Ischaemic heart disease

Doubts over troponin rapid rule out tests for MI after RAPID-TNT results revealed

Questions are being raised about the benefit of high sensitivity cardiac troponin (hs-cTnT) as part of a rapid 0/1-hour MI rule out protocol for patients with suspected ACS  following negative results from 12 month follow up data of the RAPID-TNT trial.

While previously-released 30-day results were positive, the one-year data have shown the protocol did not reduce major cardiac adverse events compared to standard protocol when hs-cTnT was used to decide on early admission or discharge.

Presenting the findings at CSANZ 2020 this week Professor Derek Chew, director of cardiology, Southern Adelaide Local Health Network and lead investigator described the outcomes as ‘surprising’ given reassuring 30-day outcomes, which were presented at the European Society of Cardiology last year.

“I don’t think [the findings] tell us that we shouldn’t be implementing the 0/1-hour protocol but we really do need to be thinking very carefully about what we do with those patients for whom we discharge and a little bit for those we rule in,” he said. Professor Chew added that low rates of functional testing might explain the long term outcomes for patients who are discharged early.

The randomised trial included 3,378 subjects with suspected ACS presenting to four emergency departments in Adelaide.

It was designed as a noninferiority study of a 0/1-hour protocol using hs-cTnT compared with a standard 0/3-hour protocol with troponin T results.

Patients in the standard care arm had hs-cTnT drawn at baseline and at three hours. Results below 29 ng/ml were blinded to the clinician and considered  normal or not elevated. Professor Chew noted that while the fifth-generation high sensitivity assay has an upper limit of normal of 14 ng/L, the hospital clinical network had not yet adopted the new high sensitivity troponin values. Instead investigators aligned the lower clinical reporting limit to that of the previous generation protocol.

However, clinicians randomised to the 0/1-hour protocol were provided unmasked results with results down below 30 ng/L.

“Because of the precision in the fifth generation assay compared to the fourth there was a bump of an improved detection of patients with myocardial injury but we did mask the results under 29 ng/L and that has enabled us to randomise patients to see what happens to practice if we actually release the results  to clinicians all the way down to five and less,” he told the meeting.

Compared to the standard protocol, patients in the 0/1-hour arm were significantly less likely to be admitted (45.5% versus 33.2%) and had a significantly shorter length of stay (5.6 versus 4.6 hours). Meanwhile the event rate – death or MI at 30 days – was the same – 1% in both groups.

But the reassuring short term findings did not play out over the subsequent 12 months with investigators noting  a ‘slight’ increase in the rate of patients presenting with myocardial infarction and recurrent myocardial injury after 30 days.

At 30 days the 0/1-hour protocol was associated with less functional cardiac testing (7.5% vs 11.0%, P<0.001), but more myocardial injury – particularly acute injury and Type 4a and Type 5 MIs. Professor Chew said this likely stemmed from greater use of invasive coronary angiography and subsequent revascularisation that persisted throughout the 12 months in the subgroup of patients with troponin below 29 ng/L.

“In other words, the early increase wasn’t associated with reduction in late angiography, In fact releasing a high sensitivity result to clinicians was associated with an increase  in the rate of angiography over the 12 month follow up,” he said.

An increase in the rate of death and recurrent MI – the primary endpoint – was also observed in those patients who were cared for under the 0/1-hour  unmasked hs-cTnT protocol. While the difference did not reach statistical significance for the overall population, Professor Chew said a split analysis by those who had hs-cTnT concentrations less than 29 mg/L and those above revealed a statistically significant difference in the group below 29 ng/L.

Secondary outcomes

Meanwhile, for secondary endpoints, there were numeric differences in myocardial injury and MI in the overall population – 1.4% in the masked group versus 2.0% in the unmasked and 2.0% versus 2.9% respectively with no difference in chronic injury and borderline significant differences for death or ACS (4.5% versus 6.0%).

Describing the results as ’surprising’ Professor Chew said strategies and recommendations about care for patients after early discharge versus early admission would need to be redefined.

