2016 Volume 80 Issue 1 Pages 211-217
Background: Limited data are available on the long-term clinical outcomes of coronary chronic total occlusion (CTO) patients who receive optimal medical therapy (OMT) compared with percutaneous coronary intervention (PCI).
Methods and Results: Between March 2003 and February 2012, 2,024 patients with CTO were enrolled in a single-center registry. Among this patient group, we excluded CTO patients who underwent coronary artery bypass grafting and classified patients into the OMT group (n=664) or PCI group (n=883) according to initial treatment strategy. Propensity-score matching was also performed. The primary outcome was cardiac death. The median follow-up duration was 45.8 (interquartile range: 22.8–71.1) months. In the PCI group, 699 patients (79.2%) underwent successful revascularization. In the propensity-score matched population (533 pairs), there was no significant difference in the rate of cardiac death between the OMT and PCI groups (hazard ratio, 1.57; 95% confidence interval, 0.91–2.72, P=0.11). In the subgroup analysis, there were no significant interactions between the PCI strategy and cardiac death among several subgroups except that regarding collateral flow grades 0–2 vs. those with grade 3 (P=0.01).
Conclusions: As an initial treatment strategy, PCI did not reduce cardiac death compared with OMT for the treatment of CTO in the drug-eluting stent era. (Circ J 2016; 80: 211–217)
The management of coronary chronic total occlusion (CTO) has remained a challenge despite the advent of wires, devices and imaging modalities.1 Although there have been numerous studies to determine the most appropriate treatment strategy, such as the retrograde approach, for CTO lesions, studies have focused on the association of successful recanalization with clinical outcome.2–5 Furthermore, 20–35% of CTO cases were not revascularized by percutaneous coronary intervention (PCI);6–8 in a substantial portion of cases, PCI is not attempted, and patients are treated with optimal medical therapy (OMT).5,9 Current guidelines recommend that PCI for CTO is reasonable (Class IIa) in patients with appropriate indications and suitable anatomy when performed by operators with appropriate expertise and can have >80% success rate.10,11 However, to date, no observational studies or randomized controlled trials have been performed in which CTO recanalization was compared with planned medical management in a head-to-head fashion. Therefore, we investigated the clinical outcomes of OMT in patients with CTO compared with those of PCI in the drug-eluting stent (DES) era.
The study population was selected from the Samsung Medical Center CTO registry. Between March 2003 and February 2012, 2024 consecutive patients with CTO were enrolled in a single-center registry. Clinical, laboratory, and outcome data were collected by a trained study coordinator using a standardized case report form and protocol. If necessary, additional information was documented by contacting the principal investigators and/or by review of hospital records. The Institutional Review Board at Samsung Medical Center approved the study protocol and waived the requirement for informed consent.
Inclusion criteria for the present analysis were: (1) consecutive patients ≥18 years of age, (2) one or more CTO lesions detected on diagnostic coronary angiography, and (3) symptomatic angina and/or a positive functional ischemia study. Exclusion criteria were: (1) previous history of coronary artery bypass graft (CABG), (2) cardiogenic shock or cardiopulmonary resuscitation as initial presentation, and (3) ST-segment elevation myocardial infarction (MI) during the preceding 48 h. Among the patients registered, 1,547 were finally included in this analysis. The patient flow of the study is shown in Figure 1. Subjects were classified into the OMT group or PCI group according to initial treatment strategy.
Scheme of group distribution in the registry. CABG, coronary artery bypass grafting; CTO, chronic total occlusion; PCI, percutaneous coronary intervention.
OMT included antiplatelet medication, β-blocker, renin-angiotensin system blockade, nitrates, calcium-channel blocker, and aggressive lipid-lowering therapy. The medication regimens of all patients were considered optimal, with doses as allowed by heart rate, blood pressure, and symptoms in the absence of justifiable relative contraindications. Coronary interventions were performed using a standard technique. All patients received a 300-mg loading dose of aspirin and a 300–600-mg loading dose of clopidogrel before the coronary intervention unless they had previously received these antiplatelet medications. Decision to perform bilateral injection and a retrograde approach, in addition to the type of wire, microcatheter, and use of intravascular ultrasound and glycoprotein IIb/IIIa receptor inhibitor, were all left to physician discretion. DES were used without restriction and the duration of dual antiplatelet therapy was determined by the treating physician.
