Tag Archives: Troponin

Cheesecake files: A new test to rule out heart attacks in just a few minutes.

Your chest hurts, you go to the hospital (good move), you get rushed through and a nurse takes some blood and measures the electrical activity of your heart.  A doctor asks you some questions.  While she does so, the blood is being tested – the results are back already! Yeah, they are negative and everything else is OK, it’s not a heart attack – you can go home.  This is the likely scenario in the near future thanks to new blood test technology which we, in Christchurch hospital’s Emergency Department, have been fortunate to be the first in the world to trial in patients. The results of our pilot study have now been published ( in a Journal of the American Medical Association (JAMA Cardiology).

About 65,000 patients a year are investigated for heart attacks in New Zealand emergency departments, yet only about 15% of them are actually having a heart attack.  New Zealand leads the world in having become the first country in the world in which all patients are assessed by an accelerated diagnostic pathway that enables rapid evaluation of the patients and can send people home after two blood tests taken two to three hours apart (see here for more).  This means many patients who once-upon-a-time would have been admitted to hospital overnight, are now able to be reassured after 4-6 hours that they are not having a heart attack and can go home.  Nevertheless, there are enormous advantages for both patient and health system to being able to come to the conclusion that the pain isn’t life threatening earlier. The cork in the bottle preventing this happening is the time it takes for a blood sample to be analysed for signs of damage to the heart. These blood tests typically take 1 to 2 hours from the time of sampling (within ~15 minutes of arrival in the ED) until the results are available for the doctor to review.  Because doctors are dealing with multiple patients at a time, their review and decisions around whether to allow the patient to go home, or to be admitted for more investigation, are further delayed.  A point-of-care test is one that happens with a small machine near the bedside and can produce results available to the doctor even while they are still examining the patient.  Until now, though, the precision of these machines has not been good enough to be used in emergency departments.  When one manufacturer told us that their new technology may now have sufficient precision we were keen to test it,  so we, in a first-in-the-world study, undertook a study in patients entering the emergency department of Christchurch hospital whom the attending doctor was investigating for a possible heart attack.

Thanks to the volunteer patients (I love volunteers) who gave some extra blood we measured the troponin concentration by this new point-of-care test (called the next generation point of care troponin I: TnI-Nx). Troponin comes from the heart muscle and is released into the blood during a heart attack. When the troponin concentrations in the blood are very very low we can be confident that the source of the patient’s discomfort is not a heart attack.  Low concentrations require a very precise measurement test. Often, a very low concentration means the patient can safely go home. In 354 volunteers we measured troponin with the TnI-Nx assay when they first came to the emergency department.  Their treatment didn’t change, and all clinical decisions were based on the normal laboratory based troponin (measured on entry to the emergency department and again 2 hours later). From the blood samples we collected and measurements we made, we could work out what could have happened if we had used the TnI-Nx results instead.

In our study the TnI-Nx troponin measurement was as good as, and possibly slightly better, than the laboratory based troponin measurement at ruling-out a heart attack. We found 57% of the patients being investigated had troponin concentrations measured with TnI-Nx below a threshold at which we could be confident that they were not having a heart-attack.  All 57 patients who were actually having a heart attack had higher concentrations.

When implemented our results may mean that instead of waiting 3-6 hours for a results, half of patients being investigated could know within about 30 minutes of arriving at the ED whether they are having a heart attack or not.  This early reassurance would be a relief to many, as well as reducing over-crowding in the emergency department and freeing up staff for other tasks.  But before we implement the new test, we must validate it in more patients – this is a study we are carrying out now.  Validation will enable us to more precisely determine a threshold concentration for TnI-Nx for clinical use which we can, with a very high degree of certainty, safely use to rule-out a heart attack.

The test also should allow people living in rural areas to get just as good care as in emergency departments because it could be deployed in rural hospital and general practices.  This would save many lengthy, worrying, and expensive trips for people to an urban emergency department.

