EVIDENCE BASED STRATEGY OF CORONARY REVASCULARIZATION:
THE ANSWER TO THE PARADIGM SHIFT IN THE TREATMENT OF CHRONIC CORONARY ARTERY DISEASE

Yukihiro Kaneko, MD, PhD; Werner Mohl, MD, PhD
Department of Cardiothoracic Surgery, University of Vienna
Vienna, Austria

The choice of treatment strategy from medical therapy, percutaneous transluminal coronary angioplasty (PTCA), and coronary artery bypass grafting (CABG) greatly influences outcome of patients with chronic coronary artery disease. Recent randomized trials and registries provide information as to the judgment of optimal treatment strategy. These studies have shown that best outcome is likely when 1- or 2- vessel disease without proximal left anterior descending artery (LAD) stenosis is treated medically. 2-vessel disease with proximal LAD stenosis or 3-vessel disease without proximal LAD stenosis is treated by PTCA or CABG. 3-vessel disease with proximal LAD stenosis or left main coronary stenosis is treated by CABG. CABG is preferred to PTCA in diabetic patients and patients with decreased left ventricular function. Recent advances in the treatment of coronary artery disease are also reviewed as they influence current treatment strategy. (Heart Views. 2000;1(9): 345-353). ©2000 Hamad Medical Corporation.

Coronary artery disease (CAD) is the leading cause of death in develope
countries. Revascularization of stenotic coronary artery greatly contributes to the treatment of CAD. Currently, two well-established revascularization techniques are practiced. One is coronary artery bypass grafting (CABG) in which autologous arteries and/or veins are used to supply blood to the coronary artery downstream to the stenotic lesion, and the other is percutaneous transluminal coronary angioplasty (PTCA) in which catheter-borne devices including balloon, stent, atherectomy-cutter, and laser are used to open stenosis from within the coronary artery. (In this article, PTCA denotes not only balloon angioplasty but all the catheter-based techniques.) In 1967, the first CABG was performed and a decade later, the first balloon PTCA was carried out. In 1987, coronary stenting was introduced in coronary revascularization. In the 1990s, the number of PTCA increased rapidly, and exceeded that of CABG. Balloon angioplasty and stenting are the two main players in contemporary PTCA. Atherectomy, laser, and radiation have subordinate roles in PTCA. CABG without cardiopulmonary bypass attracted the attention of cardiac surgeons in 1995, and has now become widely applied.Currently, we have a variety of surgical techniques and interventional coronary revascularization. To use them appropriately, we must know who will benefit from CABG and PTCA, and which strategy, CABG or PTCA, will lead to the best outcome in an individual patient. Results of comparative trials and analysis of registries are available to provide evidence-based answers to these questions. The inherent drawback of studies comparing long-term outcome of rapidly evolving treatments is the fact that clinical implications are obsolete by the time the long-term result is obtained. In this article, we try to provide clinical guidelines for coronary revascularization strategy based on the results of large studies. In addition, we review the latest technological advances in coronary revascularization, which influence indications of coronary revascularization at present.

In the 1970s and 1980s, randomized trials were performed to compare CABG with medical therapy on survival of stable patients with angina or after myocardial infarction (MI). A meta-analysis of seven such trials with a total patient number of 2649 revealed significantly lower 5- and 10-year mortalities of patients after CABG than those treated medically (10.2% vs 15.8% at 5 years, and 26.4% vs 30.5% at 10 years.1 Specifically, patients with left main and/or three-vessel disease with impaired left ventricular ejection fraction (EF) had the greatest survival extension by CABG. Patients with three-vessel disease and normal EF, or proximal left anterior descending artery (LAD) stenosis also had benefit from CABG. In contrast, patients with one- or two-vessel disease showed no mortality reduction with CABG.While these trials were ongoing, use of internal thoracic artery (ITA) as a bypass graft became prevalent, as it clearly improved graft patency and life expectancy. As the trials antedated widespread use of ITA in CABG and as medical therapy substantially improved since these trials were conducted, relevance of the trials of current practice is questioned. However, it is still believed in current practice that CABG improves survival in patients with 3-vessel disease, left main coronary artery stenosis, and/or proximal LAD stenosis especially when impaired left ventricular function or severe symptom co-exists.