Definitions and OutcomesA CTO lesion was defined as an obstruction of a native coronary artery with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0 for an estimated duration >3 months, based on the interval from the last episode of acute coronary syndrome or, in patients with no history of acute coronary syndrome, from the first episode of effort angina consistent with the location of the occlusion or previous coronary angiography.8,12,13 Successful revascularization was defined as final residual stenosis <20% and TIMI grade ≥2 flow after DES implantation, as assessed by visual estimation of the angiograms.8 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.14 All deaths were considered to be of cardiac cause unless a definite noncardiac cause could be established.15 MI was defined as recurrent symptoms with new ECG changes compatible with MI or cardiac marker level at least twice the upper limit of normal.16–18 Repeat revascularization was a composite of target vessel revascularization and non-target vessel revascularization treated with PCI or CABG.19 The primary outcome was cardiac death during follow-up. Secondary outcomes included all-cause death, MI, repeat revascularization, or major adverse cardiac event, defined as a composite of cardiac death, recurrent MI, and any revascularization with PCI or CABG during follow-up.
Statistical AnalysisComparisons for continuous variables were made using the t-test or Wilcoxon rank-sum test when applicable. Categorical data were tested using the Chi-square test. Survival curves were constructed using Kaplan-Meier estimates and compared with the log-rank test. The Cox proportional hazard model was used to compare the risks of adverse cardiac events between the OMT and PCI groups. Propensity scores were estimated using multiple logistic-regression analysis. Full nonparsimonious models were developed and included all variables shown in Tables 1,2. Cox regression analysis using pairs matched by a greedy algorithm and the nearest available pair-matching method among patients with an individual propensity score was also performed to evaluate the reduction in outcome risk. The covariate balance achieved by matching was assessed by calculating the absolute standardized differences in covariates between the 2 groups. An absolute standardized difference <10.0% for the measured covariate suggests appropriate balance between the groups. In the propensity score-matched population, continuous variables were compared with a paired t-test or the Wilcoxon signed-rank test, as appropriate, and categorical variables were compared with the McNemar’s or Bowker’s test of symmetry, as appropriate. The reduction in outcome risk was compared with the stratified Cox regression model using prognostic covariates with an absolute standardized difference >10.0% being considered candidate variables for inclusion in the multivariate models because the combination of regression adjustment in matched samples generally produces the least biased estimate.20 Cumulative incidence rates of individual clinical outcomes and composite outcomes were estimated by the Kaplan-Meier method and compared by the paired Prentice-Wilcoxon test. Statistical analyses were performed with SAS 9.2 (SAS Institute Inc, Cary, NC, USA). All tests were 2-tailed, and P<0.05 was considered statistically significant.
| Total population | Propensity-matched population | |||||||
|---|---|---|---|---|---|---|---|---|
| Medical therapy (n=664) |
PCI (n=883) |
P value | Standardized difference |
Medical therapy (n=533) |
PCI (n=533) |
P value | Standardized difference |
|
| Age, years | 65.9±11.3 | 61.5±10.8 | <0.001 | −40.8 | 64.5±11.4 | 63.5±10.3 | 0.08 | −9.6 |