This study was carried out by the Christchurch Emergency Department research group (director and senior author Dr Martin Than) in conjunction with the Christchurch Heart Institute (University of Otago Christchurch).  My colleague, Dr Joanna Young did much of the hard yards, and we thank our clinical research nurses and assistant for all they did to take blood samples, collect data, and lend a hand around the ED.  The manufacturer of the blood test, Abbott Point-of-care, provided the tests free of charge, but they were blinded to the results and all analysis was conducted independent of them.

How we envisage TnI-Nx may be used in the future to allow very early rule out of heart attacks

Please note – patients experiencing sudden onset chest-pain should always seek immediate medical attention.

I am fortunate to hold a Senior Research Fellowship in Acute Care sponsored by the Canterbury Medical Research Foundation, the Emergency Care Foundation, and the Canterbury District Health Board which enables me to participate in these studies.

ps.  You’ll have to read some of my older posts if you want to know why “Cheesecake files”

 

An even quicker way to rule out heart attacks

The majority of New Zealand emergency departments look for heart muscle damage by taking a sample of blood and looking for a particular molecule called a high-sensitivity troponin T (hsTnT).  We have now confirmed that rather than two measurements over several hours just one measurement on arrival in the ED could be used to rule out heart attacks in about 30% of patients.

What did we do?

We think this is a big deal. We’ve timed this post to meet the Annas of Internal Medicine timing for when our work appears on their website – here.  What we did was to search the literature to find where research groups may have measured hsTnT in the right group of people – namely people appearing in an emergency room whom the attending physician thinks they may be having a heart attack. We also required that the diagnosis of a heart attack, or not, was made not by just one physician, but by at least two independently.  In this way we made sure we were accessing the best quality data.

Next I approached the authors of the studies as asked them to share some data with us – namely the number of people who had detectable and undetectable hsTnT (every blood test has a minimum level below which it is said to be “undetectable” in hsTnT’s case that is just 5 billionths of a gram per litre, or 5ng/L).  We also asked them to check in these patients if the electrical activity of the heart (measured by an electrocardiogram or “ECG”) looked like there may or may not be damage to the heart (a helpful test, but not used on its own to diagnose this kind of heart attack).  Finally, we asked the authors to identify which patients truly did and did not have a heart attack.

What did we find?

In the end research groups in Europe, UK, Australia, NZ, and the US participated with a total of 11 studies and more than 9000 patients.  I did some fancy statistics to show that overall about 30% of patients had undetectable hsTnT with the first blood test and negative ECGs.  Of all those who were identifiable as potentially “excludable” or “low-risk” only about 1 in 200 had a heart attack diagnosed (we’d like it to be zero, but this just isn’t possible, especially given the diagnosis is not exact).

VisualAbstract AnnalsIM 170411

Pickering, J. W.*, Than, M. P.*, Cullen, L. A., Aldous, S., Avest, ter, E., Body, R., et al. (2017). Rapid Rule-out of Myocardial Infarction With a High-Sensitivity CardiacTroponin T Measurement Below the Limit of Detection: A Collaborative Meta-analysis. Annals of Internal Medicine, 166(10). http://doi.org/10.7326/M16-2562 *joint first authors.

What did we conclude?

There is huge potential for ruling out a heart attack with just one blood test.  In New Zealand this could mean many thousands of people a year can be reassured even more swiftly that they are not having a heart attack. By excluding the possibility of a heart attack early, physicians can put more effort into looking for other causes of chest-pain or simply send the patient happily home.   While not every hospital performed had the same great performance, overall the results were good.  By the commonly accepted standards, it is safe.  However, we caution that local audits at each hospital that decides to implement this “single blood measurement” strategy are made to double check its safety and efficacy.


Acknowledgment: This was a massive undertaking that required the collaboration of dozens of people from all around the world – their patience and willingness to participate is much appreciated. My clinical colleague and co-first author, Dr Martin Than provided a lot of the energy as well as intelligence for this project. As always, I am deeply appreciative of my sponsors: the Emergency Care Foundation, Canterbury Medical Research Foundation, Canterbury District Health Board, and University of Otago Christchurch. There will be readers who have contributed financially to the first two (charities) – I thank you – your generosity made this possible, and there will be readers who have volunteered for clinical studies – you are my heroes.

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Heart attacks in NZ – are women getting a raw deal?

