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BRAHMS copeptin assay to rule out myocardial infarction in patients with acute chest pain - Medical technology consultation document

NICE medical technologies guidance addresses specific technologies notified to NICE by manufacturers. The ‘case for adoption’ is based on the claimed advantages of introducing the specific technology compared with current management of the condition. This case is reviewed against the evidence submitted and expert advice. If the case for adopting the technology is supported, then the technology has been found to offer advantages to patients and the NHS. The specific recommendations on individual technologies are not intended to limit use of other relevant technologies which may offer similar advantages.

The National Institute for Health and Clinical Excellence (NICE) is producing guidance on using the BRAHMS copeptin assay to rule out myocardial infarction in patients with acute chest pain in the NHS in England. The Medical Technologies Advisory Committee has considered the evidence submitted and the views of expert advisers.

This document has been prepared for public consultation. It summarises the evidence and views that have been considered, and sets out the draft recommendations made by the Committee. NICE invites comments from the public. This document should be read along with the evidence base (the assessment report and assessment report summary), which is available from www.nice.org.uk/mt.

The Advisory Committee is interested in receiving comments on the following:

  • Has all of the relevant evidence been taken into account?
  • Are the summaries of clinical effectiveness and resource savings reasonable interpretations of the evidence?
  • Are the provisional recommendations sound, and a suitable basis for guidance to the NHS?
  • Are there any equality issues that need special consideration and are not covered in the medical technology consultation document?

Note that this document is not NICE's final guidance on the BRAHMS copeptin assay to rule out myocardial infarction in patients with acute chest pain. The recommendations in section 1 may change after consultation. After consultation the Committee will meet again to consider the evidence, this document and comments from public consultation. After considering these comments, the Committee will prepare its final recommendations which will be the basis for NICE’s guidance on the use of the technology in the NHS in England.

For further details, see the ‘Evaluation Pathway Programme process guide’ (available at www.nice.org.uk).

Key dates:

  • Closing time and date for comments: 5 pm on 4 April 2011
  • Second Medical Technologies Advisory Committee
    meeting: 20 April 2011

1 Provisional recommendations

1.1 The BRAHMS copeptin assay shows potential to reduce the time taken to rule out myocardial infarction in patients presenting with acute chest pain, in combination with cardiac troponin testing. However there is currently insufficient evidence on its use in clinical practice to support the case for routine adoption of the BRAHMS copeptin assay in the NHS.

1.2 Research is recommended in the UK clinical setting to compare the BRAHMS copeptin assay in combination with cardiac troponin testing for ruling out myocardial infarction against sequential cardiac troponin testing. NICE will review this guidance when new and substantive evidence becomes available.

1.3 Research should document what happens to all patients presenting with acute chest pain in the chosen clinical settings, to allow investigation of the proportion of patients for whom use of the BRAHMS copeptin assay results in changes in management. Accurate recording of the times between steps in management will be important. Outcomes should measure the resource use implications of the earlier rule out of myocardial infarction and the impact that the earlier ruling out of myocardial infarction has on decisions to discharge patients from hospital or to investigate them further. Changes in the experience of patients as a result of using the BRAHMS copeptin assay should also be reported.

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2 The technology

Description of the technology

2.1 The BRAHMS copeptin assay (Brahms UK Ltd - Thermo-Fisher Scientific) is a test for ruling out myocardial infarction in patients presenting with acute chest pain. The automated immunofluorescent BRAHMS copeptin assay is intended to be used together with cardiac troponin testing to reduce the time needed to rule out myocardial infarction.

2.2 The BRAHMS copeptin assay is intended to be used for patients presenting to hospital with acute chest pain, in whom a possible diagnosis of myocardial infarction is being considered.

2.3 The BRAHMS copeptin assay is performed in a laboratory setting on a compatible analyser.  It is claimed that a result is available in about 20 minutes.  

2.4 A negative copeptin result, together with a negative troponin result, can be used to support clinical findings and a negative electrocardiogram (ECG) in ruling out myocardial infarction soon after patients present with acute chest pain.

