Eur J Cardiothorac Surg 2008;33:4-8. doi:10.1016/j.ejcts.2007.09.029
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Revascularization strategy in patients with multivessel disease and a major vessel chronically occluded; data from the CABRI trial
Eugenio Martuscellia,*,
Fabrizio Clementia,
Mark M. Gallaghera,
Alessia D’Eliseoa,
Gaetano Chiricoloa,
Antonio Nigrib,
Benedetto Marinob,
Francesco Romeoa, on behalf of CABRI trialists
a Department of Cardiology, University of Rome "Tor Vergata", Italy
b Department of Cardiac Surgery, University of Rome "La Sapienza", Italy
Received 30 May 2007;
received in revised form 21 August 2007;
accepted 27 September 2007.
* Corresponding author. Address: University of Rome "Tor Vergata", Department of Cardiology, Viale Oxford 81, 00133 Rome, Italy. Tel.: +39 0620903996; fax: +39 0620904043. (Email: e.martuscelli{at}libero.it).
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Abstract
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Objective: In patients with multivessel coronary artery disease and total occlusion of major epicardial vessel, completeness of revascularization has not been investigated in specific trials comparing the surgical and the percutaneous revascularization strategy. Analyzing the database of the CABRI study, which randomized a substantial number of these patients, we investigated the long-term effects of a successful or unsuccessful revascularization of the occluded vessel and completeness of the revascularization. Methods and results: The CABRI study randomized 1054 patients with multivessel coronary disease to coronary bypass or to coronary angioplasty. From the database of this trial, we selected patients with a major vessel chronically occluded (103 in the bypass group and 120 in the angioplasty group). At a median follow-up of 30 months, the incidence of death or Q-wave myocardial infarction (combined end point) was significantly lower in the bypass group than in the angioplasty group (6.8% vs 17.5%, respectively; hazard ratio [HR], 0.42 [95% CI 0.17–0.98]; p
= 0.047). On univariate analysis, age, proximal occlusion, complete revascularization, revascularization of the occluded vessel and revascularization procedure were identified as significant predictors of combined end points. On multivariate analysis, independent predictors of combined end points resulted in completeness of revascularization (HR 0.26; 95% CI 0.09–0.76; p
= 0.01) and age (HR 1.07; 95% CI 1.02–1.12; p
< 0.01). Conclusion: In patients with multivessel coronary disease and chronic occlusion of a major epicardial vessel, achieving of a complete revascularization by reopening or bypassing the occluded vessel is associated with a significantly better long-term prognosis.
Key Words: Incomplete revascularization • Percutaneous coronary angioplasty • Coronary artery bypass • Chronic coronary occlusion
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1. Introduction
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Patients with a chronic occlusion of a major epicardial vessel and significant narrowing of one or both of the other coronary arteries represent a special problem in the choice of revascularization strategy. Until recently, coronary artery bypass grafting (CABG) was considered to be the treatment of choice in such patients as it provided complete revascularization more frequently than percutaneous transluminal coronary angioplasty (PTCA) [1]. With current techniques and equipment, the probability of reopening a chronic total occlusion by PTCA has increased substantially [2]. Many interventional cardiologists now choose to deal with such patients by PTCA, believing that the long-term clinical outcome is similar to that of surgery in terms of survival and acute myocardial infarction (AMI) occurrence. They draw support from randomized trials comparing surgery and coronary angioplasty in patients with multivessel coronary disease [3–8] though none of these trials were designed to address this question. Several randomized trials have compared the outcome of CABG and PTCA in multivessel coronary artery disease, but none of these specifically addressed the importance of a totally occluded major epicardial artery. Equivalence of revascularization was mandatory in some trials [3–6], effectively excluding patients with a chronic total occlusion who were considered too difficult to revascularize by PTCA in that era. In other trials the entry criteria did not exclude patients with a chronically occluded vessel [7], but such patients were recruited in numbers too few to analyze as a separate subgroup.
In the CABRI trial, 1054 patients with symptomatic multivessel coronary disease were randomized to PTCA or CABG [8]. The CABRI trial did not require equivalence of revascularization for study enrolment. Patients with a chronically occluded major vessel were considered eligible if at least one lesion in another vessel was considered to be amenable to PTCA. The CABRI cohort therefore included a substantial population of patients whose multivessel coronary disease included a chronic total occlusion of a major epicardial vessel.