Yesterday the NZ Herald published an article saying doctors are failing to spot heart attacks in thousands of women.  This sounds alarming, could it be happening in NZ? Are women getting a raw deal?  Important questions.  This post looks at the study behind the media and then at how heart attacks are being diagnosed in New Zealand.

The Herald article is evidently based on press releases related to a study published to coincide with the European Society of Cardiologist’s conference currently underway in Rome and attended by some 30,000 cardiologists, other physicians, industry types, and the Pope (yep!). The study in question comes from the University of Leeds. Here’s the Leeds Uni press release.

The US red-dress logo which is their national symbol for women and heart disease

The US red-dress logo which is their national symbol for women and heart disease

The study

The study is based on an audit of UK data collected about patients between 2004 and 2013 whose final diagnosis was a heart attack (in clinical jargon a myocardial infarction, either STEMI or NSTEMI).  The full article is available here.

The subjects were patients who at discharge from hospital had a heart attack diagnosis.  The authors looked at the preliminary diagnosis of patients when they first entered the hospital and compared that diagnosis to the final diagnosis of a heart attack.  The preliminary diagnosis was for about a 30% of patients not explicitly a heart attack – ie often something like “chest pain of uncertain cause.”  In the press release and news reports this was reported as a “misdiagnosis.”

Point 1:  The term “misdiagnosis” is inappropriately applied here.  While some forms of heart-attacks can be diagnosed in the ED, most can not.  Indeed, the guidelines for diagnosis of a heart attack require some blood measurements at least 6 hours apart.  Nowadays, the later blood sample is not done in the ED, but in a cardiology or general medicine ward.  That is, the ED physicians often don’t have all the data to make a definitive diagnosis – hence only a preliminary diagnosis is made. Most of the time the job of the Emergency department physicians is to rule-out some possible diagnoses and to identify patients at significant risk of a heart attack.  These patients are referred on to the specialist teams within the hospital who make the final diagnosis.*  Yesterday I was speaking with a cardiologist who was explaining how often cardiologists themselves disagreed over a diagnosis.  It ain’t easy.

The press releases and media reports emphasise that a larger proportion of women than men were likely to have a change between the preliminary and final diagnosis.  The Leeds University press release states women were 59% for a final STEMI diagnosis and 41% for a final NSTEMI diagnosis more likely than men to have a change from the preliminary diagnosis.

Point 2:  These numbers are not reported in the published paper!  Nor is anything about the differences between men and women discussed in the paper.  In the results section it is simply stated that those who had an initial diagnosis that changed were more likely to be older, female, and have a co-morbidity. There are some numbers related to this in a table. In the table I note that patients older than 61 compared with younger patients had at least (more if they were even older) the same odds of having a diagnosis changed as did females compared with males (it’s a little awkward in the paper because the odds ratio is written the opposite way around – but this can be rectified simply by taking the reciprocal of the odds ratio and comparing that).  There were also other predictors of a change in diagnosis (eg higher heart rate).  The cynic in me thinks that it may be for publicity reasons that the emphasis has been placed on the sex differences in press releases.

Point 3: What is important about the study is that in those who had a change in diagnosis the one-year mortality rates were higher.  While the suggestion is made that this is because of delay in time to treatment (known from other studies to be important), there are other potential reasons because of the differences in demographics and co-morbidities between the groups.

New Zealand

The study began at a time when the blood biomarkers indicative of a heart attack that are used now (troponins) were not in common use.  There have been several generations of markers, the latest of which are “high-sensitivity troponins.”  The authors’ recommended that:

“…our results… call for the earlier use and wider adoption of high sensitivity troponins as well as a focus on the systematic application of accelerated diagnostic protocols using risk scores rather than subjective clinical assessment.”

The good news is that New Zealand is now the only country in the world** to have accelerated diagnostic protocols using risk scores in place in every ED.  Furthermore, most ED’s are using the latest high sensitivity troponins.