2.5 Copeptin is a surrogate marker for arginine vasopressin, a hormone which plays a major role in the regulation of the endogenous stress response and which is present at elevated levels in myocardial infarction, heart failure and different states of shock.  Cardiac troponins (I or T) are specific to cardiac muscle and are released into circulation when irreversible myocardial damage occurs. Cardiac troponins I and T are both used as markers of cardiac necrosis. After myocardial infarction, copeptin levels are elevated 0–4 hours after the onset of symptoms whereas cardiac troponin levels peak at 12 hours.

2.6 Diabetic neuropathy can modify levels of arginine vasopressin, and therefore, levels of copeptin.  This could impair the accuracy of the BRAHMS copeptin assay for patients with diabetes mellitus.

2.7 The manufacturer’s instructions for use state that a copeptin level below 14 pmol/litre, in combination with a troponin T level lower than 0.01 microgram/litre, rules out myocardial infarction with a sensitivity of 98.8% and a negative predictive value of 99.7%.  This copeptin threshold was based on a study by Reichlin et al. (2009) in which the BRAHMS copeptin assay was used in combination with a troponin test to rule out myocardial infarction in 487 consecutive patients including those with diabetes mellitus (see 3.4). 

2.8 The benefits to patients and the NHS claimed by the manufacturer are:

  • ‘Faster diagnosis of acute myocardial infarction. Use of the BRAHMS copeptin assay together with the first troponin test removes the need for the second standard troponin test, saving a 10-12 hour wait.’
  • ‘Improved patient experience (less waiting and less anxiety).’
  • ‘Improved management of patients presenting with chest pain at Accident and Emergency by reducing the time needed to exclude acute myocardial infarction.’
  • 'A reduction in ECG monitoring and unnecessary patient admissions by excluding acute myocardial infarction in patients more rapidly, resulting in cost savings.’ 

Current management

2.9 The diagnostic pathway in hospital for patients with acute chest pain is described in ‘Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin’ (NICE clinical guideline 95).

2.10 Currently, initial assessment for myocardial infarction should include clinical history, physical examination, ECG and biochemical marker analysis. Usually, biochemical marker analysis consists of two troponin tests from samples taken at initial assessment and 10–12 hours after the onset of symptoms. The troponin tests currently used are troponin I or troponin T tests and some laboratories also use high sensitivity troponin tests.   

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3 Clinical evidence

Summary of clinical evidence

3.1 The main outcome measures for the BRAHMS copeptin assay are diagnostic sensitivity, time to rule out myocardial infarction, and length of hospital stay. Other measures of diagnostic accuracy (diagnostic specificity, positive and negative predictive values, and the likelihood ratios of the test) may also be useful in evaluating the assay and avoidance of hospital admission is a practical outcome measure which is reported and relevant.

3.2 Four relevant studies were identified, of which three were based on a single multi-centre trial (‘Advantageous predictors of acute coronary syndromes evaluation’ – APACE). In all of the studies, the intervention referred to the dual marker strategy of the BRAHMS copeptin assay combined with a troponin test, and the comparator was defined as two sequential troponin tests (at admission and 12 hours after the onset of chest pain) in addition to ECG and physical examination. Blood samples from consecutive patients with suspected myocardial infarction were taken at presentation (0 hours) and frozen before analysis. Copeptin values were tested retrospectively, and the utility of the dual marker strategy was modelled after an adjudicated diagnosis by two independent cardiologists. None of the studies assessed clinical outcomes or impact on resource use in the NHS.

3.3 In a multi-centre blinded study by Keller et al. (2010), blood samples from 1386 patients were used to compare the diagnostic values of the BRAHMS copeptin assay combined with a troponin test against those of the two sequential troponin tests, for ruling out myocardial infarction. Blood samples were taken from consecutive patients with suspected acute coronary syndrome. The authors analysed subgroups of the population with chest pain onset at less than 3 hours (n = 517), less than 6 hours (n = 806), and less than 12 hours (n = 1017) before blood sampling. The study investigated a range of copeptin threshold values (9.8, 13.0, and 18.9 pmol/litre - corresponding to the 95th, 97.5th, and 99th percentiles respectively of a healthy population). The authors reported that the highest negative predictive value was achieved with a cut-off value of 9.8 pmol/litre, irrespective of the time since onset of symptoms. At less than 3 hours from chest pain onset, the negative predictive value was 92.4% (95% confidence interval [CI] 88.2–95.4) and specificity was 66.7% (95% CI 61.3–71.8). The negative predictive value in the total of all subgroups was 95.8% (95% CI 93.9–97.2) with specificity was 68.3% (95% CI 65.1–71.3). The study also investigated the diagnostic performance of a dual marker strategy, in which the BRAHMS copeptin assay plus a high-sensitivity troponin test was used in a subgroup of 517 patients with an onset of chest pain less than 3 hours before blood sampling. The negative predictive value (using a 9.8 pmol/litre cut-off) was 99.0% (95% CI 96.6–99.9) and specificity was 63.2% (95% CI 57.8–68.4).