From the database of the CABRI study, we selected all patients with chronic occlusion of a major coronary vessel with the aim of determining whether the success of revascularization in the territory of this vessel would influence the long-term outcome regardless of the revascularization strategy.
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2. Methods
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2.1 Study population and data collection
The CABRI trial [8] enrolled 1054 patients in 26 centers throughout Europe over 53 months from July 1988. All patients undergoing coronary angiography who needed revascularization were evaluated for eligibility. Patients with single vessel coronary disease were excluded, as were those with left main coronary disease or severe triple vessel disease (defined as ‘last remaining vessel’, equivalent to two occluded main epicardial vessel), ejection fraction <0.35, overt cardiac failure, an acute myocardial infarction within the previous 10 days, or previous revascularization procedure. Patients with severe concomitant cardiac or non-cardiac illness likely to affect short-term survival were also excluded. Lesions suitable for PTCA could include total and subtotal occlusions.
At the time of the CABRI trial, PTCA implied balloon angioplasty alone in most cases, with stent implantation used as a back up in case of difficulties. Cardiac surgery was carried out usually on cardiopulmonary bypass and inclusion in the trial did not impose on the surgeon any restriction in the use of arterial or venous conduits. Only those patients for whom both cardiologists and surgeons believed could achieve clinical improvement by PTCA or CABG were randomized.
Of the patients recruited on the basis of these criteria, 541 were randomly assigned to PTCA and 513 to CABG. Annual clinical assessment for 10 years was planned and follow-up cardiac catheterization was planned as a single event 12 months after randomization. The two strategies of revascularization were compared on the basis of intention to treat, having as primary outcome mortality and symptom status at 1 year. Secondary outcomes were myocardial infarction, requirement for medications and repeat revascularization procedures.
From the CABRI database we selected all patients with chronic occlusion of one of the three major coronary vessels (left anterior descending artery, circumflex artery or right coronary artery). Of the 223 persons meeting these criteria, 121 were initially randomized to PTCA and 102 to CABG.
2.2 Baseline clinical variables
At the time of enrollment and at 1 year follow-up, clinical symptom status was assessed in terms of angina graded according to the Canadian Cardiovascular Society class, and dyspnea graded according to the New York Heart Association class. Left ventricular function was assessed by ventriculography. A history of hypercholesterolemia (total cholesterol of 
6.5 mmol/l and/or lipid lowering treatment) systemic hypertension (blood pressure 160/90 mmHg and/or hypertensive treatment), cerebrovascular disease or peripheral vascular disease was recorded. Myocardial infarction was defined by the presence of a clinical history of myocardial infarction and/or the presence of abnormal Q-waves on the 12-lead electrocardiogram.
2.3 Coronary disease variables
The angiographic criteria for trial suitability required a >50% reduction of luminal diameter viewed from two projections in two or more major epicardial vessels. At least one lesion had to be suitable for PTCA and the vessel distal to the lesion had to be at least 2 mm in diameter. Patients with chronic total occlusion were admitted if at least one lesion on another major vessel was suitable for PTCA. For the purposes of analysis, multivessel disease was defined as two or three native vessels with significant disease excluding the left main coronary artery.
2.4 Completeness of revascularization
Before randomization, cardiologists and surgeons identified target vessels, suitable for revascularization by PTCA or CABG. In patients randomized to PTCA, revascularization was considered complete if, in the target vessels, every lesion >50% could be dilated successfully (final diameter reduction <50%). In patients randomized to CABG, revascularization was considered complete if every target vessel received a venous or an arterial conduit.
