Single-Vessel Disease: Medical and Revascularization Options

James L. Orford

Peter B. Berger

Despite decades of research since the advent of coronary angiography (1) and a broad evidence base on which to base clinical decision making, on which guidelines published by the American College of Cardiology and American Heart Association are based (Table 1.1) (2), the optimal treatment of single-vessel coronary artery disease (CAD) remains controversial. The aims of an optimal treatment strategy are well defined and include the relief of angina and the prevention of future ischemic events and cardiac death. But less agreement exists on the relative merits of intensive medical therapy, percutaneous coronary intervention (PCI), or coronary bypass surgery, among such patients.

DEFINITION OF SINGLE-VESSEL CORONARY ARTERY DISEASE

The term single-vessel CAD is open to interpretation, but is usually referred to as the presence of at least a ≥70% stenosis of a major coronary artery (left anterior descending, left circumflex, or right coronary arteries) or one of their respective major branches (diagonal, obtuse marginal, posterior descending, or posterior left ventricular arteries). Factors that may influence a clinician’s treatment decision include the percent diameter of stenosis; the morphology and length of the culprit lesion; the vessel involved; the presence or absence of angiographically insignificant stenoses in other vessels; the presence or absence of comorbid medical conditions; and left ventricular systolic function.

That a correlation exists between percent diameter stenosis and stress-induced abnormalities of coronary physiology and myocardial perfusion defects is well established (3). This relationship is confounded by the shortcomings of contrast luminology (4), but is the commonly quoted rationale for revascularization of critical (≥70% percent diameter stenosis) coronary stenoses and is supported by data confirming the efficacy of both percutaneous and surgical revascularization procedures for the relief of angina pectoris (5). However, percent diameter stenosis does not reliably predict the risk of myocardial infarction (MI) or cardiac death; future thrombotic events most commonly occur at the site of angiographically insignificant stenoses due to rupture of minor plaques, because these lesions are so numerous compared to angiographically significant stenoses (6). Because it has been shown that, in patients with single-vessel disease, the mean percent of the vessel area occupied by atheroma at a segment with an angiographically normal appearance is 39%, that coronary atherosclerosis is a diffuse process, and that stenotic lesions represent only a small proportion of the total disease burden, it is appropriate to question the very concept of single-vessel disease (7).

Plaque morphology may be useful for the prediction of risk of thrombotic occlusion and may influence the treatment of single-vessel CAD. It is thought that coronary artery lesions at high risk for thrombotic occlusion share common characteristics that may favor higher shear stress and flow separation, including the presence of a branch vessel originating within the stenosis, more severe percent
diameter stenosis, steeper inflow and outflow angles of the stenosis, and longer lesions (8,9). Great interest is manifested in a number of novel imaging modalities that may identify more accurately the vulnerable plaque and guide the treatment of the coronary lesions most likely to result in coronary thrombosis and MI (10).

TABLE 1.1. ACC/AHA GUIDELINES: SELECTED GUIDELINE STATEMENTS RELEVANT TO THE ROLE OF PCI IN THE MANAGEMENT OF SINGLE-VESSEL CAD

Recommendations for PCI in Asymptomatic or Class I Angina Patients
Class I
	Patients who do not have treated diabetes with asymptomatic ischemia or mild angina with one or more significant lesions in one or two coronary arteries suitable for PCI with a high likelihood of success and a low risk of morbidity and mortality. The vessels to be dilated must subtend a large area of viable myocardium (Level of Evidence: B)
Class IIa
	The same clinical and anatomic requirements for Class I, except the myocardial area at risk is of moderate size or the patients have treated diabetes. (Level of Evidence: B)
Class III
	Patients with asymptomatic ischemia or mild angina who do not meet the criteria as listed under Class I or Class II and who have: Only a small area of viable myocardium at risk No objective evidence of ischemia Lesions that have a low likelihood of successful dilation Mild symptoms that are unlikely to be due to myocardial ischemia Factors associated with increased risk of morbidity or mortality Left main disease Insignificant disease <50% (Level of Evidence: C)
Recommendations for patients with moderate or severe symptoms (angina class II to IV, unstable angina or non-ST-elevation MI) with single- or multivessel coronary disease on medical therapy
Class I
	Patients with one or more significant lesions in one or more coronary arteries suitable for PCI with a high likelihood of success and low risk of morbidity or mortality. The vessel(s) to be dilated must subtend a moderate or large area of viable myocardium and have high risk. (Level of Evidence: B)
Class IIa
	Patients with focal saphenous vein graft lesions or multiple stenoses who are poor candidates for reoperative surgery. (Level of Evidence: C)
Class IIb
	Patient has one or more lesions to be dilated with reduced likelihood of success or the vessel(s) subtend a less than moderate area of viable myocardium. Patients with two- or three-vessel disease, with significant proximal LAD CAD and treated diabetes or abnormal LV function. (Level of Evidence: B)
Class III
	Patient has no evidence of myocardial injury or ischemia on objective testing and has not had a trial of medical therapy, or has: Only a small area of myocardium at risk All lesions or the culprit lesion to be dilated with morphology with a low likelihood of success A high risk of procedure-related morbidity or mortality (Level of Evidence: C) Patients with insignificant coronary stenosis (e.g., <50% diameter). (Level of Evidence: C) Patients with significant left main CAD who are candidates for CABG. (Level of Evidence: B)

