Management of Stable Coronary Disease

doi:10.1056/NEJMclde078169

A 65-year-old man with hypertension, obesity, and type 2 diabetesmellitus has been under your care for the past 5 years. He hasbeen receiving hydrochlorothiazide (25 mg daily) and metformin(500 mg twice daily); his blood pressure is 130/82 mm Hg, hisbody-mass index (the weight in kilograms divided by the squareof the height in meters) is 32, and his glycated hemoglobinis 7.5%. He comes to your office seeking advice about the managementof his recently diagnosed coronary artery disease. Two weeksearlier, he had presented with chest tightness and shortnessof breath after walking two blocks. His symptoms resolved withina few minutes at rest. An exercise-tolerance test on a treadmillwas performed according to the Bruce protocol, along with myocardialperfusion imaging. The patient exercised for 8 minutes, stoppingbecause of chest pressure and dyspnea; his peak systolic bloodpressure was 160 mm Hg, and his peak heart rate was 140 beatsper minute. Electrocardiography showed ST-segment depressionof 1 mm in the anterolateral leads. The perfusion study revealeda fixed perfusion defect of moderate size in the anterior walland a reversible defect of moderate size in the anterolateralwall.

The patient underwent cardiac catheterization and was foundto have multivessel coronary artery disease, with occlusionof the first diagonal branch of the left anterior descendingcoronary artery, a long lesion with 70% stenosis in the midportionof the left anterior descending coronary artery, 80% stenosiswith a calcified lesion in the proximal left circumflex coronaryartery, and 50% stenosis of the posterior descending coronaryartery. A left ventriculogram obtained during the procedureshowed anterior-wall hypokinesis and a left ventricular ejectionfraction of 45%. The patient was advised to discuss managementof his coronary artery disease with you before making a decisionabout how to proceed; you have received the results of his exercisetest and his catheterization report.

What kind of initial treatment would you find most appropriatefor this patient? Three options are outlined and each is defendedin a short essay by an expert in the management of coronaryartery disease; read the essays and then cast your vote.

Treatment Option 1

Appropriate Medical Management and Close Follow-up for Adherence and Efficacy

Salim Yusuf, F.R.S.C., Ernest Fallen, M.D.

The case vignette describes a 65-year-old man with diabetes,multiple coronary risk factors, previous myocardial infarction,multivessel coronary-artery stenosis, mild left ventriculardysfunction, and new-onset effort-induced angina and dyspnea.He has yet to receive antianginal therapy, and inadequate attentionhas been given to controlling his risk factors. The initialmanagement needed in this case is clearly medical. Its objectivesare to relieve his symptoms, reduce risk factors, prevent leftventricular remodeling, and reduce the likelihood of a majorcoronary event. There are cogent arguments against rushing inwith revascularization procedures such as PCI or CABG.

PCI as initial therapy in this untreated patient poses severalproblems. First, the patient has multiple lesions, includinga long lesion with 70% obstruction in the middle segment ofthe left anterior descending coronary artery that is technicallychallenging to treat. Second, the circumflex lesion, arguablythe culprit site (according to the nuclear perfusion scan),is less amenable to adequate dilatation, because of its calcifiedstate. Third, it is well known that PCIs of multiple vesselsare less likely to result in long-term patency in patients withdiabetes than in patients without diabetes.¹ Finally, thereis no evidence that PCI in patients with stable angina is moreeffective than optimal medical management in reducing mortality.

As for CABG, at this early stage, there are a number of operativerisks. These include inadequately treated diabetes, obesity,and reduced left ventricular function. The indication for surgeryis borderline at best. The patient has two-vessel coronary disease,without involvement of the proximal left anterior descendingcoronary artery and with potentially reversible ischemia inthe circumflex territory. Besides, CABG may be superior to medicaltherapy for the relief of angina in the long run, but our patienthas not yet received medical therapy, and therefore his responseto it is not known.

The patient has a glycated hemoglobin level of 7.5%, indicatinginadequate glucose control; the recommended therapeutic targetfor patients with diabetes is less than 6.5%. The simple reductionof calories — especially by means of a low-glycemic-indexdiet in conjunction with regular physical activity, educationabout diabetes, and adjustment of the dose of metformin (toup to 2 g per day, if the renal function is not abnormal) —should suffice to achieve both glycemic control and weight loss.Although the patient's lipid profile should be known, thereis persuasive evidence in favor of initiating treatment witha statin (with a target low-density lipoprotein cholesterollevel of 80 mg per deciliter [2.0 mmol per liter] or less) inany patient with symptomatic coronary artery disease.² The combinationof symptomatic coronary artery disease, left ventricular dysfunction,and diabetes makes the patient an ideal candidate for an angiotensin-converting–enzymeinhibitor.³ ⁴ He should also be given aspirin. There are clearindications to initiate a beta-blocker (and, if necessary, acalcium-channel blocker) for control of the angina and hypertensionand for secondary prevention of myocardial infarction and deathfrom cardiovascular causes.⁵