| Sex (male) | 509 (76.7) | 713 (80.7) | 0.05 | 10.4 | 419 (78.6) | 425 (79.7) | 0.71 | 2.9 |
| Medical history | ||||||||
| Diabetes mellitus | 318 (47.9) | 384 (43.5) | 0.09 | −8.9 | 242 (45.4) | 252 (47.3) | 0.59 | 3.8 |
| Hypertension | 439 (66.1) | 547 (61.9) | 0.09 | −8.6 | 350 (65.7) | 348 (65.3) | 0.95 | −0.8 |
| Dyslipidemia | 158 (23.8) | 289 (32.7) | <0.001 | 19.0 | 139 (26.1) | 143 (26.8) | 0.78 | 4.4 |
| Smoking | 182 (27.4) | 285 (32.3) | 0.04 | 10.4 | 156 (29.3) | 168 (31.5) | 0.45 | 4.8 |
| Chronic kidney disease |
61 (9.2) | 68 (7.7) | 0.30 | −5.6 | 47 (8.8) | 46 (8.6) | 0.99 | −0.7 |
| Family history of CAD |
73 (11.0) | 135 (15.3) | 0.01 | 11.9 | 63 (11.8) | 71 (13.3) | 0.52 | 4.2 |
| Previous history of MI |
211 (31.8) | 180 (20.4) | <0.001 | −28.3 | 144 (27.0) | 146 (27.4) | 0.95 | 0.9 |
| Previous history of PCI |
208 (31.3) | 178 (20.2) | <0.001 | −27.8 | 142 (26.6) | 142 (26.6) | NA | 0 |
| Previous CVA | 67 (10.1) | 66 (7.5) | 0.07 | −9.9 | 45 (8.4) | 47 (8.8) | 0.91 | 1.4 |
| Peripheral artery disease |
40 (6.0) | 23 (2.6) | 0.001 | −21.5 | 24 (4.5) | 20 (3.8) | 0.62 | 4.7 |
| Left ventricular ejection fraction |
53.6±12.9 | 57.6±11.3 | <0.001 | 35.7 | 55.7±11.7 | 55.6±11.9 | 0.88 | −0.9 |
| Non-ST-segment elevation ACS |
98 (14.8) | 215 (24.3) | <0.001 | 22.3 | 92 (17.3) | 97 (18.2) | 0.75 | 2.2 |
| Multivessel disease | 517 (77.9) | 595 (67.4) | <0.001 | −22.3 | 399 (74.9) | 392 (73.5) | 0.67 | −2.8 |
| CTO vessel | ||||||||
| LAD | 168 (25.3) | 373 (42.2) | <0.001 | 34.3 | 146 (27.4) | 152 (28.5) | 0.71 | 2.3 |
| LCX | 228 (34.3) | 261 (29.6) | 0.05 | −10.5 | 174 (32.6) | 170 (31.9) | 0.84 | −1.6 |
| RCA | 370 (55.7) | 383 (43.4) | <0.001 | −24.9 | 293 (55.0) | 288 (54.0) | 0.81 | −1.9 |
| Multi-CTO | 94 (14.2) | 131 (14.8) | 0.71 | 1.9 | 75 (14.1) | 74 (13.9) | NA | −0.5 |
| Blunt stump | 335 (50.5) | 385 (43.6) | 0.01 | −13.8 | 257 (48.2) | 262 (49.2) | 0.80 | 1.9 |
| Bridging collateral | 236 (35.5) | 265 (30.0) | 0.02 | −12.1 | 180 (33.8) | 179 (33.6) | NA | −0.4 |
| Calcification | 116 (17.5) | 140 (15.5) | 0.40 | −4.4 | 93 (17.4) | 95 (17.8) | 0.94 | 1.0 |
| Collateral flow | 0.46 | 0.98 | ||||||
| 0 | 21 (3.2) | 19 (2.2) | −7.0 | 14 (2.6) | 13 (2.4) | −1.3 | ||
| 1 | 138 (20.8) | 168 (19.0) | −4.5 | 116 (21.8) | 108 (20.3) | −3.8 | ||
| 2 | 269 (40.5) | 364 (41.2) | 208 (39.0) | 214 (40.2) | ||||
| 3 | 236 (35.5) | 332 (37.6) | 4.2 | 195 (36.6) | 198 (37.1) | 1.2 | ||
| Proximal or mid, CTO location |
424 (63.9) | 643 (72.8) | <0.001 | 20.3 | 354 (66.4) | 348 (65.3) | 0.74 | 2.0 |
| SYNTAX score | 19.8±9.7 | 19.6±8.8 | 0.65 | −2.4 | 19.3±9.2 | 19.1±9.3 | 0.74 | −2.0 |
Values are mean±standard deviation and median with interquartile range or n (%). ACS, acute coronary syndrome; CAD, coronary artery disease; CVA, cerebrovascular accident; MI, myocardial infarction; NA, not applicable; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.
| Total population (n=1,547) | OMT group (n=664) |
PCI group (n=883) |
Unadjusted HR (95% CI) |
P value |
|---|---|---|---|---|
| All-cause death | 142 (21.4) | 75 (8.5) | 2.64 (2.00–3.49) | <0.001 |
| Cardiac death | 66 (9.9) | 37 (4.2) | 2.48 (1.66–3.71) | <0.001 |
| MI | 12 (1.8) | 11 (1.2) | 1.50 (0.66–3.41) | 0.33 |
| Cardiac death or MI | 45 (8.4) | 32 (6.0) | 2.33 (1.58–3.45) | <0.001 |
| Any coronary revascularization | 109 (16.4) | 105 (11.9) | 1.50 (1.15–1.96) | 0.003 |
| Major adverse cardiac events* | 170 (25.6) | 141 (16.0) | 1.74 (1.39–2.18) | <0.001 |
Values are n (%). *Major adverse cardiac events included cardiac death, recurrent MI, and any revascularization with PCI or coronary artery bypass graft. CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.
