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Even slightly raised levels of troponin linked to increased risk of heart death

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Even a small increase in troponin, a protein linked to heart attacks, is associated with an up to tenfold increased risk of death, found a large study from the UK National Institute of Health Research Health Informatics Collaborative. The finding provides a a clinically meaningful prognostic marker to select patients for novel treatments targeting inflammation, the authors say.

An analysis of patients’ heart data has shown that even a small increase in a protein linked to heart attacks is linked to an increased risk of death. Clinicians use troponin testing, alongside other investigations, to determine whether a patient is having a heart attack and to inform treatment choices. It has been assumed that the higher the amount of troponin in the blood, the higher the risk of death in all age groups. In a large study, researchers from the National Institute of Health Research Health Informatics Collaborative (NIHR-HIC) led by Imperial College Healthcare NHS Trust and Imperial College London found that a raised troponin level was associated with an increase in risk of death in all age groups. This was seen even if the troponin result was slightly raised, with the increased risk of death occurring very early.

They also showed that that regardless of age, the higher the amount of troponin in the blood, the higher the risk of death in patients with a heart attack. The results suggest that even a small rise in troponin in all age groups is clinically significant and can indicate underlying health problems.

However, the team also found that, contrary to what they expected, very high levels of troponin in the blood in patients with a heart attack was associated with a lower risk of dying. They suggest that a possible reason is that patients with very high troponin levels are more likely to have a type of heart attack which can be treated by an operation to improve blood flow to the heart and therefore reduce the risk of dying.

Amit Kaura, lead author of the research and NIHR clinical research fellow at Imperial College London, said: “There have been many advances in treating heart disease yet it remains the leading cause of death in the UK and around the world. This is the first study to address the implications of raised troponin in a real-world large sample of patients across a wide range of ages. Doctors will be able to use this information to help identify the risk of early death in patients who have a troponin level measured; this could lead to interventions at a much earlier stage in a wider group of patients than are currently treated.”

The researchers found that in young patients (18-29 years), those whose blood showed a raised troponin had a 10-fold higher risk of death than those whose blood did not. This increased risk fell with age, reaching 1.5 times the risk in patients over the age of 90. Nevertheless, even in very elderly patients, raised troponin in the blood signifies a higher risk of dying. Over the age of 80, almost half of patients with a raised troponin level died within three years.

They also found that even when doctors do not think the primary problem is a heart attack, the presence of a raised troponin in the blood signifies an increased risk of death. Therefore, the troponin result provides meaningful information in all age groups, regardless of the underlying problem.

Troponins are a group of proteins that helps regulate the contractions of the heart and skeletal muscle. The heart releases troponin into the bloodstream following an injury to the heart such as a heart attack. High levels of troponin usually mean there is a problem with the heart.

Doctors carry out a blood test to measure the levels of troponin in the blood which enables them to assess the damage caused to the heart and how patients are responding to treatment. It has previously been assumed that higher levels of troponin, mean a higher mortality risk. However, it has been unclear how to manage patients who have small troponin rises, particularly if they do not have other symptoms associated with heart disease or a heart attack.

The researchers behind the study wanted to examine the impact of raised troponin across different ages, specifically the very elderly. They also wanted to investigate the significance of very small troponin levels, compared with larger levels, on patients’ prognosis.

The team analysed the anonymised cardiovascular data of more than 250,000 patients who had troponin tests at National Institute for Health Research Health Informatics Collaborative sites including: Imperial College Healthcare NHS Trust, University College London Hospitals NHS Foundation Trust, Oxford University Hospitals NHS Foundation Trust, Kings College Hospital NHS Foundation Trust and Guys and St Thomas NHS Foundation Trust from 2010-2017. The team grouped the patients by age and compared their troponin results with their outcomes over a period of three years.

The team are currently designing a trial to see if patients with a raised troponin, without a heart attack, may benefit from cardiac treatments including cholesterol lowering medication, such as a statin.