This patient's symptoms of angina would benefit from the judicioususe of a nitrate preparation. Finally, depending on his preferences,the patient should be encouraged to get involved in his owncare by regularly monitoring his own glucose levels, weight,and blood pressure. He should be followed closely over the next2 to 4 weeks to ensure that the objectives of this initial medicalapproach are being achieved. It is highly likely that with thesemeasures, both his angina and his prognosis will improve markedly.If, despite optimal medical therapy, his angina worsens andlimits his activities, then it would be reasonable to considerrevascularization.

No potential conflict of interest relevant to this article wasreported.

From McMaster University, Hamilton, ON, Canada.

Treatment Option 2

Appropriate Medical Management and PCI

Robert A. Harrington, M.D.

The decision-making process regarding therapy for this patientwith new-onset angina of Canadian Cardiovascular Society classIII begins with an assessment of risk. Risk stratification isa dynamic practice whereby the clinician incorporates newlyacquired information in a clinical-decision model that alsoconsiders the desires and preferences of the patient. In thiscase, the presence of diabetes carries both an increased riskof death from cardiac causes and an increased likelihood ofa benefit from revascularization, as compared with medical therapy.⁶

According to the well-validated Duke treadmill score, this patient'sexercise-limiting symptoms, ST-segment depression of 1 mm, andmoderate anterior perfusion defect confer on him a risk of deathfrom cardiac causes that is well within the intermediate range,which means that he would preferentially benefit from aggressivetherapies.⁷ Although coronary angiography revealed three-vesseldisease and mildly reduced left ventricular function, the diseaseof the left anterior descending coronary artery appears to beresponsible for his recent symptoms, given the findings on theimaging studies.

The patient's clinical risk factors (especially the presenceof diabetes), the abnormal results of the exercise study, andthe results of coronary angiography all provide support forcoronary revascularization (with a background of aggressivemedical therapy) as the best option. The patient does not havedisease of the proximal left anterior descending coronary artery,which would have placed him in a high-risk group for which bypasssurgery is favored over PCI.⁶ Instead, the occlusion of thefirst diagonal branch of the left anterior descending coronaryartery, the long lesion of the middle segment of the left anteriordescending coronary artery, and the lesions without inducibleischemia in the circumflex and right coronary arteries indicatethat PCI should be the preferred revascularization strategy.Although complete revascularization could be considered, theabsence of any functional data suggesting that there is ischemiaoutside the anterior distribution makes PCI in the left anteriordescending coronary artery a very reasonable choice. The 2005PCI guidelines of the American College of Cardiology, the AmericanHeart Association, and the Society for Cardiovascular Angiographyand Interventions give the procedure a class IIa recommendation(with evidence that is conflicting but overall is in support)for patients with angina of Canadian Cardiovascular Societyclass III, such as our patient.

The results of the recent Clinical Outcomes Utilizing Revascularizationand Aggressive Drug Evaluation (COURAGE) trial raise questionsabout using PCI in patients such as this man. Although the COURAGEstudy showed no benefit of PCI over optimal medical therapyregarding the composite end point of death or myocardial infarction,angina symptoms were significantly reduced with the use of PCI,a phenomenon that has been shown in multiple clinical trials.⁸The compliance with aggressive medical therapy seen in the COURAGEtrial required a Herculean effort, unlike that typically seenin routine clinical practice. Given that the use of PCI wasnot associated with incremental risk in the COURAGE study, itis reasonable and appropriate to have a discussion with thepatient about his hopes and expectations regarding lifestyleimprovement and symptom relief from the therapy chosen.

Given recent controversies, it is worth commenting on the selectionof either a bare-metal stent or a drug-eluting stent. The patient'slong lesion and diabetes increase his risk of restenosis. Therisks of restenosis and repeat revascularization can be reducedsubstantially with the use of a drug-eluting stent. But thatchoice carries with it obligatory dual antiplatelet therapy(aspirin plus clopidogrel) for at least 1 year and perhaps indefinitely.⁹ ¹⁰If the patient is thought to be at low risk for a bleeding eventand if he is likely to adhere to long-term antiplatelet therapy,then placement of a drug-eluting stent in the lesion of themiddle segment of the left anterior descending coronary arteryis his best option.

Dr. Harrington reports receiving consulting fees from Bristol-MyersSquibb and Sanofi and being the director of the Duke ClinicalResearch Institute, which receives grant support from Johnson& Johnson, Boston Scientific, Bristol-Myers Squibb, andSanofi. No other potential conflict of interest relevant tothis article was reported.