2.5 Study objectives and statistical methods
The primary aim of our analysis was to compare estimated hazard ratio for the composite endpoint of death or Q-wave myocardial infarction during a median period of 30 months of follow-up after revascularization. Using SPSS 13 software (SPSS Inc., Chicago, Illinois), independent variables were cross tabulated by treatment randomization to check comparability of treatment groups. Associations were tested for using unpaired t tests for continuous data with a normal distribution, Mann–Whitney U-test for continuous data not normally distributed and 
2 tests for categorical data. Event-free survival from death or Q-wave myocardial infarction was estimated by the Kaplan–Meier method, and differences in the two treatment groups were assessed by means of the log-rank test. Analysis of predictors of 50 months death or Q-wave myocardial infarction was performed with Cox proportional hazards regression with stepwise selection and entry criteria of p
= 0.05 and exit criteria of p
= 0.1. The proportional hazard assumption was confirmed. Patients lost to follow-up were considered at risk until the date of last contact, at which point they were censored. Bivariate correlation coefficients between variables were also computed to identify colinearity. When the correlation coefficient between two variables was >0.6, only 1 was selected in the final model. The selection was based on the results of the univariate analysis and taking into account the significance level. The variables considered as possible predictors included: occluded vessel, occluded vessel revascularization, proximal median or distal occlusion, occluded vessel, left-ventricular ejection fraction, treatment group (PTCA/CABG), diabetes, previous AMI, angina class, ejection fraction, active smoker, hypercholesterolemia, hypertension, peripheral vascular disease and previous cerebro-vascular accident. Only variables with an association <0.1 in the univariate model were considered for multivariate analysis. All analyses were based on the intention-to-treat principle. All tests of significance were two sided. A probability value <0.05 was considered significant.
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3. Results
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Patients randomized to PTCA and CABG were closely matched for clinical and angiographic characteristics (Table 1
). Mean follow-up was 30.7 and 28.1 months for PTCA and CABG, respectively. Death occurred in 12.5% (n
= 15) of the PTCA group compared with 4.9% (n
= 5) of the CABG group (p
= ns) (Table 2
). The mortality for the entire population of the CABRI study has been reported to be, in the 4 year follow-up, 10.9% in PTCA patients and 7.4% in CABG patients (p
= ns) [9]. Non-fatal Q-wave myocardial infarction occurred in 6.7% (n
= 8) of the PTCA group and in 2.9% (n
= 3) of the CABG group (p
= ns). The incidence of the composite endpoint of death or Q-wave myocardial infarction was significantly lower in the CABG group than in the PTCA group (6.8% vs 17.5%, respectively; hazard ratio [HR], 0.42 [95% CI 0.17–0.98]; p
= 0.047) (Table 2, Fig. 1
).
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Fig. 1. Event-free survival from death and Q-wave myocardial infarction at 50 months of follow-up estimated by the Kaplan–Meier method in patients submitted to CABG (dotted lines) or PTCA (solid lines).
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Of the patients initially randomized to PTCA, 46.7% (n
= 56) required a second revascularization and 10% (n
= 12) a third revascularization; the cross over to surgery was 30.8% (n
= 37) (Table 2). A successful dilatation of the totally occluded vessel occurred in 11.7% of the patients in PTCA group; whereas the occlusion was successfully bypassed in 76.5% of the patients revascularized by CABG (OR 26.3; 95% CI 12.7–54.3; p
< 0.001) (Table 2). A complete revascularization was achieved in 7.5% of the patients randomized to PTCA versus 72.8% of the patients randomized to CABG (OR 33.0; 95% CI 14.7–73.9; p
< 0.001) (Table 2). On univariate analysis, age, proximal occlusion, complete revascularization, revascularization of the occluded vessel and revascularization procedure were identified as significant predictors of the composite end points (Table 3
, Figs. 1–3
). On multivariate analysis, the only independent predictors of combined events were completeness of revascularization and patient age (Table 3).
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Fig. 2. Event-free survival from death and Q-wave myocardial infarction at 50 months follow-up estimated by the Kaplan–Meier method, in patients with successful (solid lines) or unsuccessful (dotted lines) revascularization of the vessel occluded.
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Fig. 3. Event-free survival from death and Q-wave myocardial infarction at 50 months follow-up estimated by the Kaplan–Meier method, in patients with complete (solid lines) or incomplete revascularization (dotted lines).
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4. Discussion
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The revascularization of patients with multiple vessel disease including the chronic occlusion of a major vessel has not been specifically addressed in a randomized trial. Our analysis of this subgroup of patients in the CABRI trial indicates that at the time of that trial, surgery gave a better outcome in these patients in terms of subsequent mortality and risk of AMI. The superiority of CABG over PTCA was attributable to a greater probability of complete revascularization when surgery was used. Multiple surgical series have clearly shown that completeness of revascularization is associated with better long-term results in terms of mortality and risk of AMI [10,11].
