Acknowledgment

This CME activity is supported by an educational grant from Abbott Vascular, Abbott Park, Illinois.

Disclosures

Dr. Friedewald has received honoraria from and is a speaker for Novartis, East Hanover, New Jersey. Dr. Boden has received honoraria from and is a speaker for CV Therapeutics, Palo Alto, California; Sanofi-Aventis, Bridgewater, New Jersey; and Abbott Laboratories, Abbott Park, Illinois. Dr. Stone is a member of the scientific advisory board of and has received honoraria from Abbott Vascular, Santa Clara, California; and Boston Scientific Corporation, Natick, Massachusetts. Dr. Stone is a consultant for The Medicines Company, Parsippany, New Jersey; AstraZeneca, Wilmington, Delaware; Bristol-Meyers Squibb, New York, New York; and Eli Lilly & Company, Indianapolis, Indiana. Dr. Yancy has no relevant financial relationships to disclose. Dr. Roberts has received honoraria from and is a speaker for Merck-Schering Plough, Whitehouse Station, New Jersey; AstraZeneca; and Novartis.

Disclosures

Dr. Friedewald has received honoraria from and is a speaker for Novartis, East Hanover, New Jersey. Dr. Boden has received honoraria from and is a speaker for CV Therapeutics, Palo Alto, California; Sanofi-Aventis, Bridgewater, New Jersey; and Abbott Laboratories, Abbott Park, Illinois. Dr. Stone is a member of the scientific advisory board of and has received honoraria from Abbott Vascular, Santa Clara, California; and Boston Scientific Corporation, Natick, Massachusetts. Dr. Stone is a consultant for The Medicines Company, Parsippany, New Jersey; AstraZeneca, Wilmington, Delaware; Bristol-Meyers Squibb, New York, New York; and Eli Lilly & Company, Indianapolis, Indiana. Dr. Yancy has no relevant financial relationships to disclose. Dr. Roberts has received honoraria from and is a speaker for Merck-Schering Plough, Whitehouse Station, New Jersey; AstraZeneca; and Novartis.

Objectives

At the conclusion of this activity, the participant should be able to:

• 1
  

  Define “stable coronary heart disease.”

  
  
• 2
  

  Prescribe optimal medical therapy for patients with stable coronary heart disease.

  
  
• 3
  

  Discriminate between patients with stable coronary heart disease who are candidates for medical therapy alone and patients who should receive coronary revascularization.

Introduction

Among the 17 million patients in the United States with coronary heart disease (CHD), about 10 million have angina pectoris. Chronic stable angina pectoris is the primary manifestation of CHD in about 1/2 of patients presenting with CHD for the first time. Silent myocardial ischemia, defined as “objective documentation of myocardial ischemia in the absence of angina or angina equivalents,” is common, occurring in 30% to 40% of patients with previous acute myocardial infarction (AMI) and in about 3% of apparently healthy subjects aged <60 years and >10% of those aged >70 years. Thus, stable CHD is common. A newly diagnosed patient with CHD poses complex treatment challenges, with 3 strategic options: coronary artery bypass grafting (CABG); percutaneous coronary intervention (PCI), usually in conjunction with intracoronary coronary stenting; and optimal medical treatment alone. In this Editor’s Roundtable, the faculty members discuss current perspectives on these treatment modalities in patients with stable CHD, with a focus on relevant recent clinical research and its clinical implications.

Discussion

Dr. Friedewald : Let’s first distinguish between the pathophysiology of the different forms of acute coronary syndrome (ACS) and stable CHD, because this distinction affects treatment and outcomes.

Dr. Stone : Most cases of stable angina pectoris and silent myocardial ischemia are due to coronary artery atherosclerosis that is 50% to 70% stenotic in cross-sectional area. The resulting obstruction to coronary arterial blood flow limits hyperemic fractional coronary flow reserve and results in myocardial ischemia during periods of increased myocardial oxygen demand, such as exercise, often with angina pectoris or other “anginal-equivalent” symptoms. These plaques tend to be very stable and progress slowly. In contrast, most ACS events involve relatively rapid plaque progression, usually caused by rupture of a thin-capped fibroatheroma with erosion of lipid-rich, metabolically-active plaque with T-cell and macrophage infiltration. The ruptured plaque releases tissue factor and other prothrombotic elements, resulting in coronary thrombosis. At that point the clinical manifestation of unstable angina pectoris, non-ST-segment myocardial infarction (non-STEMI) or ST-elevation myocardial infarction (STEMI), can occur, depending on the degree of coronary artery narrowing, the presence of collateral coronary vessels, and the effectiveness of endogenous fibrinolysis. In patients with ACS, timely coronary revascularization with either PCI or CABG is often lifesaving. Other patients with plaque rupture, however, may be asymptomatic or experience atypical chest pain, with rapid plaque progression manifest as the major sequelae of plaque rupture.

