Where cardiac biomarkers were once considered a supplementary aid to clinical diagnosis and the electrocardiogram, they are now integral to diagnostic, prognostic and management algorithms
Paul O Collinson
MA MB BChir FRCPath FACB MD
Departments of Chemical Pathology
and Cardiology, St George’s Hospital and Medical
School, London, UK
It is 19 years since the measurement of cardiac troponins was first described; now they form the diagnostic gold standard for acute myocardial infarction. Similarly, while the routine measurement of natriuretic peptides first became possible only seven years ago, it is now potentially available in every routine and urgent care laboratory, as well as being available by
point-of-care testing (POCT). It is therefore worth considering how recent advances in measurement technology can be combined with biomarkers to deliver a more clinically efficient and more cost-effective service.
Sensitive cardiac troponin assays
The holy grail of biomarker testing is to be able to conclusively rule in or out a myocardial infarction when the patient first presents to hospital. To date, we have not been able to achieve this and the criticism of troponin measurements has been that they take too long to become positive. Recommendations for biomarker measurement typically include protocols involving sampling out to 12 hours from admission. This needs to be made faster and better – and soon. In any health-economic evaluation the major component of cost is length of hospital stay. The sooner we can achieve an accurate diagnosis, the sooner appropriate patient management can be initiated and the shorter will be the patient’s length of stay.
Sensitive troponin assays for earlier diagnosis
The more sensitive an assay is, the more rapidly it will be able to detect the appearance of a marker in the circulation. Current sampling protocols are based on the assay performances of an earlier generation of troponin assays. The redefinition of myocardial infarction has resulted in the development of assays that are more sensitive, with two goals: one is to be able to detect a true 99th centile; the second is to improve assay imprecision at the low end of the range. A byproduct is that troponin elevations can be detected significantly earlier (Figure 1).
A recently published study has shown conclusively that the use of a more sensitive iteration of a cardiac troponin I assay is able to detect 60% of cases at first presentation of myocardial infarction that previously had an undetectable troponin.
Using a low diagnostic cut-off with a very sensitive troponin I assay, it is possible to diagnose all those patients with myocardial infarction presenting with more than six hours of chest pain and over 80% of those who present earlier. The same study also demonstrated that troponin measurements were more sensitive than measurement of traditional early markers such as myoglobin and CK-MB. This means that not only will the sensitive troponin assay make the diagnosis significantly earlier, but also that measurement of additional
biomarkers of necrosis is not required. This raises the possibility that much more rapid, accelerated protocols can be used on admission and at three and six hours from admission. Sensitive troponin assays allow the definition of a proper reference population. This means that it is possible to define a rate of change of biomarker which can then be used for very early diagnosis. The use of rate of change of creatine kinase and its MB isoenzyme substantially shortened the time required when these are used as diagnostic tests.[4,5] The use of a sensitive troponin assay will allow the same methodology to be applied. The use of a very rapid, less-than-two hour, rule-out protocol utilising rate of change is currently being investigated. With appropriate patient selection, safe and effective rule-out of myocardial infarction in low-risk patients (who make up the majority of patients seen) may be possible within three hours of hospital admission. This has a major potential impact on length of stay and hence hospital costs.
Does rapid diagnosis translate into cost savings?
Can rapid biochemical diagnosis be incorporated into a management algorithm to allow early and rapid discharge of the patient from a hospital bed or from the chest pain clinic?
There is a large body of evidence going back at least 15 years that shows that rapid biochemical testing combined with an appropriate decision tree translates into reduced length of stay. The question then is what should be the target for turnaround time. Current guidelines recommend a 60-minute turnaround time, but it is apparent that if rule-out can be achieved in three hours or less, 60 minutes represents a substantial proportion of the decision time and may not be appropriate.
There is already evidence that rapid provision of diagnostic information can substantially shorten the length of stay and hospital costs. A study that utilised a relatively unsophisticated form of POCT, which was nevertheless equivalent to the diagnostic methodology used in the laboratory at the time, was able to show a substantial reduction in the length of hospital stay. Overall, length of stay in the rule-out cohort fell by 28%, which translated into a significant cost saving of £286 per patient for the period of study.