Among the 2,024 registered patients, 477 patients who underwent CABG were excluded. The remaining patients were classified into the OMT group (n=664) or the PCI group (n=883) according to initial treatment strategy. In the PCI group, 699 patients (79.2%) underwent successful revascularization. Baseline clinical and angiographic characteristics are shown in Table 1. Compared with patients in the PCI group, those in the OMT group had a higher prevalence of old age, previous history of MI and PCI, peripheral artery disease, low left ventricular ejection fraction, multivessel disease, right coronary artery with CTO, blunt stump, and bridging collateral, but a lower prevalence of dyslipidemia, smoking, family history of coronary artery disease, presentation of acute coronary syndrome, and proximal or mid-portion CTO location. After performing propensity-score matching for the entire population, a total of 533 matched patient pairs were created (Table 1). The c-statistic for the propensity score model was 0.73. There were no significant differences in the baseline clinical or angiographic characteristics of the OMT and PCI groups for the propensity-matched subjects. The medications at discharge are listed in Table S1.
Stress tests such as treadmill test, stress echocardiography, stress single-photon emission computed tomography, computed tomography myocardial perfusion imaging, and stress cardiac magnetic resonance were performed in 693 patients. Of these, 497 patients showed a positive functional ischemia test.
Clinical OutcomesOf 184 patients in the failed PCI group, reduction of collateral flow occurred in 14 patients (7.6%), coronary artery dissection in 6 patients (3.3%), and coronary artery perforation in 3 patients (1.6%). The median follow-up duration was 45.8 (interquartile range: 22.8–71.1) months. Table 2 shows the cumulative clinical outcomes of the study groups. Cox regression analysis showed that, compared with the PCI group, the OMT strategy was associated with a higher incidence of cardiac death (OMT vs. PCI: 9.9% vs. 4.2%, unadjusted hazard ratio [HR] 2.48, 95% confidence interval [CI] 1.66–3.71, P<0.001), while OMT and PCI groups had comparable incidences of MI (1.8% vs. 1.2%, unadjusted HR 1.50, 95% CI 0.66–3.41, P=0.33). After 1:1 propensity-score matching, cardiac death during follow-up was not significantly different in the OMT and PCI groups (8.3% vs. 5.8%, HR 1.57, 95% CI 0.91–2.72, P=0.11) (Figure 2, Table 3).
Kaplan-Meier curves in the OMT (red line) vs. PCI groups (blue line) in propensity-matched populations. OMT, optimal medical therapy; PCI, percutaneous coronary intervention.
| Propensity-matched population (n=1,066) |
Medical therapy (n=533) |
PCI (n=533) |
HR (95% CI) |
P value |
|---|---|---|---|---|
| All-cause death | 98 (18.4) | 62 (11.6) | 1.87 (1.27–2.76) | 0.002 |
| Cardiac death | 44 (8.3) | 31 (5.8) | 1.57 (0.91–2.72) | 0.11 |
| MI | 8 (1.5) | 7 (1.3) | 1.75 (0.51–5.98) | 0.37 |
| Cardiac death or MI | 45 (8.4) | 32 (6.0) | 1.62 (0.94–2.79) | 0.08 |
| Any coronary revascularization | 92 (17.3) | 67 (12.6) | 1.19 (0.81–1.76) | 0.38 |
| Major adverse cardiac events* | 133 (25.0) | 96 (18.0) | 1.29 (0.93–1.78) | 0.12 |
Values are n (%). *Major adverse cardiac events included cardiac death, recurrent MI, and any revascularization with PCI or coronary artery bypass graft. Abbreviations as in Tables 1,2.
To determine whether the outcomes according to PCI strategy (vs. OMT) observed in the overall population were consistent, we calculated the unadjusted HR for cardiac death in various complex subgroups (Figure 3). Compared with the OMT group, a better clinical outcome for the PCI strategy in terms of cardiac death was observed in patients with collateral flow grade 3 or left ventricular ejection fraction <40%. In contrast to other subgroups with no significant interactions between the PCI strategy and cardiac death, there was a significant interaction between the PCI strategy and cardiac death among the subgroup regarding collateral flow grades 0–2 vs. those with grade 3 (P=0.01).
Comparative unadjusted hazard ratios of cardiac death for subgroups in propensity-matched populations of the OMT and PCI groups. CI, confidence interval; CTO, chronic total occlusion; LAD, left anterior descending artery; LVEF, left ventricular ejection fraction; OMT, optimal medical therapy; PCI, percutaneous coronary intervention.
In the present study, we investigated the clinical outcomes of an OMT strategy in patients with CTO compared with PCI strategy in the DES era. The major findings of this study were as follows: (1) as an initial treatment strategy, PCI had a success rate of 79.2% but did not reduce cardiac death compared with OMT during the follow-up period in a propensity-matched population, (2) even though the primary outcome was comparable between PCI and OMT as an initial treatment strategy, the rate of cardiac death was significantly lower in the PCI group among CTO patients with well-developed collateral flow as identified on subgroup analysis.