Dr. Roberts : Very few patients with stable CHD have been studied at necropsy. Unless these patients die suddenly, which places them in the category of sudden coronary death, or have an unrelated traumatic accident, there is no opportunity to examine the coronary arteries or myocardium. I have seen a few patients at necropsy with chronic angina pectoris, and most have about a third of the lengths of their 4 major coronary arteries narrowed >75% in cross-sectional area.

Dr. Friedewald : Patients with stable CHD have about the same amount of coronary artery narrowing by plaque as do patients with unstable CHD?

Dr. Roberts : That is correct. In AMI, thrombi are superimposed on atherosclerotic plaque. In unstable angina, however, small mural thrombi may be present, but they do not obstruct coronary arterial blood flow.

Dr. Boden : The stenotic fibrotic atherosclerotic plaque is the usual lesion that causes chronic angina, but it is unlikely to rupture and cause ACS. There is a spectrum of different types of coronary artery stenoses with varying degrees of quiescence and disease activity, such as inflammation throughout the coronary arterial tree in patients with atherosclerotic disease.

Dr. Friedewald : The diagnosis of angina pectoris can be difficult, especially in women and patients with diabetes mellitus. How do you assess these patients?

Dr. Boden : Diagnostic evaluation of angina pectoris largely depends on patient gender and age at the time of first presentation. In middle-aged or older individuals with typical exertional chest discomfort, 90% of the diagnoses of angina pectoris can be made based on patient history alone. The resting and exercise electrocardiogram add to diagnostic accuracy. The diagnosis of angina pectoris is more difficult in younger persons who do not have strong CHD risk factors and in premenopausal women. Women more often present with atypical features, such as “sharp” chest pain. In those individuals, in whom the pretest probability for CHD is low or when their symptoms are difficult to assess, directly proceeding to noninvasive diagnostic evaluation is appropriate, using either standard treadmill exercise testing—often false-positive in women, even though the guidelines still advocate it—or to myocardial perfusion imaging.

Dr. Roberts : Dr. Sam Levine used to say that angina pectoris is diagnosed by history alone: one either has angina or is a liar.

Dr. Stone : The patient history, combined with risk factor assessment, is critical to the accurate diagnosis of angina pectoris. When a high pretest probability is present, such as in a 70-year-old man with symptoms of classical exertion-induced chest discomfort relieved by rest, and who also has multiple risk factors for CAD (coronary artery disease), I perform cardiac catheterization without prior functional studies. For patients with atypical features and a lower pretest probability, however, I start with noninvasive studies, typically nuclear or echo stress testing. However, a useful test for the patient with a low pretest probability of CAD is multislice computed tomography, which I believe will be used more and more for assessing stable CHD.

Dr. Roberts : Since the first episode of angina pectoris is automatically considered unstable , how many episodes of angina must occur before it is considered stable ?

Dr. Stone : Chronic stable angina has to start sometime, and the question is, When is it going to accelerate into a true ACS rather than becoming chronic stable angina? I find the Braunwald classification of unstable angina pectoris to be useful. It states that severe angina should be regarded as unstable for 2 months from the time of onset, or occur 3 or more times per day, even when it is longstanding. Other characteristics of unstable angina are episodes that are progressing in frequency, brought on by decreasing degrees of provocation, and occurring at rest.

Dr. Friedewald : I use the term “stable CHD” rather than “chronic stable angina” in this discussion. Do you agree with this terminology?

Dr. Stone : I agree with the change, because the amount of myocardial ischemia determines the prognosis much more than symptoms . The degree of angina, however, is sometimes the catalyst for prompt coronary angiography and revascularization.

Dr. Boden : There is renewed interest in silent myocardial ischemia, which is often a difficult diagnosis. Silent myocardial ischemia is particularly common in patients with diabetes mellitus, which raises the question whether we should more aggressively look for ischemia in asymptomatic diabetics and other persons with multiple atherosclerotic risk factors.

Dr. Friedewald : In patients with stable CHD, do you advocate revascularization with either PCI or CABG?

Dr. Stone : There are 2 basic reasons to consider coronary revascularization with PCI or CABG in stable CHD: (1) for quality of life when medical treatment is inadequate and (2) to prevent death or AMI. There is a body of data in support of revascularization to prevent death or AMI in patients with stable CHD in whom ischemia is present. None of these studies, however, were definitive large-scale randomized trials proving that revascularization compared to medical therapy reduces death and AMI in patients with a large amount of myocardial ischemia. There is, however, sufficient evidence to warrant such studies.