3.4 Part of the APACE trial was a single-centre blinded study in which blood samples from 487 consecutive patients were used to compare the diagnostic values of the BRAHMS copeptin assay combined with a troponin test against those of the two sequential troponin tests, to rule out myocardial infarction (Reichlin et al. 2009). A range of copeptin cut-off values was evaluated in the study (9, 14, 20, and 24 pmol/litre). The authors concluded that a copeptin level of less than 14 pmol/litre in combination with a troponin T level of 0.01 micrograms/litre or lower correctly ruled out myocardial infarction with a sensitivity of 98.8%, a negative predictive value of 99.7%, specificity of 77.1% and a positive predictive value of 46.2% (no confidence intervals were reported). A 9 pmol/litre cut-off value gave a negative predictive value of 100%, and the lowest negative predictive value of 98.9% was a result of using a 24 pmol/litre cut-off value.

3.5 In one published abstract from the APACE trial, blood samples from 1170 patients were used to compare the diagnostic values of the BRAHMS copeptin assay plus a high-sensitivity troponin test against those of the two sequential troponin tests, to rule out myocardial infarction (Heinisch et al. 2010). The area under the ROC curve was significantly higher for the BRAHMS copeptin assay combined with a high sensitivity troponin test (0.956; 95% CI 0.943-0.967) than the area under the ROC curve (0.947; 95%CI 0.933-0.959) for the high sensitivity troponin test alone (p = 0.006). The Committee considered information from the full unpublished manuscript of this study but it remains academic in confidence at the time of writing.

3.6 An unpublished study (conference abstract) from the APACE trial compared the diagnostic values of the BRAHMS copeptin assay combined with a troponin test against those of the two sequential troponin tests, to rule out myocardial infarction in diabetic patients (Reichlin et al. 2010). Blood samples from 227 diabetic patients were used. Copeptin levels were significantly higher in diabetic patients diagnosed with myocardial infarction compared with diabetic patients with other diagnoses (median 34.1 versus 8.3 pmol/litre, p < 0.001). The BRAHMS copeptin assay combined with a troponin test resulted in an area under the ROC curve of 0.91 (95% CI 0.87–0.96), which was significantly higher than the area under the ROC curve of 0.85 (95% CI 0.77–0.92) for the troponin test (p = 0.02).

Committee considerations

3.7 The Committee noted evidence that the BRAHMS copeptin assay (combined with troponin measurement) provides a high level of sensitivity for ruling out myocardial infarction in patients with acute chest pain.

3.8 The Committee noted that a variety of threshold values have been investigated to determine the ideal ‘cut off’ for ruling out myocardial infarction. They noted that the manufacturer’s instructions for use state that for patients with suspected acute coronary syndrome, a copeptin level below 14 pmol/litre, in combination with a troponin T level lower than 0.01 microgram/litre, rules out myocardial infarction with a sensitivity of 98.8% and a negative predictive value of 99.7%. The Committee considered that clear definition of a threshold value is important for any further clinical evaluation of the BRAHMS copeptin assay.

3.9 The Committee considered that there was evidence to support the concept of using the BRAHMS copeptin assay as part of a diagnostic process to rule out myocardial infarction. However, the available trials were not designed to evaluate the relevant clinical outcomes and changes to the care pathway, including the influence of ruling out myocardial infarction earlier using the BRAHMS copeptin assay on resource use and on decisions to discharge patients from hospital or to investigate them further.

3.10 The Committee considered the RATPAC trial (‘Randomised assessment of treatment using panel assay of cardiac markers’) to exemplify the type of study that could assess the clinical outcomes and impact on the healthcare system of using the BRAHMS copeptin assay.