The Angioplasty Compared with Medicine Study (ACME) compared PTCA with medical therapy in 212 male patients with single vessel disease enrolled between 1987 and 1990.2 The patients receiving PTCA showed significant reduction in angina and prolonged exercise time at 6-month., whereas survival after PTCA was similar to survival with medical therapy. In a subsequent trial, PTCA was compared with medical treatment in 101 male patients with 2-vessel disease and 227 male patients with 1-vessel disease.3 PTCA resulted in improved freedom from angina and longer exercise duration, but improvement was less in patients with 2-vessel disease than with 1-vessel disease.The second randomized Intervention Treatment of Angina (RITA-2) compared PTCA with medical therapy in patients with single-and multi-vessel disease.4 From 1992 to 1996, patients in whom medical therapy and coronary angioplasty were considered as acceptable alternatives were enrolled in the trial. Patients in whom early revascularization was considered necessary for symptom relief or for prognostic benefit were not eligible. Stents were used in 8.7% of those randomized to PTCA. The result indicated that early interventions with PTCA were associated with greater symptomatic improvement. No statistical difference was observed in all-cause death (PTCA 2.2% vs medical 1.4%) and cardiac death (1.0% vs 0.6%) during median of 2.7-year follow-up. However, death or definite MI occurred more frequently in patients randomized to PTCA (6.3% vs 3.3%, P= 0.02), supporting the argument that PTCA should be reserved for those whose quality of life is impaired in spite of optimal medical therapy.Medicine, Angioplasty or Surgery Study (MASS) evaluated CABG, PTCA, and medical treatment in patients with isolated proximal LAD stenosis.5 Both revascularization techniques resulted in symptomatic relief and reduced ischemia on treadmill. All three strategies resulted in similar incidence of death and incidence of MI.

Between 1986 and 1989, 9 randomized clinical trials comparing modern CABG with balloon PTCA was started including Bypass Angioplasty Revascularization Investigation (BARI), Coronary Angioplasty versus Bypass Revascularization Investigation (CABRI), Emory Angioplasty Surgery Trial (EAST), German Angioplasty Bypass-surgery Investigation (GABI), Toulouse trial, estudio Randomizado Argentino de Angioplastia vs Cirugia (ERACI), the first Randomized Intervention Treatment of Angina (RITA-1), MASS, and Lousanne trial. Characteristics of the trials are summarized in table 1.5-13 A total of 5163 patients suitable for both CABG and PTCA are enrolled in these 9 trials. All of the trials excluded left main coronary artery stenosis, recent MI, low EF, or previous revascularization. GABI excluded asymptomatic patients.RITA-1 enrolled patients with single-and multi-vessel disease; Lousanne and MASS enrolled patients with isolated proximal LAD disease (1-vessel disease); andthe other 6 trials recruited patients with multi-vessel disease. CABRI and EAST permitted incomplete revascularization, the others did not. CABRI and RITA-1 included vessels with total occlusion. Follow-up periods ranged from 1 to 5 years. The ITA was commonly used as a bypass graft in CABG, whereas PTCA technique was balloon dilatation only except in few patients.Results of the trials and meta-analysis are summarized in Table 2.14-16 GABI showed mortality difference favoring PTCA at 1 year. No other trials or meta-analysis showed statistical difference in long-term mortality.In 3 trials, CABG resulted in statistically more frequent in-hospital Q-wave myocardial infarction (QMI). However, statistical difference was not found in long-term QMI frequency in any trials or meta-analysis. Most studies found that CABG resulted in greater freedom from angina; statistical differences were shown in 4 trials. The rate of re-intervention was 4 to 10-fold higher for PTCA in every trial.Functional status, emotional health, and employment after PTCA were similar to those after CABG in BARI and RITA-1. Medical cost benefit of PTCA decreased during follow-up. In BARI, initial cost of PTCA was 65% that of CABG, but 5-year cost of PTCA was 95% that of CABG. In 3-vessel disease, the 5-year cost of PTCA equaled that of CABG. Meta-analysis of trials for isolated proximal LAD disease (MASS, Lousanne, a subgroup of RITA-1) suggested risk differences in favor of CABG.14

Table 1. Characteristics of randomized trials comparing CABG with PTCA.

Table 2. Short-term results of randomized trials comparing CABG with balloon PTCA.

* P < 0.05, revasc. = revascularization.

