Biomarkers and Surrogate Endpoints: Advancing Clinical Research and Applications

Cardiovascular II

Stable Cardiovascular Disease

Background

In patients with stable coronary artery disease (CAD), the atherosclerotic process can induce a host of coronary functional and anatomic abnormalities that eventually affect myocardial performance. A number of factors likely contribute to this process, including procoagulant tendencies, inflammation, metabolic abnormalities, coronary microcalcification, oxygen radicals, and oxidized lipids. The treatment is usually multitargeted, frequently focused on clinical presentation of ischemia. The relevant biomarker might target coronary flow limitations and/or abnormalities, expression of ischemia, such as perfusion, myocardial metabolism or left ventricular function, or factors involved in CAD. Ischemia can be assessed directly by myocardial metabolic assessment (³¹P or other techniques), indirectly by perfusion techniques, such as nuclear imaging or MRI, or by ECG changes (ambulatory ECG).

Agenda

Moderators: Robert Califf, M.D., Duke University

Robert S. Balaban, M.D., National Heart, Lung, and Blood Institute

Targeted Topics: Asymptomatic Coronary Artery Disease, Chronic Ischemic Cardiomyopathy

Electron Beam Computerized Tomography

Douglas P. Boyd, Ph.D., University of California, San Francisco

Nathaniel Reichek, M.D., Medical College of Pennsylvania and MCP Hahnemann University

Angiography and Vascular Reactivity and Flow

Edwin L. Alderman, M.D., Stanford University Medical Center

Steven Reis, M.D., University of Pittsburgh Medical Center

ECG Monitoring

Peter H. Stone, M.D., Brigham and Women’s Hospital

Bernard Chaitman, M.D., St. Louis University Medical Center

Myocardial Imaging

Robert Bonow, M.D., Northwestern University Medical School

Gerald M. Pohost, M.D., University of Alabama, Birmingham

Other Markers: Inflammatory, Infectious, Hemostatic, Lipids, and Others

Paul M. Ridker, M.D., Brigham and Women’s Hospital

Burton E. Sobel, M.D., University of Vermont

Edwin L. Alderman, M.D., Stanford University Medical Center

Clinical Trials Challenges

Janet Wittes, Ph.D., Statistics Collaborative

Discussant: Robert R. Fenichel, M.D., Ph.D., Center for Drug Evaluation and Research, U.S. Food and Drug Administration

Summation and Recommendations

ABSTRACTS

Calcium as a Biomarker for Atherosclerosis Progression and Regression in Coronary Artery Disease

Douglas P. Boyd, Ph.D.

Atherosclerosis is a silent disease that develops slowly over decades of life until it manifests itself in clinical coronary artery disease with symptoms including angina, heart attack, heart failure, and sudden death. The treatment of atherosclerosis involves lifestyle modifications and medical treatment of lipid disorders. Histologic studies have shown that approximately 20 percent of the volume of plaque in coronary atherosclerosis is marked by detectable levels of calcium (Rumberger et al. 1995). Although soft plaques with no detectable calcium exist, large studies have shown that 96 percent of asymptomatic patients with clinical coronary disease as demonstrated by angiography have detectable coronary calcium (Laudon et al. 1999). Other studies have shown that the prevalence of calcium correlates with increased risk of future coronary events, and the greater the amount of calcium, the higher the risk (Arad et al. 1996). The risk, sometimes expressed as an “odds ratio,” can be 20:1 or higher and is independent of the presence or absence or symptoms of cardiac disease. In the past, coronary artery calcification (CAC) could be detected by fluoroscopy. However, the results were variable due to the relative insensitivity of the fluoroscopic technique and the requirement of a skilled operator. Today the “gold‑standard” for the detection and quantification of CAC is electron beam CT (EBCT) scanning using a 100 millisecond scan speed. Recent research has focused on the reproducibility of CAC scores and the ability of such quantitation to track the progression and regression of atherosclerotic disease. Callister and colleagues (1998) demonstrated in a retrospective study of 149 patients the ability to track disease progression after 12 to 15 months of treatment with a statin drug. Untreated patients advanced in plaque volume by 52 percent. Those treated who achieved a final low‑density lipoprotein (LDL) cholesterol level of less than 120 mg per deciliter had a net regression of about 7 percent. Regression analysis showed an association with the degree of regression and the final LDL level achieved. These kinds of drug studies depend on the accuracy of CAC scoring. With higher accuracy, the longitudinal interval could be shortened and fewer patients would need to be logged into a blind study. Currently, CAC is scored using an Agatston score (Agatston et al. 1990), which approximates the mass of calcium present, and a volume score, which estimates a plaque volume. The major sources of error include motion artifact, electrocardiograph triggering errors, resolution blurring, and variability in background subtraction as determined by a threshold. All of these issues can be addressed by technical improvements, many of which are under way. Some of the improvements will be made in the EBT scanner itself (reduce scan speed to the 35‑50 msec range, introduce multiple slices, increase resolution by doubling detector pitch), and others require improvements in the CAC scoring workstation algorithms (interpolation scoring, linearization, and normalyzation of background using self‑calibration). These techniques and others will advance the accuracy of CAC in future years, thus providing an increasingly precise biomarker for early detection, monitoring of treatment, and for interventional research studies in coronary artery disease.

