe disease. Fifth, we did not routinely evaluate the amount of viable myocardium or ischemia of study patients using functional ischemia testing. Finally, the high rates of complete arterial graft and off-pump surgery or successful PCI seen in our hospital and the low rates of MI may have been affected by racial differences or underestimation, and this may limit the generalizability of our results.
In patients with CTO and well-developed collateral circulation, revascularization coupled with medical therapy significantly decreased the long-term risk of cardiac death, all-cause death, and MACE compared with treatment with medical therapy alone. Based on our results, revascularization may be recommended as an initial treatment in patients with CTO and well-developed collateral circulation. A large-scale randomized trial is needed to confirm these findings.
The authors have reported that they have no relationships relevant to the contents of this paper to disclose. Drs. Jang and Yang contributed equally to this work.
- Abbreviations and Acronyms
- coronary artery bypass grafting
- chronic total occlusion
- major adverse cardiac events
- myocardial infarction
- percutaneous coronary intervention
- Received September 2, 2014.
- Revision received October 10, 2014.
- Accepted October 24, 2014.
- American College of Cardiology Foundation
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