Cardiac markers in acute coronary syndromes—refining our knowledge

R.M Califf*

Division of Cardiology, Department of Medicine, Duke University Medical Center, Duke Clinical Research Institute, P.O. Box 17969, Durham, NC 27715, USA

Received October 22, 2002; accepted October 23, 2002 * Tel.: +1-919-668-8820; fax: +1-919-668-7103
calif001{at}mc.duke.edu

See doi:10.1016/S1095-668X(02)00322-6and doi:10.1053/S1095-668X(02)00312-2for thearticles to which this editorial refers.

Just a few years ago, we appeared to be stymied in advancing the ability to predict outcomes in patients with acute coronary syndromes (ACS). A combination of refined clinical observation,advances in measurement of pathobiology, and large studies with expert application of statistical methods, however, has advanced this field beyond the ability of the clinical world to keep pace. Inthe last 5 years, the troponins,1–3 better clinical statistical models,4–6 C-reactive protein (CRP),7 and brain natriuretic peptide (BNP)8 have all shown promise for providing biological insight and for predicting outcome. One can legitimately ask the question: who cares to know about risk if one cannot do anything about it? Thus, in addition to adding knowledge (always a worthy goal), it is imperative to take risk stratification into the era of informed decision-making.

In this month's edition of the Journal, we are fortunate to have two articles that further refine previous knowledge. Lenderink et al.9 offer a long-term look at the prognosis and treatment-effect implications from the CAPTURE Trial. Oldgrenet al.10 take advantage of a failed clinical-development program with the drug inogatran to evaluate the intercorrelations of markers thought to reflect myocardial damage, inflammation, and thrombin inhibition in the acute phase of ACS.

Both of these studies exemplify an important development in the collaboration between academia and industry in the clinical-trials field. For years, the medical-products industry hascollected large amounts of information with much greater quality (albeit at much greater expense) than typical academic studies. In most fields, however, these data have not been used beyond extensive reports to regulatory authorities and primary publications. For both of the trials, not only were the databases available for academic pursuits, but they actually were shared with the academic coordinating centers that helped organize the trials. These studies are important bookmarks in anevolving public-private partnership aimed at takingadvantage of data collection by both sectors to maximize our knowledge of the field.

The report from Lenderink et al.9 extends the power of troponin measurement to identify patients likely to benefit from glycoprotein (GP) IIb/IIIainhibitor therapy. Furthermore, it points out that CRP, despite its confirmed prognostic importance, has no ability to discriminate patients who would benefit from GP IIb/IIIa inhibition. These findings add to the growing understanding that biomarkers may provide specific information about which therapeutic approaches are beneficial in addition to identifying the risk of future events. These findings, combined with many others, place troponin in the special category of a marker that should direct therapy. Unfortunately, while CRP is increasingly recognized as an excellent stratifier of prognosis, data are not available to identify specific therapies that should be used. More recent data are now raising the question of whether CRP should beused to direct the strategy of revascularization rather than acute medical therapy. Thus, wemay be entering an era of ‘protein-directedtherapy’.

In contrast, the report by Oldgren et al.10attempts to use intercorrelation of measurements of tissue damage and inflammation to provide pathophysiological insight. The basic findings are that although CRP elevations relate to troponin elevations, the relationship is far from fullyexplanatory, and that fibrinogen levels remainelevated for at least a month after the acute event. The report also confirms the prognostic importance of all three components of this interrelated biology: necrosis, inflammation, and thrombosis. They make the case that ACS represents a state in which there is an acute inflammatory response to the clinical event, as well as a smouldering state of inflammation presumably before and long after the acute event.

Although dissection and reduction of these biological systems into their components is essentialto increase our understanding of the situation,ultimately the goal is to develop diagnostic and therapeutic combinations that will reduce the probability that a person with ACS, or even more important, a person at risk of ACS, will die or have major events that impair their quality of life. For this to happen, various steps will be needed. First, more studies will need to measure an array of biomarkers combined with a full description of clinical characteristics. Second, adequate statistical methods will be needed to sort out which characteristics and markers provide novel information and which are redundant or unnecessary. Third, to truly know when a marker should be used to drive treatment, comparative clinical trials will need to embed biomarkers in their designs, to produce a much larger body of data than the pioneering work of the CAPTURE trial. Finally, practitioners will need to develop systems to allow ascertainment of markers at the right time to allow rational use of the marker to guide therapy. Preliminary data indicate that although troponin is now widely measured in the United States, therapy differs little as a function of the result. The reason for this failurein translation of knowledge may be the prolonged time between ordering the troponin test and seeing the result (this has been termed the ‘vein to brain’ time).

The time delay between concept and application of diagnostic markers is formidable, but these two studies provide important examples of advances in knowledge made possible by partnership between academia and industry, thereby allowing sharingof data and advancement in the understanding of disease in the context of pursuit of commercial application of products.

References

  1. Ohman EM, Armstrong PW, Christenson RH, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. GUSTO IIa Investigators. N Engl J Med. 1996;335:1333–1341[Abstract/Free Full Text]
  2. Newby LK, Christenson RH, Ohman EM, et al. Value of serial troponin T measures for early and late risk stratification in patients with acute coronary syndromes. The GUSTO-IIa Investigators. Circulation. 1998;98:1853–1859[Abstract/Free Full Text]
  3. Antman EM, Tanasijevic MJ, Thompson B, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996;335:1342–1349[Abstract/Free Full Text]
  4. Boersma E, Pieper KS, Steyerberg EW, et al. Predictors of outcomes in patients with acute coronary syndromeswithout persistent ST-segment elevation. Results froman international trial of 9461 patients. The PURSUIT Investigators. Circulation. 2000;101:2557–2567[Abstract/Free Full Text]
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  6. Morrow DA, Antman EM, Charlesworth A, et al. TIMI riskscore for ST-elevation myocardial infarction: a convenient, bedside, clinical score for risk assessment at presentation: an InTIME II trial substudy. Circulation. 2000;102:2031–2037[Abstract/Free Full Text]
  7. Patel VB, Robbins MA, Topol EJ. C-reactive protein: a ‘golden marker’ for inflammation and coronary artery disease. Cleve Clin J Med. 2001;68:521–524 [p. 527–34][Medline]
  8. Antman EM. Decision making with cardiac troponin tests. N Engl J Med. 2002;346:2079–2082[Free Full Text]
  9. Lenderink T, Boersma E, Heeschen C, et al. Elevated troponin T and C-reactive protein predict impaired outcome for 4 years in patients with refractory unstable angina, and troponin T predicts benefit of treatment with abciximab in combination with PTCA. Eur Heart J. 2003;24:77–85[Abstract/Free Full Text]
  10. Oldgren J, Wallentin L, Grip L, et al. Myocardial damage, inflammation and thrombin inhibition in unstable coronary artery disease. Eur Heart J. 2003;24:86–93[Abstract/Free Full Text]




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