The major determinant of the reduction in length of stay was more efficient decisionmaking. This was a combination of reduction in turnaround time and the use of a structured decision-making protocol.
Similarly, a prospective observational study, which introduced a contemporary point-of-care system to the coronary care unit, showed a reduction in costs of 25% ($17,163 vs $12,882).
The use of a structured decision-making protocol is an integral component of all these studies, which have successfully demonstrated more efficient chest pain management in CCUs and in chest pain units. The combination of a sensitive troponin assay, a structured decision-making protocol and POCT may prove to be the ultimate strategy for biomarkers of myocardial necrosis.
Measurement of B-type natriuretic peptide in acute care
Initial studies with natriuretic peptides were performed in the clinical scenario of presentation with dyspnoea. Dyspnoea has a number of differential diagnoses, of which cardiac failure is one of the most important. Diuretics can be life-saving in the patient with severe pulmonary oedema. Unfortunately, diuretics are catastrophic if the patient is dehydrated with pneumonia. In such a patient, induction of a profound diuresis will produce circulatory collapse and may lead to death.
The diagnostic efficiency of measurement of both B-type natriuretic peptide (BNP) and Nterminal pro-BNP (NTproBNP) has been shown to be very good on its own and to improve upon clinical judgement alone. In the Breathing Not Properly study, relying on clinical judgement alone had a maximum accuracy of only 73%, but incorporating BNP measurement increased accuracy to 83%. Similarly, in the PRIDE study, NTproBNP measurement was significantly better than clinical judgement, increasing the area under the receiver operating characteristic curve from 0.90 to 0.94.
Just as with troponin measurement, the ability to arrive at the correct diagnosis more rapidly would seem to, as a matter of course, reduce hospital length of stay. A number of studies have demonstrated that this is true. The BASEL study, a prospective randomised controlled trial, compared two matched patient groups. One group had BNP measured; the result was available to the clinician and was combined with clinical assessment of the patient. The other group had clinical assessment and standard investigations alone. BNP testing shortened hospital stay and reduced costs both in the short term by $1,800 per patient and in the long term by $2,500 per patient.
Similar studies have been performed for NTproBNP with an estimated cost reduction of $1,000 per patient when NTproBNP measurement is used in addition to clinical assessment.
Even within the hospital, preliminary measurement of BNP or NTproBNP can be used to screen patients before requesting an echocardiogram. This will reduce the number of echocardiograms required by as much as 58%, so freeing up the service for patients who need it, as well as preventing delays in discharging patients where heart failure is not the cause of their breathlessness.
Measurement of BNP and NTproBNP in primary care
Guidelines from the European Society of Cardiology recommend the use of BNP or NTproBNP testing prior to referral from the primary to the secondary care setting. The reason for this is that it has been estimated that as many as 60% of patients referred to a heart failure clinic do not in fact have heart failure and have had a wasted journey.
Including NTproBNP measurements in the initial evaluation of patients with suspected heart failure by general practitioners improves the accuracy of diagnosis by 21% and is superior to various combinations of clinical observation, history and ECG.
Age- and sex-specific decision limits are needed in the primary care setting as values of BNP and NTproBNP are much lower than in patients with acute dyspnoea.[18,19]
The use of a decision-making algorithm that utilises measurement of NTproBNP has the potential to reduce costs by preventing the inappropriate referral of patients.20 Validating this in a real patient population shows a cost saving of $79 per patient screened with an initial NTproBNP measurement.[20,21]
Combining imaging modalities with biomarker measurement
Handheld echocardiography has been developed and can be used in routine clinical practice. The combination of NTproBNP measurement and echocardiography can be shown to be a more cost-effective method of assessment than referral to cardiac outpatients. When attempting to detect presymptomatic disease, the combination of NTproBNP plus portable echocardiography allows a very cost-efficient method of identifying high-risk individuals.