In BARI, difference of 5-year overall mortality between treatment groups round to 2.9 percentage points (95% CI, -0.2 – 6.0%) in favor of CABG. Cardiac mortality was significantly higher after PTCA (Table 4). Specifically, significantly worse survival was observed after PTCA in diabetic patients being treated with insulin or oral hypoglycemic agent at baseline. 17 In non-diabetics, overall and cardiac mortalities were similar after CABG and PTCA. Similar difference favoring CABG in diabetics was observed in CABRI (2-year CABG mortality 3.5%, PTCA 15.6%), but no difference was found for diabetics in EAST.In BARI, 5-year cardiac mortality of diabetics was 2.9% after CABG with use of IMA graft, 18.2% after CABG with only saphenous vein graft, and 20.6% after PTCA. Thus, survival benefit of CABG in diabetics appeared to be based on use of IMA graft.

Between 1984 and 1990, 9263 patients with symptomatic CAD patients were referred to cardiac catherization at Duke University. 18 Patients received medical therapy. PTCA or CABG as an initial treatment strategy. In patients with 1–vessel disease, there was no statistically significant advantage in risk-adjusted 5-year survival for revascularization over medical therapy. In patients with 2-vessel disease without severe (>95%) proximal LAD disease, PTCA resulted in most favorable outcome. In patients with 3-vessel disease or 2-vessel plus severe proximal LAD stenosis, CABG provided significant survival advantage.

Table 3. 5-year overall, and cardiac mortality of diabetics and
non-diabetics in BARI.

Hannan et al. compared 3-year all-cause mortality in New York State CABG registry with PTCA registry from 1993 to 1995, each containing data of about 30000 patients.19 In this registry 11.8% of PTCA patients received stents. After adjusting mortality for severity of illness, survival benefit was shown for CABG in patients with proximal LAD stenosis of more than 70% regardless of vessel disease number, and patients with 3-vessel disease without proximal LAD lesion. Patients with 1-vessel disease without proximal LAD stenosis showed better survival with PTCA. (Table 4) Along with EAST randomized trial, patients eligible for the trial who were not randomized because of physician or patient refusal were followed in a registry.20 The baseline features of 450 patients in the registry closely resembled those of 392 randomized patients. In the registry, there was a bias favoring CABG in patients with 3-vessel disease, and favoring PTCA in patients with 2-vessel disease containing only 1 lesion in each vessel system. Three-year survival for the registry patients were 96.4%, which was significantly better than that of the randomized patients of 93.4% (P=0.04). The better outcome in the registry is likely to suggest that an experienced physician’s judgment based on angiographic finding and on clinical evaluation of the patient, may provide better outcome than therapy by protocol or random choice.

Randomized trials comparing CABG or PTCA with medical therapy

ACIP compared revascularization with medical therapy in 558 patients with ischemia during exercise or asymptomatic ischemia during ambulatory ECG (patient entry between 1991 and 1993).21 Seventy-eight and 12% of patients were randomized to drug therapy guided by angina; drug therapy guided by angina and ambulatory ECG; and revascularization by CABG or PTCA as deemed most appropriate by the physicians. At a 2-year follow-up, mortality and combined frequency of death or MI were significantly less in the revascularization group (mortality: angina-guided drug 6.6%, vs angina-and ambulatory ECG-guided drug 4.4%, vs revascularization 1.1%, P< 0.02; death or MI; 12.1 vs 8.8 % vs 4.7 %, P < 0.04). Patients with ž 50% LAD stenosis benefited the most from revascularization. Randomized trials comparing balloon PTCA with stent PTCA Balloon PTCA is limited by two persistent difficulties: acute vessel closure immediately after intervention and restenosis during the first 6 months of follow-up. Intracoronary stents have reduced both adverse events. Because balloon PTCA and stenting can be performed concomitantly, they have complementary roles in revascularization, whereas PTCA and CABG have rather competitive roles.Three randomized trials using first generation stent, Benestent I (516 patients enrolled between 1991 and 1993), STRESS (407 patients enrolled from 1991 and 1993), and START (452 patients enrolled between 1992 and 1995) comparing stent with PTCA alone showed that stents significantly reduced restenosis.22-24 Restenosis rates after PTCA were 32, 42, and 37%, while restenosis rates after stent replacement were 22, 32, and 22% in Benstent I, STRESS, and START, respectively. However, long-term all-cause death and MI after stent placement were similar to those after PTCA in all trials. In Benestent I, bleeding and vascular complications were significantly higher with stenting.The advent of heparin-coated stents, improvement in guide-wire design, and modification of anticoagulation regimen further reduced the frequency of restenosis and vascular complications. Benestent II, in which 827 patients were enrolled between 1995 and 1996, compared second-generation stent implantation with balloon PTCA.25 Six-month restenosis rate after stent implantation was 16% compared to 31% after balloon (P=0.001). There was no difference in death and MI at 6 months. The difference in restenosis from PTCA was largest in LAD, but no difference was seen in RCA. Rate of early stent thrombosis was 0.16%. The frequency of vascular complications was reduced to 10%, similar to that of balloon PTCA.