Key References

Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte M Jr, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827‑832.

Arad Y, Spadaro LA, Goodman K, Lledo‑Perez A, Sherman S, Lerner G, Guerci AD. Predictive value of electron beam computed tomography of the coronary arteries, 19‑month follow‑up of 1173 asymptomatic subjects. Circulation 1996;93:1951‑1953.

Callister, TQ, Raggi, P, Cooil, B, Lippolis, NJ, and Russo, DJ. Effect of HMG‑CoA Reductase inhibitors on coronary artery disease as assessed by electron‑beam computed tomography, N Engl J Med 1998;339:1972‑1978.

Laudon DA, Yukov LF, Breen JF, Rumberger JA, Wollan PC, Sheedy PF. Use of electron‑beam computed tomoraphy in the evaluation of chest pain patients in the emergency department. Ann Emerg Med 1999;33:15‑21.

Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwart RS. Coronary artery calcium area by electron beam computed tomography and coronary atherosclerotic plaque area: A histopathologic correlative study. Circulation 1995;15:2157‑2162.

Electron Beam‑Computed Tomography

Nathaniel Reichek, M.D.

Electron beam‑computed tomography (EBCT) is a highly effective method for detection of calcific coronary atherosclerosis. Thus, the EBCT calcium score is a very useful marker of the extent of coronary atherosclerosis, particularly for studies of clinical epidemiology. Stratification of a population by calcium score correlates well overall with likelihood of coronary stenoses and prevalence of coronary events. In populations with chest pain, those with normal EBCT calcium scores have a much lower likelihood of coronary stenoses than those with high calcium scores. Effective treatment of hyperlipidemia can be associated with a reduction in calcium score. However, the calcium score also has many important limitations that limit use as a biomarker for coronary atherosclerosis at the present time. The variability of calcium score on repeat EBCT is excessively high. Age‑dependent increases in score complicate interpretation. The method may not identify patients with early disease and potentially hazardous vulnerable plaques. A high calcium score is sensitive but nonspecific as a marker for coronary stenoses. Although scores may change with lipid‑lowering treatment or increase over time as part of the natural history of coronary atherosclerosis, there is no evidence that such changes correlate with changes in the actual extent of atherosclerosis or risk of clinical events.

Key References

Baumgart D, Schmermund A, Goerge G, Haude M, GeJ, Adamzik M, Sehnert C, Altmaier K, Groenmeyer D, Seibel R, Erbel R. Comparison of electron beam computed tomography with intracoronary ultrasound and coronary angiography for detection of coronary atherosclerosis. J Am Coll Cardiol 1997;30:57‑64.

Budoff MJ, Georgiou D, Brody A, Agatston AS, Kennedy J, Wolfkiel C, Stanford W, Shields P, Lewis RJ, Janowitz WR, Rich S, Brundage BH. Ultrafast computed tomography as a diagnostic modality in the detection of coronary artery disease: A multicenter study. Circulation 1996;93:898‑904.

Callister TQ, Cooil B, Raya SP, Lippolis NJ, Russo DJ, Raggi P. Coronary artery disease: Improved reproducibility of calcium scoring with an electron‑beam CT volumetric method. Radiology 1998;208:807‑814.

Callister TQ, Raggi P, Cooil B, Lippolis NJ, Russo DJ. Effect of HMG‑CoA reductase inhibitors on coronary artery disease as assessed by electron‑beam computed tomography. N Engl J Med 1998;339:1972‑1978.