3.11 The Committee considered that using the BRAHMS copeptin assay might have beneficial effects on the experience of patients presenting with acute chest pain, by ruling out myocardial infarction earlier in a proportion of them, but there was no available evidence about this.

3.12 The Committee was uncertain about the proportion of patients presenting with acute chest pain who would, in practice, be discharged earlier as a result of introducing the BRAHMS copeptin assay.

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4 NHS considerations

System impact

4.1  ‘Each year, over 15 million people attend an emergency department in England and Wales. It has been estimated that 2.4% of attendances are because of chest pain, representing 360 000 emergency department attendances’ (Goodacre et al. 2005). Based on this large number of patients, any reduction in the time taken to rule out myocardial infarction using the BRAHMS copeptin assay potentially offers significant cost savings to the NHS.

Committee considerations

4.2 The Committee recognised that reducing the time taken to rule out myocardial infarction could speed up patients’ discharge from hospital, or hasten their access to investigation for alternative diagnoses, followed by appropriate treatment.

4.3 The Committee was advised that the amount of time saved before ruling out myocardial infarction could be influenced by delays such as transporting blood samples and running more than one analyser in the laboratory.  

4.4 The Committee was advised that clinicians might have a low threshold for keeping patients with chest pain in hospital for observation and further investigations, even if the BRAHMS copeptin assay and troponin tests suggested that they had not had a myocardial infarction.

4.5 The Committee was also uncertain, on the basis of the available evidence, what resources would be saved as a result of earlier discharge, especially if patients had already been transferred from accident and emergency departments to other wards, and if discharge was brought forward by only a few hours.

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5 Cost considerations

Cost evidence

5.1 The economic evidence comprised an unpublished cost-effectiveness study and a new cost analysis to assess the costs and savings to the NHS of using the BRAHMS copeptin assay. A randomised controlled trial and economic evaluation of care in a chest pain observation unit was used as a cost reference (Goodacre et al. 2004).

5.2 The unpublished USA-based cost-effectiveness study from the APACE trial (see 3.2) compared the economic benefit of using the BRAHMS copeptin assay combined with a troponin test within the diagnostic pathway against the current diagnostic pathway, which included two sequential troponin tests. The study was in 1247 patients presenting with chest pain at the emergency department (Twerenbold et al., 2010). Myocardial infarction was ruled out in patients who had undetectable levels of troponin I (less than 0.01 micrograms/litre) and a copeptin level of less than 14 pmol/litre at presentation. Myocardial infarction was the adjudicated diagnosis in 199 patients (16%). Comparing results from the two diagnostic pathways showed that myocardial infarction was ruled out earlier in 712 patients (57%) with the BRAHMS copeptin assay. Median time to discharge was 350 minutes when two sequential troponin tests were used and 90 minutes (p > 0.001) with the BRAHMS copeptin assay. The mean treatment cost of the current diagnostic pathway was $1285 per patient compared with $898 per patient with the use of the BRAHMS copeptin assay (95% CI $363–412, p < 0.001).

5.3 The new cost analysis submitted by the manufacturer compared the costs of using the BRAHMS copeptin assay combined with a troponin test (intervention) with the costs of using two sequential troponin tests (comparator) to rule out myocardial infarction in a UK NHS setting.

5.4 The cost of the BRAHMS copeptin assay stated in the manufacturer’s submission is 15 per assay.

5.5 The cost model submitted by the manufacturer included the cost of the BRAHMS copeptin assay (15) and the troponin test (4), unspecified laboratory costs (7.20), monthly service costs of the analyser (1000) and cost per bed day in the medical admissions unit (300) where it was assumed that patients would be admitted for investigation.

5.6 To calculate the cost of the time taken to rule out myocardial infarction, the manufacturer used a cost of 300 per bed day in a medical admission unit. The cost of the bed day was comparable with costs presented in Goodacre et al. (2004) that assessed the cost effectiveness of providing care for patients with acute chest pain in a UK setting. In the manufacturer’s cost model it was assumed that once myocardial infarction had been ruled out patients would be discharged from hospital.