Challenges for the future
Although integrated pathways with biomarkers clearly save money, the cost saving is on the patient episode rather than on a discrete budget line. The tendency is for hospitals to think in silo budgeting terms and not to think in terms of total
A more flexible financial mindset is required considering total cost whereby an increased spending in one area will generate substantial savings overall. The challenge for the laboratory is to build a consensus with clinical colleagues and managers to achieve this type of process transformation.
1. Thygesen K, et al. Universal definition of myocardial infarction. J Am Coll Cardiol 2007;50(22):2173-95.
2. Melanson SE, et al. Earlier detection of myocardial injury in a preliminary evaluation using a new troponin I assay with improved sensitivity. Am J Clin Pathol 2007;128(2):282-6.
3. Eggers KM, et al. Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction. Am Heart J 2004;148(4):574-81.
4. Collinson PO, et al. Early diagnosis of myocardial infarction by timed sequential enzyme measurements. Ann Clin Biochem 1988;25(Pt 4):376-82.
5. Collinson PO, et al. Early diagnosis of acute myocardial infarction by CK-MB mass measurements. Ann Clin Biochem
6. Collinson PO, et al. Rapid enzyme diagnosis of patients with acute chest pain reduces patient stay in the coronary
care unit. Ann Clin Biochem 1993;30(Pt 1):17-22.
7. Collinson PO, et al. A prospective randomized controlled trial of point-ofcare testing on the coronary care unit. Ann Clin Biochem 2004;41(Pt 5):397-404.
8. Apple FS, et al. Decreased patient charges following implementation of point-of-care cardiac troponin monitoring in acute coronary syndrome patients in a community hospital
cardiology unit. Clin Chim Acta 2006;370(1-2):191-5.
9. Maisel AS, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347(3):161-7.
10. Januzzi JL Jr, et al. The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Am J Cardiol 2005;95(8):948-54.
11. Mueller C, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350(7):647-54.
12. Mueller C, et al. Cost-effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea. Arch Intern
13. Moe GW, et al. N-terminal pro-Btype natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVE-CHF study. Circulation 2007;115(24):3103-10.
14. Siebert U, et al. Cost-effectiveness of using N-terminal pro-brain natriuretic peptide to guide the diagnostic assessment and management of dyspneic patients in the emergency department. Am J Cardiol 2006;98(6):800-5.
15. Remme WJ, Swedberg K. Guidelines for the diagnosis and treatment of chronic heart failure. Eur Heart J 2001;22(17):1527-60.
16. Zaphiriou A, et al. The diagnostic accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected heart failure: results of the UK natriuretic peptide study. Eur J Heart Fail 2005;7(4):537-41.
17. Wright SP, et al. Plasma aminoterminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: a randomized, controlled trial. J Am Coll Cardiol
18. Tang WH, et al. National Academy of Clinical Biochemistry Laboratory Medicine practice guidelines: clinical utilization of cardiac biomarker testing in heart failure. Circulation 2007;116(5): e99-109.
19. Hildebrandt P, Collinson PO. Amino-terminal pro-B-type natriuretic peptide testing to assist the diagnostic evaluation of heart failure in symptomatic primary care patients. Am J Cardiol 2008;101(3A):25-8.
20. Collinson PO. The cost effectiveness of B-type natriuretic peptide measurement in the primary care setting: a UK perspective. Congest Heart Fail 2006;12(2):103-7.
21. Lim TK, et al. Value of primary care electrocardiography for the prediction of left ventricular systolic dysfunction in patients with suspected heart failure. Int J Cardiol 2007;115:73-4.
22. Lim TK, et al. Cost effectiveness of the B type natriuretic peptide, electrocardiography, and portable echocardiography for the assessment of patients from the community with suspected heart failure. Echocardiography 2007;24(3):228-36.
23. Galasko GI, et al. What is the most cost-effective strategy to screen for left ventricular systolic dysfunction: natriuretic peptides, the electrocardiogram, hand-held echocardiography, traditional echocardiography, or their combination?
Eur Heart J 2006;27(2):193-200.