Optimal drug therapy evolves over time, as do PTCA and CABG. In the last decade, efficacy of aspirin on survival of patients with stable angina was established.26 Beta-blockers, and slow-release or long-acting channel antagonists are effective in relieving anginal symptoms. Beta-clinical trials have shown that low-density lipoprotein (LDL) lowering drugs can decrease the risk of ischemic event in patients with CAD. In the Scandinavian Simvastatin Survival Study (4S), treatment with an HMG-CoA reductase inhibitor (statin) in patients with documented CAD with a total cholesterol between 212 and 308 mg/dl was associated with 30% to 35% decrease in both mortality and major coronary events.28 The Cholesterol And Recurrent Events (CARE) study reveals that treatment with HMG-CoA resulted in 24% reduction in risk for fatal or non-fatal MI in patients with previous MI and cholesterol levels <240 mg/dl, and LDL levels between 115 and 174 mg/dl.29 The 1989 U.S. Surgeon General’s report concluded that smoking increased cardiovascular mortality by 50%. Patients who continued to smoke after acute MI have a 22% to 47% increased risk of death.30 Therefore, smoke cessation program should be applied to all smokers with CAD. The benefit of hypertension treatment in patients with hypertension (blood pressure over 140 mmHg systolic or over 90 mmHg diastolic) and chronic stable angina has been established.31 Pharmacologic treatmenis necessary when life-style modification and dietary alterations fail to normalize blood pressure. Beta-blockers or long-acting calcium channel antagonists are useful in patients with angina. Angiotensin II converting enzyme inhibitor is recommended in patients with left ventricular dysfunction. Although advances in drug therapy for chronic CAD were modest, several recent studies have provided the basis for evidence-based drug therapy of CAD.

Table 5. Guidelines for coronary revascularization. 

CPR = Cardiopulmonary resuscitation. EF= left ventricular ejection fraction.

Conventional CABG is performed under cardiac arrest with the use of cardiopulmonary bypass (CPB). Minimally invasive CABG surgery has rapidly expanded in the hope that it may reduce surgical stress. Off-pump CABG on a beating heart through a limited incision is referred to as MIDCAB (minimally invasive direct coronary artery bypass) or LAST (Left Anterior Small Thoracotomy operation), and off-pump CABG on a beating heart through a standard sternotomy incision is referred to as OPCAB (off-pump coronary artery bypass).32 OPCAB and MIDCAB eliminates CPB and global cardiac ischemia, thereby precluding whole-body inflammatory responses evoked by CPB and generalized cardiac cytokine deployment cause by myocardial ischemia at the expense of mechanical and ischemic insult on local myocardium. MIDCAB is intended to reduce surgical stress further by minimizing the surgical incision. Both techniques are aimed at reducing short-term mortality and morbidity, and their drawbacks are technical difficulty and difficult access to the circumflex and right coronary arteries. Most cardiac surgeons performing MIDCAB and OPCAB think that, to render CABG less invasive, avoidance of CPB (difference between conventional CABG and OPCAB) is preferable to avoidance of large incision (difference between OPCAB and MIDCAB).33 Early small-numbered non-randomized clinical experiences of MIDCAB and OPCAB showed excellent short-term results. 34 Some studies indicate excellent outcome combined use of left IMA-to-LAD MIDCAB and PTCA in patients with multivessel disease designated as integrated revascularization.35 BARI indicates that intended incomplete revascularization by PTCA did not compromise long-term survival in non-diabetic patients.36 Therefore, delayed integrated revascularization, that is, MIDCAB plus conditional PTCA when symptom persists after MIDCAB, may be a reasonable option in non-diabetic with multivessel disease. There exists a plethora of reports with the use of MIDCAB or OPCAB. However, all these studies have small volume with non-randomized design, and provides only short-term results. It is too early to define the role of MIDCAB, OPCAB, and integrated revascularization in the paradigm of coronary revascularization. Randomized trials to assess the efficacy of MIDCAB and integrated revascularization are currently underway.