5.7 In the cost model it was assumed that when using the BRAHMS copeptin assay combined with a troponin test, the two tests were performed at the same time. If the first troponin test was positive, the copeptin test result would be disregarded. The model assumed that the cost of the copeptin test was incurred regardless of the troponin test result. The two sequential troponin tests were 12 hours apart regardless of the result of the first troponin test. The time horizon in the cost model encompassed the period up to the second troponin test (a period of 12 hours from admission).

5.8 In the cost analysis, it was assumed that the time saved by the early ruling out of myocardial infarction using the BRAHMS copeptin assay was 10 hours. The external assessment centre considered this time saving to be the uppermost limit and additional sensitivity analysis was therefore undertaken.

5.9 In the manufacturer’s cost analysis, the cost savings of using the BRAHMS copeptin assay combined with a troponin test were 58.24 per patient compared with using two sequential troponin tests.

5.10 The main cost savings in the cost analysis were from a reduction in time spent in the medical admissions unit.

5.11 The sensitivity analyses reported that the parameter with the largest influence on cost savings was the length of time saved by the early ruling out of myocardial infarction using the BRAHMS copeptin assay. The base case assumed a saving of 10 hours. The sensitivity analysis showed the time saved would have to be less than 2 hours for the BRAHMS copeptin assay combined with a troponin test not to result in cost savings. Results were also sensitive to the cost of a bed day in a medical admissions unit. In the base case this was 300. Additional analysis showed the cost would have to be below 100 for the BRAHMS copeptin assay combined with a troponin test to no longer be cost saving.

5.12 The false negative rates of the BRAHMS copeptin assay combined with a troponin test and the two sequential troponin tests were not considered in the cost model, and so additional costs associated with re-admission were not included. However, biochemical marker tests are part of the initial assessment for myocardial infarction, which can also include clinical history, physical examination and ECG, so the cost consequence of a false negative result is uncertain.

Committee considerations

5.13 The Committee was advised that the assumption of a 10 hour reduction in time taken to rule out myocardial infarction using the BRAHMS copeptin test was an overestimation. One important reason was that many patients do not present at an accident and emergency department for several hours after the onset of chest pain, so the second troponin test can be carried out earlier than 12 hours after presentation.

5.14 The Committee was advised that if a laboratory does not have access to a compatible analyser for the BRAHMS copeptin assay, additional costs would be incurred from purchasing an additional analyser and there would also be additional costs for technician time taken to run samples on two analysers. The cost analysis submitted by the manufacturer included a monthly service cost for the analyser and unspecified laboratory costs per test, but did not allow for the possibility that extra technician time may be incurred. The Committee was advised that the additional costs for technician time may be higher for assays that are needed ‘out of hours’.

5.15 The Committee discussed the potential influence that using the BRAHMS copeptin assay could have on the costs of hospital care. They considered that ruling out myocardial infarction earlier could increase the speed of transfer from high cost settings such as medical admissions units to lower cost units for further investigation.

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6 Conclusions

6.1 The Committee considered that the BRAHMS copeptin assay is a promising new development for the early ruling out of myocardial infarction in patients presenting with chest pain. However, there was uncertainty about the proportion of patients presenting with chest pain who would benefit from its use, and about the amount of time and resources that would be saved in practice.

6.2 The Committee concluded that good quality clinical trials are needed to support the potential of the BRAHMS copeptin assay to offer advantages to patients and the NHS. The Committee wished to give strong encouragement to further research, with relevant outcome measures, on the use of the BRAHMS copeptin assay for the early ruling out of myocardial infarction.

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7 Implementation

7.1 NICE intends to develop tools, in association with relevant stakeholders to help organisations put this guidance into practice.

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8 Related NICE guidance

  • Chest pain of recent onset: assessment and diagnosis of recent onset chest pain or discomfort of suspected cardiac origin. NICE clinical guideline 95 (2010). Available from www.NICE.org.uk/guidance/CG95
  • Unstable angina and NSTEMI: the early management of unstable angina and non-ST-segment-elevation myocardial infarction. NICE clinical guideline 94 (2010). Available from www.NICE.org.uk/guidance/CG94
  • Myocardial perfusion scintigraphy for the diagnosis and management of angina and myocardial infarction (partially updated by NICE clinical guideline 95). NICE technology appraisal guidance 73 (2003). Available from www.NICE.org.uk/guidance/TA73

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Bruce Campbell

Chairman, Medical Technologies Advisory Committee

March 2011