“The interpretation of troponin requires a profile if there’s nothing else our protocols have told us it’s that and getting that message across is a critical factor to embed in practice. What I think we need to do a better job of is to enhance that interpretation and try to provide relative specific risks so that we can make rational choices about investigations.”

Based on a ‘highly explorative’ analysis Professor Chew noted that while there was no difference in the rate of statin use or PTY12 use among patients who had experienced a primary endpoint or recurrent ACS, over the 12-month period there were ‘striking’ differences between those who did not get functional testing [19.2% vs 6.2%] and those who received angiography.

In a Q&A session following the presentation, Professor Chew suggested the disparity between state versus federal government funding of outpatient versus inpatient cardiac care could have played a role in the sharp drop in functional testing with early discharge.

“The federal government pays for outpatient testing in the community whereas the state governments pay for activity in hospitals so there is a disconnect there and I wonder, to an extent, whether our trial results are a function of how national policies reside around investigating cardiac disease between the outpatient  and inpatient setting.”

“In Australia there really had been a lot of effort put into establishing early outpatient functional testing and it proved to be a challenge for people to provide that and so the reassurance that the rule out provided did lead to an unguided, but big, reduction in testing and if I look at the number of patients who had subsequent events without a functional test it does seem to be surprisingly more than one might expect,” he added.

He said the observations – though ‘highly speculative’ – raise the question: ‘while we know it’s safe to discharge these patients, is what we do from downstream testing the issue that we need to delve into?”

Intermediate group

Another participant in the CSANZ 2020 virtual meeting, Professor Nicholas Mills, consultant interventional cardiologist at the Royal Infirmary of Edinburgh said the findings were ‘disappointing’.

“The overriding ambition with these assays are that they improve sensitivity and they lead to better care and better outcomes. But in that pre specified sub group analysis of 91% of the study population – those with unmasked cardiac troponin concentrations where I think we would have anticipated the greatest benefit would have been seen – the opposite was the case, with an excess in the outcomes that I think matter to us as clinicians and to patients, which is recurrent acute coronary events and death.”

He added that more needed to be done to understand the risks and how to mange the intermediate group in rapid rule out pathway.

“I have some reservations about how we mange the intermediate group in the pathway … this is often call the observe zone which is a group of individuals with slightly raised cardiac troponin concentrations who I think definitely are at increased risk of events and [we need] to really drill down into whether their care changed as a consequence of the accelerated pathway .”

Also speaking at the Q&A, Professor William Parsonage, Senior Staff Cardiologist, Royal Brisbane & Women’s Hospital, argued against using troponin as a binary test.

“We’ve spent a lot of time explaining to people about not treating everything that is above the 99th centile as type 1 MI – have we now gone to the other end of the spectrum where we need to reinforce the idea that something below the 99th centile doesn’t necessarily rule out coronary artery disease? My perception with these rule out [protocols] is always that we’re ruling out an acute event but we’re definitely not ruling out coronary artery disease and I’m not sure we’ve got that message across well enough to the broader clinical community,” he added.

Professor Chew also noted that, anecdotally, there was ‘a good number’ of type 4 and type 5 MI at 12 months.

“So all up I think we are seeing this shift in practice  where actually the reassurance that we get for 30 day outcomes  is good for ED discharge but not necessarily good for late outcomes and that we need better systems for shifting our investigative pathways out of the hospital into the peri hospital space.”

Professor Mills agreed that guidelines have so far not addressed recommendations about important decisions associated with downstream care following early rule out pathways particularly well leading to varied clinical practice.

“When implementing rapid rule out pathways in Scotland  I think one of my concerns and concerns shared with colleagues in the ED  were that we were removing that decision making that was often taking place over a prolonged period of time with multiple interactions with clinicians through the front door to a very compressed period of time that gives you less time for patients to to explain what it is that’s worrying them and less time for observation and therefore the recommendations associated with early rule out pathways about what the downstream care and follow up  with these patients are are really important.”

(Editor’s note: In the original version of this article, comments were attributed to Dr Martin Than when they were made by Professor William Parsonage. We apologise for the error.)

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