The use of drug-eluting stents in multivessel stenting, as discussedin this essay, is an off-label use.

From the Duke Clinical Research Institute and the Division ofCardiovascular Medicine, Duke University Medical Center, Durham,NC.

Treatment Option 3

Appropriate Medical Management and CABG

Robert A. Guyton, M.D.

Treatment of coronary atherosclerosis has become progressivelyconcordant with our knowledge of coronary pathophysiology. Anginais caused by coronary stenoses that limit flow, whereas myocardialinfarction is generally caused by blockage related to unstableplaques, often separate from flow-limiting stenoses. Systemicmedical therapy decreases the risks of both infarction and death.PCI treats short vascular segments and is effective in patientswith an acute coronary syndrome or angina caused by discretestenosis. PCI, even with drug-eluting stents, has no demonstrablebenefit with regard to infarction or death, since future blockageelsewhere is usually the culprit, not restenosis of the shortsegment.

CABG bypasses the proximal two thirds of epicardial vessels,thus also bypassing both current stenoses and most future blockagesfrom nascent plaques that are currently hemodynamically insignificant.¹¹Accordingly, the addition of CABG to medical therapy in earlyrandomized trials did extend the survival of patients with advanced,multifocal disease, such as three-vessel disease or lesser diseasethat includes the proximal left anterior descending artery.These trials evaluated the medical therapy that was availableat the time and CABG as it was practiced at the time (with higheroperative mortality and few arterial conduits). Among patientswith multivessel disease, CABG is associated with a survivaladvantage over PCI that is similar to the survival advantageof CABG over medical therapy. There was minimal survival advantagein patients with early coronary disease when enrollment in randomized,controlled trials was limited to patients in whom PCI was projectedto achieve "equivalent revascularization" to CABG (5-year postprocedurerisk ratio for death after PCI vs. CABG, 1.13; P>0.05; inthe Arterial Revascularization Therapies Study [ARTS]).¹¹ Amongpatients in trials with less restrictive enrollment, a largersurvival advantage has been found for patients with multivesseldisease (5-year relative risk of death after PCI vs. CABG, 1.65;P=0.016; in the Stent or Surgery Trial [SOS]).¹¹ Data from "realworld" registries provide support for a survival advantage fromCABG in patients with any category of multivessel disease, amongwhom the 3-year risk-adjusted hazard ratio for death after CABG,as compared with death after stenting, is 0.76 to 0.64 (P<0.05for all comparisons).¹²

In this patient with new-onset angina, survival advantage isthe only justification for performing early PCI or CABG. MultivesselPCI has no survival advantage in patients with diabetes and,with a 12-month rate of thrombosis of 4.3% when performed withdrug-eluting stents,¹³ it may be detrimental.

The New York State Registry would categorize this patient ashaving significant ( $≥$ 70% stenosis) two-vessel disease with involvementof the nonproximal left anterior descending coronary artery;patients in this group have a 3-year hazard ratio for deathafter CABG, as compared with PCI with stenting, of 0.76 (P=0.02).The patient has diabetes and is obese; among patients in theCOURAGE trial, neither of these characteristics was alteredby the intensely supervised medical therapy in the study. Thepatient is a good candidate for CABG, with a predicted riskof death from the procedure of less than 1%, according to theSociety of Thoracic Surgeons National Database Risk Calculator,and a 0.8% risk in experienced off-pump centers.¹⁴ He has advanced,multifocal coronary atherosclerosis, with disease in four majorepicardial vessels. The patient is on the cusp of being classifiedas having three-vessel disease, according to the usual definitionsused in randomized controlled trials (>50%, or $≥$ 50%, stenosis).His perfusion scan, showing a moderate fixed (perhaps "hibernating")defect plus a moderate reversible defect, adds up to a largearea of hypoperfusion. His diminished ventricular function doesnot increase the relative benefit of CABG when added to medicaltherapy for multivessel disease, but it does almost double theabsolute 5-year potential mortality benefit from the additionof CABG. This patient should receive intense medical therapyand off-pump CABG with at least two arterial conduits.

Dr. Guyton reports the receipt by the Division of CardiothoracicSurgery at Emory University of research and educational grantsfrom Medtronic, Guidant, Edwards Laboratories, St. Jude, Sorin,U.S. Surgical, and Baxter. No other potential conflict of interestrelevant to this article was reported.

The use of drug-eluting stents in multivessel stenting, as discussedin this essay, is an off-label use.

From the Division of Cardiothoracic Surgery, Department of Surgery,Emory University School of Medicine, Atlanta.

Given your knowledge of the condition and the points made bythe experts, which treatment option would you choose? Base youropinion on the published literature, your past experience, recentguidelines, and other sources of information, as appropriate.Indicate your choice by using the Cast Your Vote button below.You may also submit comments after you vote (maximum of 175words).