In the Christchurch ED, different sex-specific thresholds of the troponin used for risk stratifying and diagnosing heart attacks are used.  This is because in the general healthy population males have slightly higher values of these troponin measurements than females.  Therefore, to avoid underdiagnoses of females a lower diagnostic threshold is used.  Furthermore, in a study we were part of and lead by our Brisbane based colleagues, using sex-specific threshold helped improvs risk prediction for future adverse events in women.

Conclusion

In New Zealand it is less likely that women are getting a raw deal.


 

*perhaps the Pope a.k.a @Pontifix [literally the “bridge builder”] could help bridge the divide between ED physicians and cardiologists – generally ED physicians rule-out heart attacks, Cardiologists rule-in heart attacks.

** although Queensland also has this and they like to think of themselves as a country sometimes

Cheesecake Files: Embargoed until

Every now and again a Journal doesn’t want us to talk publically about our own paper until it they publish it.  This is simply so they can make more of a splash with it.  This was the case of an article I have been involved with published today in the Cardiology journal of the American Medical Association*. 

What’s it about?

Ruling out a heart attack in the emergency department is difficult.  Readers of this blog would have read about various other ways we’ve developed to be part of it (eg here).  They depend on many things including the type of blood measurement used and the timing of that.  These markers – called troponins – detect damage to the heart muscle.

In this study led by Ed Carlton of Southmead hospital in Bristol, UK, we evaluated whether a single measurement of very low levels of a comparatively new blood biomarker called “High-sensitivity troponin I” could alone rule out heart attacks within 30 days when someone presented to the emergency department with chest pain (Here Ed speak about the study here).

3155 patients at 5 hospitals in New Zealand (Christchurch), Australia and the UK participated of whom 291 had a heart attack (277 were having a heart attack on the day they presented to ED, the other 14 had one within 30 days).

We found that 594 (18.8%) of patients had such a high sensitivity troponin I concentration below the limit at which it could reliably be detected.  ie next to nothing. These we can say tested negative.  Three of them (0.5%) it turned out did have a heart attack.

Why the splash?

The editor got quite excited about this and another study and wrote an editorial to accompany the studies:

“To manage costs and the adverse effects of overcrowding in the ED, it is a high priority to rapidly and safely identify patients with a sufficiently low probability for acute coronary syndrome (<0.5%-1%) so that they can be discharged efficiently and avoid unnecessary testing.”

He was impressed that this study had been “tested in robustly sized, geographically diverse, clinically relevant populations.”

And concludes

“Taken together with prior studies the findings from the studies of Neumann et al and Carlton et al lend strong support to the notion that accelerated diagnostic protocols that incorporate [high sensitivity troponins] can facilitate earlier triage while maintaining an acceptable [rate of false negatives].

One of the features of interest to the readers of this US journal is that the high-sensitivity troponins are not yet available in the US, however they eventually will be and how they are used is of particular interest.

Part of a figure from the publication showing how choosing different troponin thresholds to rule-out patients affects how sensitive the test is.

Part of a figure from the publication showing how choosing different troponin thresholds to rule-out patients changes how sensitive the test is.

Why not perfection?

Of course we would love to never have a false negative (or false positive).  However, the reality of medicine is that this is not possible.  We could, of course, simply admit everyone, do more invasive tests,  or “wait and see” if they develop a heart attack. There are, though, risks as well as costs with admitting people to hospitals.  If I may speculate for a moment, the rise in superbugs resistant to antibiotics is only likely to increase those risks in the future – hence the importance of studies such as this. It is important that we get the balance of risk right.

What are the next steps?

All of New Zealand now has some kind of accelerated diagnostic pathway for chest pain patients that incorporates serial troponin measurements.  At some stage we will implement, monitor, and measure the addition of an even more accelerated rule-out for some patients with just one troponin.  Watch this space.

_________________

* Carlton, E., Greenslade, J., Cullen, L., Body, R., Than, M. P., Pickering, J. W., Aldous, S.A., Carley, S,. Hammett, C., Kendall, J., Kevill, B., Lord, S.J., Parsonage, W.A., Greaves, K. (2016). Low concentrations of high-sensitivity cardiac troponin I at presentation in the evaluation of emergency department patients with suspected acute coronary syndrome. JAMA Cardiology. http://doi.org/10.1001/jamacardio.2016.1309