Dr. Yancy : Do these studies suggest that myocardial ischemia in the absence of frank angina is predictive of poor outcomes and therefore that these patients should be treated with coronary arterial revascularization?

Dr. Boden : Myocardial ischemia may be the major driver of ACS, and trials to date have shown a consistent signal that coronary arterial revascularization may ameliorate myocardial ischemia more effectively than even the best medical therapy. They have not yet proven whether the reduction in myocardial ischemia from revascularization leads to reduced incidence of AMI or death. Two meta-analyses of the outcomes of revascularization in patients with stable angina pectoris have not found evidence that PCI reduces the incidence of death or AMI in patients who have not had a prior AMI. In contrast, there are abundant data to support the benefits of revascularization in ACS. Thus, many believe that revascularization reduces coronary events only in patients with significant myocardial ischemia in stable CHD, or in those with ACS, including non-STEMI and STEMI.

Dr. Yancy : What is appropriate medical treatment for unstable angina pectoris?

Dr. Stone : The mainstays of medical therapy in unstable angina include aspirin, clopidogrel or prasugrel, a statin with our without ezetamide, a β blocker, and an antithrombin agent, either heparin or the direct thrombin inhibitor bivalirudin. The use of glycoprotein IIb/IIIa inhibitors in patients undergoing PCI is also still frequent but is declining, especially in patients treated with a thienopyridine and bivalirudin.

Dr. Boden : I prefer using both a glycoprotein IIb/IIIa inhibitor and an antithrombin agent. Downstream microembolization of atheromatous debris may cause coronary microcirculatory obstruction and decrease myocardial perfusion, so complete platelet inhibition is desirable.

Dr. Yancy : What is the optimal medical therapy for stable CHD?

Dr. Stone : All patients with stable CHD regardless of whether they have had coronary revascularization, should be treated with aspirin, a statin and—depending on left ventricular function, renal function, and blood pressure—an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker and a β blocker. Diet and exercise also are essential. A P2Y ₁₂ antagonist is principally added in patients who undergo PCI but may be considered in those with established vascular disease at high atherothrombotic risk and low bleeding risk.

Dr. Boden : The pharmacological treatment of patients with stable CHD and patients with ACS is virtually identical, centered on aggressive treatment of hypertension, abnormal lipids—both high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein (HDL-C)—and diabetes mellitus. CHD should be treated as a systemic disease with focal exacerbations, which requires a pluralistic approach whereby medical treatment and coronary artery revascularization are not competing, alternative strategies; rather, they are complementary and additive. Optimal medical therapy means that everyone with any amount of CHD should be treated aggressively from the first time they are diagnosed. Stable angina pectoris covers a wide spectrum of presentations and treatment strategies. At 1 end of the spectrum is the patient who develops angina pectoris in stage 1 of the Bruce exercise testing protocol. That patient fails the test and has a high likelihood of incurring an ACS, even when the criteria for stable angina are not met. Such a patient needs coronary angiography and likely will require coronary revascularization. At the other end of the spectrum is the patient who gets through Bruce stage 3 or 4 but has some transient angina at the end of exercise along with <1-mm ST-segment depression on the electrocardiogram: a mildly positive stress test. That patient can be managed by simply beginning or intensifying medical treatment without proceeding to cardiac catheterization. Chronic angina pectoris, however, is comprised of a spectrum of pathophysiological conditions that cannot be simply categorized into an “all-or-nothing” or “yes-or-no” disease state.

Dr. Yancy : When do you consider performing coronary arterial revascularization in the patient with chronic stable myocardial ischemia?

Dr. Stone : That decision depends on the patient’s degree of symptoms, physical limitation, and extent of ischemia. I am comfortable treating the patient who has angina only once every 1 to 2 weeks with a small amount of myocardial ischemia with medications alone.

Dr. Roberts : How do you quantify myocardial ischemia?

Dr. Stone : The most useful data are obtained via the nuclear technetium-99 sestamibi scan, although echocardiography and MRI (magnetic resonance imaging) may also be quantitated.

Dr. Boden : I agree. Myocardial perfusion imaging is best for assessing the extent of myocardial ischemia, which should dictate the timing of coronary arteriography and revascularization.

Dr. Stone : For all those patients in the middle of the spectrum of chronic angina, the amount of myocardial ischemia on the nuclear scan becomes the deciding factor.

Dr. Roberts : Do you perform a nuclear scan on everybody with angina?

Dr. Boden : Most patients with angina. The left ventricular high lateral wall and posterolateral wall can be electrocardiographically silent. Myocardial perfusion imaging provides a greater probability of detecting prognostically important myocardial ischemia, whereas electrocardiography and other tests alone are too insensitive and do not provide as much disease quantification.