The work is part of the NIHR Health Informatics Collaborative (NIHR-HIC) which Imperial College London and Imperial College Healthcare NHS Trust is part of. The NIHR-HIC was established to improve the quality and availability of patient data for research purposes. This will enable researchers to gain new insights into areas such as the effectiveness of different treatments and what factors influence patient outcomes and recovery.

Abstract
Background: The incremental long-term prognostic value of high-sensitivity C-reactive protein (hsCRP) above troponin in a large real-world cohort of unselected patients presenting with suspected acute coronary syndromes (ACS) is unknown. We hypothesised that a mildly elevated hsCRP is associated with mortality risk in patients with suspected ACS, independent of troponin level.
Methods: We used the National Institute for Health Research Health Informatics Collaborative data of 257,948 patients who had a troponin measured at 5 cardiac centres. We excluded patients with clinically abnormal white cell counts and hsCRP >15 mg/L to try limiting the population to those without overt infections, malignancies or systemic inflammatory conditions that may confound our analyses. Patients were divided into four hsCRP groups (<2, 2–4.9, 5–9.9 and 10–15 mg/L) and the association between hsCRP levels and all-cause mortality assessed. Results: There were 102,337 patients included in the analysis (hsCRP <2 mg/L (n=38,390), 2–4.9 mg/L (n=27,397), 5–9.9 mg/L (n=26,957) and 10–15 mg/L (n=9,593)). figure 1A displays cumulative mortality per hsCRP group, revealing increasing mortality with each consecutive group. figure 1B further stratifies the groups according to dichotomised peak troponin level as positive or negative. This shows the greatest mortality for patients in the highest hsCRP group who also had a positive troponin assay (36.0% at 3 years). In Cox regression analysis with time-dependent covariates, even mildly raised hsCRP was an independent predictor of mortality over time, after adjusting for age, gender, haemoglobin, white cell count, platelet count, creatinine and troponin positivity. There was a positive and graded relationship between hsCRP level and mortality at baseline, which remained at 3-years (hazard ratio (95% CI) of 1.32 (1.18–1.48) for those with hsCRP 2.0–4.9mg/L, and 1.40 (1.26–1.57), and 2.00 (1.75–2.28) for those with hsCRP 5–9.9 mg/L and 10–15 mg/L, respectively. We explored whether inclusion of hsCRP could better reclassify the population into at-risk mortality groups. The association with 30-day, 1-year and 3-year mortality was assessed using three different risk models (model 1: age, gender, haemoglobin, creatinine; model 2: model 1 plus troponin (positivity versus negativity); model 3: model 2 plus hsCRP groups. For cumulative mortality at each time point, each successive model was better able to discriminate risk than its precursor (p<0.0001); such that inclusion of troponin and hsCRP gave the most robust risk discrimination. Model 3 achieved an AUROC >0.8 at 30 days, 1-year and 3-year mortality, surpassing the use of troponin on its own.
Conclusion: These multi-centre, real-world data from a large cohort of patients with suspected ACS identify hsCRP as a clinically meaningful prognostic marker in addition to troponin levels and point to its potential utility in selecting patients for novel treatments targeting inflammation.

Authors
Amit Kaura, Adam Hartley, Vasileios Panoulas, Ben Glampson, Jim Davies, Abdulrahim Mulla, Kerrie Woods, Joe Omigie, Anoop D Shah, Keith Channon, Jonathan N Weber, Mark R Thursz, Paul Elliott, Harry Hemingway, Bryan Williams, Folkert Asselbergs, Michael O’Sullivan, Dorian Haskard, Graham Lord, Narbeh Melikian, Daryl Francis, Wolfgang Koenig, Divaka Perera, Ajay Shah, Rajesh Kharbanda, Riyaz Patel, Jamil Mayet, Ramzi Khamis

Imperial College London material

BMJ abstract

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