Due to recent advances in stent technology, current PTCA result is substantially better than that few years ago. Because of low incidence of restenosis with the use of second generation stents, stent is recommended to be placed after balloon PTCA when angiographically suitable. It is estimated that more than 60% of current catheter coronary interventions include the use of stents. Reducing the incidence of restenosis by stenting will perhaps ameliorate outcome after PTCA, and this prompted researchers to perform randomized trials comparing stents with CABG (ARTS, SOS, and SIMA), which are now underway.Stenting of acute or threatened closure after balloon angioplasty also contributed to improving PTCA result. With the use of stents, the frequency of bail-out emergency CABG after PTCA has been reduced from 3 – 5 % to < 1 %. In addition, reliable stent back-up for coronary dissection after balloon PTCA allowed balloon PTCA to be carried out more aggressively. Aggressive balloon expansion results in greater dilatation with a residual stenosis of less than 30% (stent-like result), leading to lower restenosis rate comparable to stenting. In other words, stent-like balloon result is a by-product stenting. Atherectomy, laser and radiation are still investigational and their contributions to contemporary PTCA are small. CommentsBased on evidences established in randomized trials and non-randomized registries, we advocate guidelines of coronary revascularization. (Table 5) The guidelines are not strict and are amendable according to evolution of medical treatment and revascularization technology.13,37 Clinical guidelines have inherent problems. First, no matter how clever we try to categorize CAD patients, it is impossible to predict outcomes accurately in an individual patient because every patient is unique. Therefore, guidelines must be flexible, and choice of treatment strategy must be made in the light of all the medical and social information of the patient. Second, guidelines are rapidly outdated as treatment modalities evolve over time. Third, because differences of survival rate among treatment strategies are small in most patients, patient preference will greatly influence the strategy choice.38 As an example we will discuss current recommended treatment strategy for isolated 70% stenosis in LAD. The possible options are medical therapy, balloon PTCA with conditional stents when stent-like result is not obtained, elective stenting, conventional on pump left ITA-to-LAD CABG, OPCAB, and MIDCAB. Among these 6 options, 5 options except conventional CABG have witnessed considerable modification in the lastt 5 years. Evidence-based medicine predicts the best primary management to be medical therapy when symptom is mild and controllable by medication, and if the symptom is medication resistant, CABG or PTCA will be indicated. Randomized trials have shown that conventional CABG provides a slightly better survival outcome and definitely higher freedom from re-intervention than those after PTCA at the cost of surgical pain and slightly higher in-hospital MI rate. The benefit of CABG over PTCA is not clinically significant, and can be converted by patient preference.Stents have significantly reduced restenosis rate. Benestent II showed a restensosis rate in LAD-stent implantation of 16% vs 38% for balloon. Therefore, it is unknown whether conventional CABG still provides better overall outcome than stent-PTCA. If patient’s predominant concerns are body appearance and avoidance of re-intervention, MIDCAB will be a preferred option.38 Currently, no evidence exists concerning the optimal choice among stent- PTCA, OPCAB or MIDCAB, and conventional CABG in such case. Physicians have to select the best treatment strategy and choose between well established but outdated modalities and newer, seemingly better, but less-established modalities. Evidence-based selection of revascularization strategy will be more complicated for multi-vessel disease because intended incomplete revascularization by PTCA or MIDCAB may be a reasonable option in non-diabetics.

We have learned a vast amount of information from comparative trials and large-sized registries comparing different modes of treatment for chronic CAD. Evidence-based selection of a treatment modality could be made taking into consideration a patient’s individual risks factors As newer techniques are invented and introduced in the clinical arena, and as intended incomplete revascularization provides survival outcome similar to complete revascularization iselected patients, the choice of the best treatment strategy becomes increasingly difficult. However, we believe that well-trained physicians will make optimal or near-optimal treatment strategy based on their experience, sound clinical judgment and currently available medical information from large clinical trials.

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Correspondence to: Werner Mohl, MD, PhD, Department of Cardiothoracic Surgery, University of Vienna, Wahringer Gurtel
18-20, A-1090 Vienna, Austria Fax: 43 1 40400 – 6789
E-mail: werner.mohl@univie.ac.at