Dr. Friedewald : A huge percentage of patients do not take prescribed medicines. How does poor medication adherence factor into whether a patient with stable myocardial ischemia is treated with drugs or with coronary revascularization?

Dr. Boden : The CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines) trial demonstrated a good job of utilizing evidence-based medical therapies to treat ACS. There is no good reason why the same level of treatment in patients with stable CHD cannot be achieved. Medical nonadherence to a large extent is due to physicians’ doing poor jobs in reinforcing messages to patients that they must stay on medical therapy. There is a false presumption that coronary arterial revascularization is a way to avoid medications. We are doing our patients a disservice if we do not treat all of them, regardless of whether they have had coronary revascularization, with the same degree of therapeutic aggression, which includes reinforcing the need to take medications. This instruction and insistence require a lot of patience and commitment by physicians.

Dr. Friedewald : Unfortunately, some physicians do not feel a strong responsibility to promote patient adherence to pharmacological or nonpharmacological therapy.

Dr. Stone : I agree that some medications—especially aspirin, P2Y ₁₂ antagonists, and statins (and β blockers and ACE inhibitors when appropriate)—should be continued in patients who have had coronary arterial revascularization. However, many patients do not need antiangina medications after revascularization.

Dr. Boden : Nitrates and calcium channel blockers do not improve outcomes.

Dr. Stone : Often they can be discontinued after revascularization.

Dr. Yancy : There are multiple lines of evidence demonstrating that performance improvement strategies substantially improve adherence to evidence-based therapies in patients with CHD, heart failure, hypertension, and other diseases. With a program like Get With the Guidelines, which focuses on CHD and heart failure, nearly 90% adherence to evidence-based strategies can be achieved, but that is based on inpatient surveys. In the outpatient setting, we are uncertain how many patients receive medical treatment as advocated by guidelines.

Dr. Stone : There is greater implementation of guideline-based medical therapies in patients undergoing PCI than in patients who undergo either CABG or medical therapy alone.

Dr. Boden : That is consistent with my belief that interventional cardiologists are important drivers of primary care physicians’ treatment of cardiovascular patients. If interventionalists believe that a drug or drug combination is important, other physicians generally follow. Our challenge, as cardiologists, is to make sure that when referring patients back to their primary care physicians, we emphasize to them the importance of continuing the medical therapy we started. Primary care physicians have less and less time to spend with patients and are not given financial incentives to lower the low-density lipoprotein cholesterol (LDL-C) or blood pressure to optimal levels.

Dr. Friedewald : How does medical treatment compare with PCI in reducing myocardial ischemia?

Dr. Stone : In the presence of significant myocardial ischemia—involving at least 10% of the left ventricle, based on the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation) nuclear substudy—optimal medical therapy does not reduce ischemic burden. Following PCI and intracoronary stent implantation, however, there is significant reduction in myocardial ischemia. Thus, patients with a large amount of myocardium at risk should, in most cases, undergo coronary revascularization, especially patients with significant symptoms.

Dr. Boden : I agree, but the COURAGE nuclear substudy was underpowered. Among 314 patients, only 20% had myocardial ischemia involving >20% of the left ventricular wall. Most had minimal or no myocardial ischemia.

Dr. Stone : That is exactly the point. Patients with minimal myocardial ischemia do well with medical treatment alone. Numerous studies, however, including COURAGE, have shown that patients with myocardial ischemia involving >10% of the left ventricle have significantly increased mortality with medical therapy alone.

Dr. Boden : In a Medicare database population study, only 44% of patients had any type of noninvasive test to document myocardial ischemia within 90 days preceding an elective PCI for stable angina. If that study is representative of practices in the USA, we need to better advocate exercise or nuclear testing for patients with stable CHD.

Dr. Friedewald : Let’s discuss the SYNTAX (Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery) trial and its implications for surgery in stable CHD.

Dr. Boden : SYNTAX is a study in which “there is something for everyone.” It showed, in terms of the quadruple end point (death from any cause, stroke, AMI, repeat coronary vascularization), that CABG was superior to PCI. But for the death/AMI/stroke end point, a prognostically important composite, there was no difference between CABG and PCI at 1 year. Both surgeons and interventionalists claim “victory,” but both forms of revascularization were efficacious. CABG, however, is more invasive, carries a higher risk of stroke, and a lot of patients, when given the choice, prefer to avoid surgery.

Dr. Yancy : Were there not some long-term benefits better with CABG than with PCI in SYNTAX?

Dr. Stone : There is similar incidence in the rates of death and AMI, an increased rate of stroke with CABG, and increased need for repeat revascularization procedures with PCI. Many other end points, such as reoperation, wound infection, mediastinitis, and neurocognitive impairment, were not measured or emphasized. Given the lower morbidity of PCI, most patients prefer this less invasive approach. The trade-off is increased risk of a stroke with CABG versus increased need for CABG after PCI. Longer term data are required before any definitive conclusions can be drawn from this study.