The site of the lesion also is of prognostic significance and influences treatment decisions when treating single-vessel CAD. For example, a stenosis of the proximal left anterior descending (LAD) is likely to be viewed differently to a similar stenosis of an obtuse marginal branch (11). Furthermore, cumulative distribution functions have been calculated that allow an estimation to be made of the percent of culprit lesions lying proximal at any given distance from the ostium; this allows the clinician to model the feasibility of prophylactic drug-eluting stenting (DES) to minimize the risk of subsequent proximal plaque rupture (12). Such a revascularization strategy, if shown to reduce the incidence of future coronary events, would significantly alter the treatment of CAD.

PERCUTANEOUS CORONARY INTERVENTION VERSUS MEDICAL THERAPY

A number of important randomized, controlled trials have compared balloon angioplasty (BA) with medical therapy for the treatment of single-vessel CAD. The Angioplasty Compared to Medicine (ACME) trial prospectively randomized 212 patients with stable, Canadian Cardiac Society (CCS) I or II angina with provocable myocardial ischemia and single-vessel subocclusive coronary disease to primary therapy of either percutaneous transluminal coronary angioplasty (PTCA/BA) or medical therapy (5). After 6 months of follow-up, the angioplasty group was more likely to be free of angina (64% versus 46%, p <0.01) and achieved greater improvements in exercise duration (2.1 versus 0.5 minutes, p <0.0001). No difference was noted in the incidence of death or MI, as one might expect in a small study of low-risk patients, but the angioplasty group required more repeat revascularization procedures (angioplasty or bypass surgery).

Follow-up at 2 years of this trial population confirmed sustained benefit following BA; 62% of patients in the angioplasty group were free of angina, compared with 47% of patients in the medical group (p <0.05), exercise duration was improved by 1.33 minutes in the angioplasty group, but decreased by 0.28 minutes in the medical group (p <0.04) (13).

In the Medicine, Angioplasty, or Surgery Study (MASS) trial, 214 patients with stable angina, normal ventricular function, and a proximal LAD stenosis >80%, were prospectively randomized to bypass surgery with an internal mammary artery (n = 70), BA (n = 72), or medical therapy (n = 72) (14). After an average of 3 years follow-up, the primary endpoint (cardiac death, MI, or refractory angina requiring revascularization) had been reached in two patients (3%) assigned to bypass surgery, 17 assigned to angioplasty (24%), and 12 assigned to medical therapy (17%; p = 0.0002, angioplasty versus bypass surgery; p = 0.006, bypass surgery versus medical treatment; p = 0.28, angioplasty versus medical treatment). No patient allocated to bypass surgery needed a further revascularization procedure, compared with eight and seven patients, respectively, assigned to coronary angioplasty and medical treatment (p = 0.019). Both revascularization protocols led to greater symptomatic relief and a lower incidence of ischemia on a treadmill test. No difference was observed in the incidence of death or MI among the three treatment protocols in this small study of low-risk patients.

The Second Randomized Intervention Treatment of Angina (RITA-2) randomized 1,018 patients with angiographically proven CAD to either BA and medical therapy, or medical therapy alone (15). Approximately 60% of the patients had single-vessel disease. Death or non-fatal MI occurred in 6.3% of patients treated with BA and 3.3% of patients treated with medicines alone (p = 0.02). No difference was observed in the incidence of death alone (11 BA, 7 medical therapy). Of the patients in the BA group, 7.9% required bypass grafting, and a 11.1% required further nonrandomized BA. In the medical group, 23% underwent a revascularization procedure during follow-up. Angina was less severe in the BA group; there was a 16.5% absolute excess of grade 2 or worse angina in the medical group 3 months after randomization (p <0.001), which attenuated to 7.6% after 2 years. Total exercise time (Bruce protocol) also improved in both groups, with the BA group achieving a mean advantage of 35 seconds at 3 months (p <0.001). No significant interaction was observed between treatment and number of diseased vessels, but insufficient data were available for reliable evaluation of the primary endpoint according to number of diseased vessels (single-vessel versus multivessel disease).