In the case of PTCA, there are conflicting data regarding the importance of completeness of revascularization. Bourassa et al., using data from the National Heart, Lung, and Blood Institute percutaneous Transluminal Coronary Angioplasty Registry, showed that the adjusted risk of mortality at 9 years was independent of the completeness of revascularization. Patients with incomplete revascularization by PTCA were more likely to subsequently undergo CABG (32 vs 14%, p
< 0.001) [12]. Similar results were found in the Arterial Revascularization Study (ARTS) trial [13]. More recently, Hannan et al. compared the long-term outcome of 21,925 patients revascularized by PTCA [14]. Patients with incomplete revascularization had a significantly higher mortality and the worst rate of survival was found in patients with a major epicardial coronary artery totally occluded.
These results are in agreement with results obtained by Ivanhoe et al. [15], Suero et al. [16], Olivari et al. [17]. They showed that a revascularization procedure, which includes the successful opening of the occluded vessel, is associated with a better outcome in terms of survival and AMI occurrence. A possible explanation of this is that a PTCA that treats one or two vessels but leaves another vessel occluded exposes the patient to dramatic consequences if the treated vessel occludes suddenly. In a study by Puma et al. [18], 2216 patients with chronic occlusion of a single vessel were followed to determine the natural history of this condition. Freedom from death and AMI was low at 3 years (87%) and very low at 15 years (52%); the authors concluded that the mortality rate in this population might still be considered to be excessive in the long term, suggesting that the occluded vessel might exert a deleterious effect beyond what would be expected.
Our study addresses the question of the best option in the revascularization strategy of patients with multivessel coronary disease involving the total occlusion of a major vessel, a subgroup commonly encountered in clinical practice but poorly represented in the randomized trials. Our data clearly show that completeness of revascularization is the only independent predictor of the combined end point of mortality and AMI (HR 0.26; 95% CI 0.09–0.76); a complete revascularization was obtained in our study much more frequently in the surgical group than in the PTCA group, principally due to the frequent failure of PTCA in the revascularization of the occluded vessel.
Successful opening of a chronically occluded coronary vessel is still a challenge in the patient with multiple vessel disease. The rate of procedural success in the 1990s was between 46% and 75% depending on the number of vessels diseased and on the location of the occlusion, with the worst results obtained in patients with triple vessel disease and occlusion of the right coronary artery [15]. More recent advances including the use of special dedicated guidewires have substantially increased the procedural success [2], but the real cost benefit of such procedures in large series or randomized trials is unknown.
In our study, coronary stenting was used as a back up procedure in patients with poor immediate angiographic results or in case of acute post procedural vessel closure. This can be considered a limitation of our study.
In the years since the study, techniques of percutaneous intervention have evolved with a great expansion in the use of stents, and recently with the introduction of drug eluting stents. In spite of the limited techniques available at the time, the composite end point of death or AMI in the overall CABRI population was not influenced by the revascularization strategy, showing that percutaneous revascularization by traditional methods can be as effective as the surgery in multivessel disease without total occlusion.
This is confirmed by the 5 year follow-up of the BENESTENT trial [19] which showed that mortality and AMI occurrence were similar (p
= ns) in patients revascularized by balloon PTCA or stent PTCA.
A recent meta-analysis comparing bare and drug eluting stents [20] has further confirmed that new endocoronary devices can substantially reduce the need for a subsequent revascularization without any significant modification of the composite end points as mortality and AMI.
Data regarding the viability of the myocardium in the territory of the occluded vessel were not available; and this can be considered another limitation of the study; therefore it was impossible to assess the long-term effects of the revascularization depending on the presence of viable myocardium. Patients with a chronically occluded major artery were admitted to randomization if at least one lesion was suitable for PTCA and, above all, if cardiologists and surgeons believed that they could achieve clinical improvement by PTCA or CABG.
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5. Conclusions
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Our study shows that in patients with multivessel coronary disease including the chronic occlusion of a major epicardial vessel, surgery can offer a higher probability of full revascularization and a higher probability of remaining alive and free of AMI in the long term. If a percutaneous revascularization strategy is attempted, every effort must be made to reopen the occluded vessel and obtain complete revascularization. If this proves impossible, a surgical approach should be reconsidered.
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Abstract
1. Introduction