Dr. Boden : I agree that SYNTAX must be interpreted with caution. One thing that I see too often is playing the “surgery card” in younger patients who have “surgical anatomy.” I dislike this strategy, because there is only 1 opportunity to get really good revascularization with CABG. I am far more inclined to use CABG in patients 55 to 70 years of age when a good durable outcome is likely. Performing multivessel PCI to avoid CABG also buys time for patients on medical therapy to get their risk factors under better control. Some experts believe that 3 to 5 years after the procedure, CABG has much better outcomes than PCI.

Dr. Stone : There may be some subsets of patients with CHD in whom CABG is better, but many patients with left main coronary artery obstruction may do as well or better with PCI than CABG. In SYNTAX, at least 2/3 of patients in the left main coronary artery intervention group had excellent outcomes with PCI. In contrast, patients with severe triple-vessel CHD had very high repeat revascularization rates with PCI, despite paclitaxel-eluting stents. Although it is reasonable to perform CABG on patients with triple-vessel CAD and relatively simple anatomy, SYNTAX suggests that patients with complex triple-vessel coronary disease fare better with CABG. Of note, however, that there are now better stents available than used in SYNTAX. PCI results have also been significantly improved with better pharmacology and other strategies. So the results of SYNTAX are already somewhat outdated.

Dr. Yancy : How do you interpret noninferiority with the SYNTAX results?

Dr. Stone : Noninferiority, strictly defined, depends on the margin of noninferiority that is accepted and tested. SYNTAX was powered for 1 primary end point, the composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year, and it did not demonstrate noninferiority for PCI compared to CABG. Technically, all other end points in SYNTAX should be considered exploratory and hypothesis generating.

Dr. Roberts : What were the symptoms of patients in SYNTAX?

Dr. Stone : Patients enrolled in SYNTAX presented with the entire gamut of clinical symptoms, from silent myocardial ischemia to unstable angina pectoris.

Dr. Yancy : Does the fact that clopidogrel was used in only 70% of patients in SYNTAX affect your interpretation of the results?

Dr. Boden : I was involved in the CHARISMA (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance) trial, and the overall end points for that trial—death, AMI, and stroke—showed no superiority of aspirin plus clopidogrel versus aspirin in stable non-AMI or non-ACS patients. There was, however, a definite benefit with clopidogrel for the secondary end points of death, AMI, stroke, and recurrent myocardial ischemia, as well as for the primary end point in those who had established CHD. Thus, it comes down to how studies like SYNTAX and CHARISMA are interpreted. The purists say such studies are hypothesis generating, but it is unlikely there will ever be another trial like CHARISMA. I believe that post-AMI patients and all other patients with extensive CHD, based on the prespecified analysis of CHARISMA, derive benefit from dual antiplatelet therapy. Patients who receive PCI and a stent require dual antiplatelet therapy for at least 1 year.

Dr. Friedewald : Let’s discuss the patient with diabetes mellitus and the FREEDOM (Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease) trial.

Dr. Boden : FREEDOM is an ongoing National Institutes of Health–funded trial involving patients with multivessel CHD and diabetes mellitus randomized to CABG or to PCI with drug-eluting stents in the context of optimal medical therapy. The target sample size is 2,600 patients. FREEDOM will be an important study, because the best revascularization strategy in the diabetic patient with multivessel coronary artery disease is currently uncertain. I see too many patients with diabetes mellitus who have had PCI or CABG and who keep returning to the hospital with elevated blood sugar and blood pressure and low serum high-density lipoprotein cholesterol. It is not a surprise that these patients also return with new CHD or with disease progression. They need much more aggressive control of their risk factors; otherwise, no changes in revascularization protocols will translate into better clinical outcomes.

Dr. Friedewald : What is the role of ranolazine in treating stable CHD?

Dr. Boden : Recurrent angina pectoris is a common problem, and there remain unmet needs in its medical treatment, even in the setting of successful PCI. Ranolazine is a late sodium channel inhibitor, which in the MERLIN–TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST Elevation Acute Coronary Syndromes–Thrombolysis In Myocardial Infarction 36) trial significantly reduced recurrent myocardial ischemia as a secondary end point but had no effect on the indices of death or AMI. It appears that patients with chronic stable angina benefit from ranolazine, so this drug should be considered a component of optimal medical therapy.

Dr. Stone : Patients who require nitrates, calcium channel blockers, β blockers, and ranolazine for control of chronic angina should have coronary arteriography and possible PCI. Refractory angina is rare after PCI and intracoronary stent implantation.