Detrano R, Hsiai T, Wang S, Puentes G, Fallavollita J, Shields P, Stanford W, Wolfkiel C, Georgiu D, Budoff M, Reed J. Prognostic value of coronary calcification and angiographic stenoses in patients undergoing coronary angiography. J Am Coll Cardiol 1996;27:285‑290.

Devries S, Wolfkiel C, Fusman B, Bakdash H, Ahmed A, Levy P, Chomka E, Kondos G, Zajac E, Rich S. Influence of age and gender on the presence of coronary calcium detected by ultrafast computed tomography. J Am Coll Cardiol 1995;25:76‑82.

Rumberger JA, Behrenbeck T, Breen JF, Sheedy PF. Coronary calcification by electron beam computed tomography and obstructive coronary artery disease: A model for costs and effectiveness of diagnosis as compared with conventional cardiac testing methods. J Am Coll Cardiol 1999;33:453‑462.

Wexler L, Brundage B, crouse J, Detrano R, Fuster V, Maddahi J, Rumberger J, Stanford W, White R,Taubert K. Coronary artery calcification: Pathophysiology, epidemiology, imaging methods and clinical implications. A statement for health professionals from the American Heart Association. Circulation 1996;94:1175‑1192.

The Electrocardiogram as a Surrogate Marker for Clinical Research in Stable Coronary Disease

Peter H. Stone, M.D. and Bernard Chaitman, M.D.

The presence of myocardial ischemia, as evidenced by the electrocardiogram (ECG), is an independent, noninvasive predictor of adverse clinical outcomes in patients with stable coronary disease (CAD). The presence of ST‑segment depression on the resting ECG predicts increased morbidity and mortality. The development of exercise‑induced ST‑segment depression is the standard noninvasive marker of poor prognosis and serves as the fundamental clinical guide to identify the need for coronary angiography and revascularization for millions of patients with CAD. Episodes of ST‑segment depression during routine daily activities, identified by ambulatory ECG (Holter) monitoring, provides incremental prognostic information. Treatment of ischemic jeopardy with revascularization or pharmacologic strategies improves both prognosis and the ECG markers of ischemia. It remains unknown, however, whether the improved prognosis is due to the improvement in ischemia, as indicated by the ECG marker, or to an improvement in the fundamental coronary anatomy that is responsible for the adverse cardiac events (i.e., presence of a vulnerable atherosclerotic plaque). The improvement in prognosis may be due only to the improved coronary anatomy and not to the improvement in ischemia per se (or the ECG marker of ischemia). Treatments may improve coronary anatomy, with a subsequent improvement in prognosis, even with the persistence of ECG markers of ischemia. The Asymptomatic Cardiac Ischemia Pilot (ACIP) Study was designed to determine whether there was an incremental prognostic benefit from aggressively reducing ECG markers of ischemia in addition to simply controlling anginal symptoms. Patients were randomized to one of three strategies: (1) medications to alleviate angina only, (2) medications to alleviate angina and abolish as much ECG marker of ischemia as possible, and (3) revascularization. Although only a pilot study, there was the suggestion that progressive reduction in the ECG markers of ischemia was associated with a progressive improvement in prognosis. Large‑scale trials are being planned to explore these associations. If such research indicates that improved ECG markers are strongly correlated with improved prognosis, then ECG markers may be sufficient both to guide clinical care decisions and to develop and approve new treatment strategies.

Key References

Chaitman BR, Stone PH, Knatterud GL, Forman SA, Sopko G, Bourassa MG, Pratt C, Rogers WJ, Pepine CJ, Conti CR. Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: Impact of anti‑ischemia therapy on 12‑week rest ECG an exercise test outcomes. The ACIP Investigators. J Am Coll Cardiol 1995;26:585‑593.

Knatterud GL, Bourassa MG, Pepine CJ, Geller NL, Sopko G, Chaitman BR, Pratt C, Stone PH, Davies RF, Rogers WJ, et al. Effects of treatment strategies to suppress ischemia in patients with coronary artery disease: 12‑week results of the ACIP study. J Am Coll Cardiol 1994;24:11‑20.

Moss AJ, Goldstein RE, Hall WJ, Bigger JT Jr, Fleiss JL, Greenberg H, Bodenheimer M, Krone RJ, Marcus FI, Wackers FJ, et al. Detection and significance of myocardial ischemia in stable patients after recovery from an acute coronary event. JAMA 1993;269:2379‑2385.