The optimal management strategy of CTO has not been fully elucidated despite the advent of revascularization technology and imaging modalities. To date, there are no prospective randomized studies studying the efficacy of OMT on clinical outcome in CTO patients compared with attempted PCI as the initial management strategy, despite a substantial portion of CTO patients being unsuitable for PCI because of blunt stump, heavy calcification, tortuosity, or long occlusion length with low probability for success.21 Moreover, previous studies focused on the association of successful CTO revascularization with clinical outcome compared with failed PCI among patients who underwent PCI.2–5,22 Therefore, we investigated the clinical outcomes of the OMT strategy in patients with CTO compared with those receiving a PCI strategy in the DES era.
In the previous randomized Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) and the Medicine, Angioplasty, or Surgery Study (MASS II) trials conducted in patients with stable coronary artery disease, OMT was not inferior to PCI as an initial strategy.23,24 Similarly, our study showed that, as an initial treatment strategy, PCI did not reduce the primary outcome compared with OMT alone during the follow-up period in a propensity-matched population. A substantial portion of our cohort had stable coronary disease and multivessel disease, and similar populations were also included in the COURAGE and MASS II trials. Accordingly, these findings suggest that the additive benefit of PCI in combination with OMT may not be significant in the setting of stable coronary disease.
A recent meta-analysis of 23 observational studies comparing successful vs. failed PCI for CTO demonstrated that successful PCI recanalization of a CTO appears to be associated with improved long-term clinical outcome compared with a failed intervention.22 To date, most observational studies in which successful CTO recanalization was compared with failed CTO-PCI in a head-to-head fashion did not include patients managed medically without a CTO-PCI attempt. Accordingly, the strengths of our study may reflect the purely clinical significance of PCI as a planned treatment strategy by comparison with medical management alone for the treatment of CTO.
Subgroup analysis regarding the burden of ischemia, such as CTO location and Syntax score, showed comparable results between the PCI and OMT groups; however, the rate of cardiac death was significantly lower in the PCI group than in the OMT group in CTO patients with well-developed collateral flow. Previous studies reported that patients with well-developed collateral flow have less extensive transmural myocardial injury and more viable myocardium.25,26 In addition, another study demonstrated impairment of endothelial and smooth muscle cell functions in the coronary segment distal to the CTO with low-grade collateral circulation.27 We suspect that recanalization of a CTO with abundant collaterals may reduce ventricular remodeling and the predisposition to ventricular arrhythmia that leads to sudden cardiac death by improving myocardium viability, endothelial cell function or ischemic burden in the territory supplied by the CTO. Accordingly, an aggressive recanalization strategy should be considered in patients with well-developed collateral flow.
Study LimitationsFirst, the nonrandomized nature of the registry data could have resulted in selection bias. The selection of treatment strategy was influenced by patient characteristics and by patient and doctor preferences. In particular, older patients with more complex lesions, such as those with a moderately or severely calcified lesion, blunt stump, bridging collateral flow and 2 or more vessel diseases, preferred medical treatment to PCI. In addition, we did not have information on comorbidities such as cancer or chronic obstructive pulmonary disease. Although we performed propensity score-matched analysis to adjust for potential confounding factors, the propensity score-matched analysis not only does not correct for unmeasured variables and also does not overcome initial selection bias. Accordingly, 2 ongoing randomized controlled trials, DECISION CTO (Drug-Eluting stent Implantation Versus Optimal Medical Treatment in Patients with Chronic Total Occlusions) and EURO-CTO (European study on the Utilization of Revascularization vs. Optimal Medical Therapy for the treatment of Chronic Total Coronary Occlusions) comparing OMT with a strategy of attempted CTO recanalization may confirm the findings of the present study. Second, we have no information on accurate documentation of the viability or ischemic burden in the territory supplied by the CTO and compliance with medical therapy over time. Third, we did not determine functional performance or quality of life pre- or post-procedure in the patients with CTO.
As an initial treatment strategy, PCI with a success rate of approximately 80% in real-world practice did not reduce cardiac death compared with OMT. Randomized controlled trials comparing OMT with a strategy of attempted CTO recanalization may confirm the findings of the present study.
None.
Supplementary File 1
Table S1. Medications at discharge of patients with coronary chronic total occlusion and OMT or PCI as initial strategy
Please find supplementary file(s);
http://dx.doi.org/10.1253/circj.CJ-15-0673