Dr. Boden : Recurrent angina after successful PCI is fairly common, but it may not be refractory.

Dr. Stone : It depends on the complexity of the disease. Most patients with extensive coronary disease who undergo successful CABG have only minimal or no postoperative angina.

Dr. Boden : Nonetheless, recurrent angina and myocardial ischemia are more common than is reported, I believe due to its being inadequately treated, both with coronary revascularization and with medical therapy.

Dr. Friedewald : What are the implications of JUPITER (Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin) for the treatment of patients with stable CHD?

Dr. Boden : I believe JUPITER has been overinterpreted. It is an important study in high-risk primary prevention. There is a 5-component event end point, and the benefit of rosuvastatin versus placebo at 2 years showed only 9 fewer events per 1,000 treated patients. Although this is statistically significant, is it clinically or biologically important?

Dr. Yancy : It is estimated that the number of JUPITER-like patients who are untreated in the USA is in the millions.

Dr. Boden : We all need to invest more time, effort, and resources on cardiovascular disease prevention. As it pertains to public policy, however, I am unconvinced that JUPITER’s results justify putting as many persons on a statin, as some suggest.

Dr. Roberts : Angina pectoris is an extremely expensive disease. Patients with angina undergo exercise testing, nuclear studies, coronary arteriography and angioplasty, stent implantation, and CABG, and they take a lot of expensive drugs regardless of the procedures. Prevention of angina by taking a lipid-lowering drug is relatively inexpensive. I think the JUPITER trial is wonderful, clearly demonstrating that LDL-C <55 is better than <100 or even <70 mg/dl.

Dr. Stone : The JUPITER results are not difficult to interpret. C-reactive protein (CRP) is a definite, although modest, predictor of cardiovascular death and other events. In JUPITER, patients with LDL-C <130 mg/dl and hs-CRP (high-sensitivity CRP) ≤2 mg/dl had a 20% reduction in all-cause mortality and significant reductions in the incidence of unstable angina, stroke, and AMI. In this regard, the results of the trial are definitive. The study has only become controversial because many object to the use of CRP as an entry criterion. But the results are the results within the population tested.

Dr. Boden : Those were, however, all relative risk reductions.

Dr. Stone : It is true that the absolute benefits were small, but the relative benefits were definite, and there were reductions in the individual end points of all-cause mortality, myocardial infarction, stroke, and the revascularization. Thus, although the absolute benefits were small, when applied to millions of persons, thousands of deaths and adverse events could be prevented. But can we afford it? That is the real question. We need to see a formal cost-effectiveness analysis.

Dr. Roberts : Lipid-lowering medications are inexpensive compared to hospitalizations and in-hospital procedures. Of course, a plant-based diet would make expenses even less, indeed much less.

Dr. Friedewald : What is the significance of a low serum HDL-C in patients with stable CHD?

Dr. Boden : A recent retrospective observational study assessed 1,032 patients with ACS, all of whom received an intracoronary drug-eluting stent (DES) and optimal medical therapy. About 1/2 of the patients had an HDL-C <40 mg/dl. The HDL-C in this patient population was a powerful discriminator for death and major cardiac events both at 30 days and 1-year post DES implantation. Greg Brown and I, as principal investigators, are starting a large National Institutes of Health–funded trial that will study secondary prevention in patients with established vascular disease. Patients with CAD, cerebrovascular disease, and peripheral arterial disease will be randomized into 2 treatment groups: patients taking simvastatin plus extended-release niacin and patients taking simvastatin alone. The baseline level for HDL-C is 34 mg/dl and for triglycerides 191 mg/dl. The study end points will be death, AMI, stroke, and hospitalization for recurrent ACS. Our goals are to determine (1) whether the hypothesis that combination dyslipidemic therapy is superior to statin monotherapy and (2) whether there is incremental benefit in raising the HDL-C.

Dr. Friedewald : Do you believe that when the LDL-C is <50 mg/dl, the HDL-C level is still an important risk factor?

Dr. Boden : Yes, although I know that many lipid experts believe when the LDL-C is <50 mg/dl, other risk factors are less important. We have known for many years from the Framingham study data that HDL-C and LDL-C are independent predictors of cardiovascular events. In the PROVE-IT (Pravastatin or Atorvastatin Evaluation and Infection Therapy) study, with an on-treatment LDL-C of 62 mg/dl in patients with recent ACS who were taking atorvastatin 80 mg/day, there was a 2-year event rate of 22%. That is not optimal. I believe that even after reduction in the total LDL-C, there remains a small, dense form of LDL-C or atherogenic pattern of LDL-C. We need to prove, however, that combination dyslipidemic therapy aimed at more than 1 target improves clinical outcomes.