Rogers WJ, Bourassa MG, Anderws TC, Bertolet BD, Blumenthal RS, Chaitman BR, Forman SA, Geller NL, Goldberg AD, Habib GB, et al. Asymptomatic Cardiac Ischemia Pilot (ACIP) Study: Outcome at 1 year for patients with asymptomatic cardiac ischemia randomized to medical therapy or revascularization. The ACIP Investigators. J Am Coll Cardiol 1995;26:594‑605.

Stone PH, Chaitman BR, Forman S, Andrews TC, Bittner V, Bourassa MG, Davies RF, Deanfield JE, Frishman W, Goldberg AD, MacCallum G, Ouyang P, Pepine CJ, Pratt CM, Sharaf B, Steingart R, Knatterud GL, Sopko G, Conti CR. Prognostic significance of myocardial ischemia detected by ambulatory ECG, exercise treadmill testing, and ECG at rest to predict cardiac events by one year (the ACIP Study). Am J Cardiol 1997;80:1395‑1401.

Plasminogen Activator Inhibitor Type 1 (PAI‑1) and Vasculopathy

Burton E. Sobel, M.D.

Insulin‑resistant states, including type 2 diabetes mellitus, are associated with increased concentrations of plasminogen activator inhibitor type‑1 (PAI‑1) in blood and in extracted coronary atheroma as well as with an increased incidence of acute coronary syndromes, known to be precipitated by rupture of vulnerable atherosclerotic plaques. However, plaque rupture is potentiated by proteolysis. Accordingly, the parallel relationship between augmentation of concentrations of an inhibitor of proteolysis and plaque vulnerability appears to be paradoxical. The following resolution is proposed. Reduced cellularity of plaques may result when high concentrations of PAI‑1 in early atheroma inhibit migration of vascular smooth muscle cells into the neointima. Such migrating cells subsequently proliferate. If their total number is reduced, the composition of plaques may be altered throughout development with reduction of vascular smooth muscle cell content and consequent additional changes. In aggregate, such changes may render mature, complex plaques vulnerable to rupture mediated by proteolysis responsible for degradation of thin fibrous caps on relatively acellular, lipid‑laden plaques. Accordingly, high PAI‑1 in blood may be a marker of plaque vulnerability.

Key References

Ehrmann DA, Schneider DJ, Sobel BE, Cavaghan MK, Imperial J, Rosenfield RL, Polonsky KS. Troglitazone improves defects in insulin action, insulin secretion, ovarian steroidogenesis, and fibrinolysis in women with polycystic ovary syndrome. J Clin Endocrinol Metab 1997;82:2108‑2126.

Fattal PG, Schneider DJ, Sobel BE, Billadello JJ. Post‑transcriptional regulation of expression of plasminogen activator inhibitor type 1 mRNA by insulin and insulin‑like growth factor 1. J Biol Chem 1992;267:12412‑12415.

Haffner SM. The insulin resistance syndrome revisited. Diabetes Care 1996;19:275‑277.

Juhan‑Vague I, Vague P, Alessi MC, Badier C, Valadier J, Aillaud MF, Atlan C. Relationships between plasma insulin, triglyceride, body mass index, and plasminogen activator inhibitor 1. Diabete Metab 1987;13:331‑336.

Loskutoff DJ, van Aken BE, Seiffert D. Abnormalities in the fibrinolytic system of the vascular wall associated with atherosclerosis. Ann N Y Acad Sci 1995;748:177‑183.

McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors responsible for impaired fibrinolysis in obese subjects and NIDDM patients. Diabetes 1994;43:104‑109.

Schneider DJ, Ricci MA, Taatjes DJ, Baumann PQ, Reese JC, Leavitt BJ, Absher M, Sobel BE. Changes in arterial expression of fibrinolytic system proteins in atherogenesis. Arterioscler Thromb Vasc Biol 1997;17:3294‑3301.

Sobel BE. The potential influence of insulin and plasminogen activator inhibitor type‑1 on acceleration of macrovascular disease in type 2 diabetes. Proceedings of the Association of American Physicians, submitted.

Sobel BE, Woodcock‑Mitchell J, Schneider DJ, Holt RE, Marutsuka K, Gold H. Increased plasminogen activator inhibitor type‑1 in coronary artery atherectomy specimens from type 2 diabetic compared with nondiabetic patients: A potential factor predisposing to thrombosis and its persistence. Circulation 1998;97:2213‑2221.