The Atorvastatin Versus Revascularization Treatment (AVERT) trial randomized 341 patients with stable CAD (asymptomatic or Canadian Cardiovascular Society Class I or II angina) and normal left ventricular ejection fraction to either medical treatment with atorvastatin (80 mg per day) or percutaneous revascularization and usual medical care (16). Approximately 57% of the patients randomized had single-vessel CAD. Thirteen percent of the patients who were randomized to the intensive lipid-lowering treatment with atorvastatin experienced an ischemic event, compared with 21% of the PCI group (p = 0.048). This difference was due to a reduction in the need for subsequent revascularization procedures and hospitalizations for worsening angina. As compared with the patients who were treated with angioplasty and usual care, the patients who received atorvastatin had a significantly longer time to the first ischemic event (p = 0.03) (Fig. 1.1). No difference was noted in the incidence of death, MI, resuscitated cardiac arrest, or revascularization. The results of this trial have proved to be particularly controversial. The study cohort represents a highly selected population and is likely subject to significant referral bias. Furthermore, the difference in the composite primary endpoint was driven by the difference in the highly subjective endpoint of “worsening angina with evidence of myocardial ischemia resulting in hospitalization” (25 patients versus 11 patients); surveillance for evidence of restenosis in patients who had undergone PCI may have biased these findings. The Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial compares aggressive medical therapy with aggressive medical therapy and contemporary PCI for patients with stable angina pectoris. This should more adequately answer the questions raised by the AVERT trial.

The Asymptomatic Cardiac Ischemia Pilot (ACIP) study randomized 558 patients with coronary anatomy suitable for revascularization (PCI or bypass surgery) and at least one episode of asymptomatic ischemia (ambulatory ECG or treadmill exercise test) to one of three strategies: (a) medication to suppress angina (angina-guided strategy), (b) medication to suppress both angina and ambulatory
ECG ischemia (ischemia-guided strategy), and (c) revascularization strategy (angioplasty or bypass surgery) (17). The revascularization group received less medication and had less ischemia on serial ambulatory ECG recordings and exercise testing than those assigned to the medical treatment strategies. Most important, the mortality rate was 4.4% in the angina-guided group, 1.6% in the ischemia-guided group, and 0% in the revascularization group (overall, p = 0.004; angina-guided versus revascularization, p = 0.003; other pairwise comparisons, p = NS). The frequency of the individual endpoints of MI, unstable angina, stroke, and congestive heart failure were not significantly different, but the incidence of the composite endpoint of death, MI, nonprotocol revascularization, or hospital admission at 1 year was 32% using the angina-guided strategy, 31% using the ischemia-guided strategy, and 18% using the revascularization strategy (p = 0.003). Subgroup analyses suggested that the benefit associated with revascularization was most evident in patients with proximal LAD stenosis or multivessel disease and, therefore, the relevance of this data to the broader population of patients with single-vessel CAD is debatable. It also is not possible to determine whether the benefit with revascularization was common to both PCI and bypass surgery patients.

Figure 1.1. Comparison of angiographic restenosis rates: BA versus bare metal stents (STRESS, BENESTENT) and bare metal stents versus drug-eluting stents (RAVEL, SIRIUS, TAXUS I and II). STRESS = Stent Restenosis Study, BA versus bare metal stent. (BENESTENT, Belgium Netherlands Stent study, BA versus bare metal stent; RAVEL, Randomized Study with the Sirolimus-Coated Bx Velocity, Balloon-Expandable Stent in the Treatment of Patients with de Novo Native Coronary Artery Lesions, bare metal stent versus sirolimus drug-eluting stent; SIRIUS, Sirolimus-Eluting Stent in Coronary Lesions, bare metal stent versus sirolimus drug-eluting stent; TAXUS I, bare metal stent versus paclitaxel drug-eluting stent; TAXUS II, bare metal stent versus paclitaxel drug-eluting stent; SR, slow release; and MR, moderate release.)

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