Dr. Friedewald : When do you measure the CRP?

Dr. Boden : I usually obtain CRP levels on patients with ACS. I use the CRP as a guide as to how aggressively I should treat the LDL-C and the HDL-C.

Dr. Stone : Data from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, which involved 14,000 patients with ACS, also showed that the baseline CRP is an important multivariate predictor of both short-term and long-term mortality. CRP is a marker for systemic inflammation and has prognostic utility.

Dr. Friedewald : How useful is the serum troponin level in ACS?

Dr. Stone : Troponin measurements in patients with ACS are prognostically important. The troponin level correlates with the amount of coronary atherosclerosis, the number of diseased coronary arteries, and early mortality. It also corresponds with the response to early coronary revascularization. Troponin also may be useful in patients with chronic angina pectoris. About 5% of patients having PCI for sable CHD have preprocedure elevation of troponin, which correlates with the risk for in-hospital death and AMI. The troponin level in patients with established CAD represents underlying myonecrosis and has prognostic value as well as helping identify patients who best respond to coronary revascularization.

Dr. Boden : Troponin elevation after PCI is attributable to distal coronary microemboli. For this reason, I try to block platelet activity in patients undergoing PCI as much as possible with aspirin, clopidogrel, bivalirudin, and a thrombin inhibitor.

Dr. Stone : In ACUITY, troponin-positive patients pretreated with aspirin, clopidogrel, and bivalirudin had virtually identical 30-day and 1-year rates of death and AMI as patients receiving aspirin, clopidogrel, heparin, and a glycoprotein IIb/IIIa inhibitor. Moreover, patients treated only with bivalirudin rather than heparin and a glycoprotein IIb/IIIa inhibitor had markedly fewer episodes of major bleeding, with a trend toward lower late mortality.

Dr. Friedewald : How does treatment with the DES compare with the bare-metal stent (BMS) in patients with stable CHD?

Dr. Stone : There is a now a prodigious amount of data from multiple randomized trials and registries comparing DES with BMS. To summarize the collective results from these studies, with follow-up to 5 years, DES and BMS have comparable rates of death and AMI. DES, however, is associated with a 50% reduction in target lesion or target vessel revascularization, so it is significantly more efficacious. With everolimus-eluting stents, there is evidence from the SPIRIT (Randomized Comparison of Everolimus-Eluting and Paclitaxel-Eluting Stents: 2-Year Clinical Follow-Up From the Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients With De Novo Native Coronary Artery Lesions) II and SPIRIT III trials that there is even further reduction in major adverse cardiovascular events, including fewer repeat revascularizations for lower stent restenosis and possibly even reduced rates of death and AMI. Unfortunately, DES trials have not adequately studied indicators of quality of life or cost-effectiveness, although Medicare data suggest that the overall costs to the health care system are either decreasing or at least increasing at a slower rate than inflation with DES compared to BMS as fewer patients have CABG than PCI.

Dr. Friedewald : How long should patients take clopidogrel after receiving an intracoronary stent?

Dr. Stone : The current recommendations are to use aspirin indefinitely and clopidogrel for at least 12 months after stenting (whether DES or BMS), although it should be noted that minimal data suggests that >6 months is necessary, and long-term use must be balanced against the ongoing risk of major bleeding. Fortunately, enrollment is ongoing in a large-scale trial that will determine the utility of 1 year compared to 2.5 years of dual antiplatelet therapy after intracoronary stenting, although these results will not be available for many years.

Dr. Yancy : What do you believe is a reasonable end point for adoptability by the practicing community and regulatory bodies when a new stent is developed?

Dr. Stone : At a minimum for approval of a new drug-eluting stent, manufacturers need to conduct robust preclinical testing with porcine animal data for several years that show no significant adverse toxic vascular effects. For example, there should be no medial necrosis or significant vascular remodeling, only low levels of inflammation, and rapid and complete stent endothelialization. Clinical testing should include a pivotal complete clinical study with >1,000 patients at 1 year and significant safety data for 2 years. The extent of investigation also depends on whether the stent contains a new molecular entity, for which the Food and Drug Administration requires data on >2,000 patients.

Dr. Yancy : Is late stent thrombosis—≥12 months after implant—a real phenomenon?

Dr. Stone : Yes, and it occurs more frequently with the DES than with the BMS. It is somewhat offset by thrombotic events after restenosis with BMS, so the overall rates of thrombosis may be similar with the 2 types of stents. But late stent thrombosis is a major concern to physicians and patients that must be eliminated with safer stents in the future.