Uusitupa MI, Niskanen LK, Siitonen O, Voutilainen E, Pyorala K. 5‑Year incidence of atherosclerotic vascular disease in relation to general risk factors, insulin level, and abnormalities in lipoprotein composition in non‑insulin‑dependent diabetic and nondiabetic subjects. Circulation 1990;82: 27‑36.

Inflammatory Biomarkers in the Prediction of Future Coronary Events Among Apparently Healthy Men and Women

Paul M. Ridker, M.D., M.P.H.

Myocardial infarction and stroke commonly occur among individuals without hyperlipidemia. In an attempt to better predict future coronary events, epidemiologic studies have explored a series of novel risk factors including biomarkers of inflammatory function. Specifically, recent large‑scale prospective studies indicate that nonspecific inflammatory markers, such as C‑reactive protein and serum amyloid A, as well as direct markers of cellular adhesion (soluble intercellular adhesion molecule 1) and cytokine activation interleukin‑6 are all elevated many years in advance among those at high risk for future events. This has been shown for women as well as men and is present in subgroups of patients traditionally considered low risk. Further, the predictive value of inflammatory markers appears to be additive to that of total and high‑density lipoprotein cholesterol. Because these inflammatory changes are present many years in advance and likely reflect the presence of unstable lesions, the use of inflammatory markers in the clinical setting may provide a mechanism for early detection and intervention for those at high risk for future coronary disease.

Key References

Ridker PM. Fibrinolytic and inflammatory markers for arterial occlusion: the evolving epidemiology of thrombosis and hemostasis. Thromb Haemost 1997;78:53‑59.

Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Hennekens CH. Plasma concentration of C‑reactive protein and risk of developing peripheral vascular disease. Circulation 1998;97:425‑428.

Ridker PM, Glynn RJ, Hennekens CH. C‑reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation 1998;97:2007‑2011.

Ridker PM, Haughie P. Prospective studies of C‑reactive protein as a risk factor for cardiovascular disease. J Invest Med 1998;46:391‑395.

Ridker PM, Hennekens CH, Roitman‑Johnson B, Stampfer MJ, Allen J. Plasma concentration of soluble intercellular adhesion molecule 1 and risks of future myocardial infarction in apparently healthy men. Lancet 1998;351:88‑92.

Ridker PM, Hennekens CH, Roitman‑Johnson B, Stampfer MJ, Allen J. Ridker PM, Cushman M, Stampfer MJ, Tracey RP, Hennekens CH. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men. N Engl J Med 1997;336:973‑979.

Ridker PM, Rifai N, Pfeffer MA, Sacks FM, Moye LA, Goldman S, Flaker GC, Braunwald E for the Cholesterol and Recurrent Events (CARE) Investigators. Inflammation, pravastatin, and the risk of coronary events after myocardial infarction in patients with average cholesterol levels. Circulation 1998;98:839‑844.

Coronary Angiographic Imaging as a Surrogate Measurement of Atherosclerosis and Treatment Interventions

Edwin L. Alderman, M.D.

Coronary angiography has the advantages of direct lumen quantitation, correlation with current clinical status, and demonstrated strengths in multiple randomized studies of risk factor interventions (e.g., exercise, hypolipidemic drugs, etc.). Computer-assisted quantitation has been successfully used to detect atherosclerosis regression or progression. Its applicability in clinical trials is limited by necessity for invasive procedures, technical constraints on image resolution (epicardial vessels only), and indirect relationship of a lumen measurement with intramural disease and with occurrence of clinical events. Intramural disease is better evaluated using intracoronary ultrasound, which can visualize plaque volume and composition. However, serial image quality is dependent on attention to the details of the imaging protocol, retention of image resolution from acquisition to core lab analysis (transfer media) and the criteria used to select lesions and segments for quantitation. Statistical decisions arise regarding selection of individual diameter measurements (e.g., minimum, mean, etc.), whether visually diseased or nondiseased segments are included, and manner of integration of lesion or segment quantitation data into a patient-by-patient analysis.

Key Reference

Haskell WL, Alderman EL, Fair JM, Maron DJ, Mackey SF, Superko HR, Williams PT, Johnstone IM, Champagne MA, Krauss RM, Farquhar JW. Effects of intensive multiple risk factor reduction on coronary atherosclerosis and clinical cardiac events in men and women with coronary atherosclerosis: The Stanford Coronary Risk Intervention Project (SCRIP). Circulation 1994;89:975‑990.