Dr. Boden : I also agree that late stent thrombosis occurs, although its true prevalence is unknown. Most patients who present late will have an AMI, and in those in whom it is fatal and a necropsy is not performed, it is unknown whether the AMI is caused by stent stenosis. It also raises the question of optimal duration of treatment for dual antiplatelet therapy. The guidelines advocate 1 year after implant, but I prefer to treat longer. At least 20% of patients who receive aspirin and clopidogrel do not respond optimally, some perhaps due to genetic variability.

Dr. Stone : It is difficult to diagnose stent thrombosis. Stent thrombosis is, however, only 1 of the adverse events that can occur after revascularization, and to put this event in perspective, it is important to consider the harder end points of death and AMI. The overall death and AMI rates in patients receiving DES compared to BMS are not increased, and efficacy is much greater. Very late stent thrombosis, however, is 1 causative mechanism of AMI that might be reduced through better pharmacological treatment or safer devices, which would further improve outcomes.

Dr. Friedewald : What are the economics of optimal medical therapy versus coronary arterial revascularization?

Dr. Boden : In a study like COURAGE, where the primary outcome showed no difference between PCI plus optimal medical therapy versus optimal medical therapy alone, it is important to determine whether there is an incremental cost benefit of PCI. For patients enrolled in COURAGE with stable CHD, whether using the metric of life-years gained or quality-adjusted life-years gained, the average incremental cost-effectiveness ratio (ICER) was estimated at about $300,000 in terms of life-years gained over the in-trial duration (up to 7 years) and $206,000 for the quality-adjusted life-year–gained ICER. For other proven therapies, such as aspirin, clopidogrel, statins, and β blockers, the quality-adjusted life-years gained is <$30,000, with $50,000 as the benchmark that health economists have deemed to be cost effective. Thus, PCI is considerably more expensive in terms of the economic benefit. With a quadrant analysis, in only about 1% to 3% of the replicates is PCI dominant over optimal medical therapy. Conversely, in 20% of the replicates, optimal medical therapy is superior to PCI as a more cost-effective strategy. It is unclear whether these numbers will affect utilization rates. In the USA, there are very divergent rates of PCI, with overuse in some areas.

Dr. Friedewald : The 2009 appropriateness criteria for coronary revascularization states, “Physicians and other stakeholders should continue to acknowledge the pivotal role of clinical judgment in determining whether revascularization is indicated for the individual patient.” Would you all agree that this statement applies to treatment of patients with stable CHD?

Dr. Boden : Yes. Results of all strategy trials must ultimately be applied to the bedside and individualized. There is no trial that is a surrogate for thoughtful clinical decision making. We have to be careful not to paint either optimal medical therapy or PCI with a bad brush. Clinical judgment is the most important determinant in making a decision of what is best for individual patients with stable CHD.

Dr. Stone : I agree.

Dr. Friedewald : Closing comments?

Dr. Boden : We have learned a great deal over the last 2 decades about the benefits of PCI for patients with CHD. Patients with STEMI and other types of ACS benefit from PCI or myocardial revascularization in decreased death rates, AMI, stroke, and preservation of left ventricular function. For patients with stable CHD, we now have data from COURAGE to support the importance of optimal medical therapy as an important treatment option. We must abandon the belief that these are opposing treatment strategies or that they are mutually exclusive; rather, they are additive and complementary. Atherosclerotic disease is a systemic disease with focal exacerbations. There needs to be greater focus on treating this disease aggressively.

Dr. Stone : Optimal medical therapy, including lifestyle adjustments such as smoking cessation, weight control, exercise, and optimal pharmacotherapy, needs to be the foundation for the effective management of all patients with CAD. The question then becomes, When is coronary revascularization appropriate? For patients with STEMI, non-STEMI, and high-risk unstable angina pectoris, an early invasive approach with revascularization, when dictated by the anatomy, clearly improves outcomes. For patients with stable angina, there is increasing evidence that patients with significant myocardial ischemia and/or lifestyle-limiting symptoms have an improved prognosis by early revascularization. Patients with lesser degrees of myocardial ischemia or symptoms that are relatively easily controlled by antianginal medications and who are adherent to therapy often can be satisfactorily managed with medical therapy alone.

Dr. Yancy : We must firmly embrace a quality-focused, evidence-based approach in care, with added attention to outpatients.

Dr. Roberts : The progress in treating patients with myocardial ischemia in the last 40 years is remarkable. However, it can never be good enough as long as average body weight continues to increase. The average body mass index in the USA is about 28, and the average LDL-C is about 130 mg/dl. Waiting until an atherosclerotic event occurs before we treat is very expensive. Atherosclerosis is due to abnormalities of serum cholesterol, mostly from eating calories high in cholesterol and saturated fats. If we all existed on a plant-based diet, we would not have needed this discussion.

Dr. Friedewald : Thank you.