High-STEACS: Sensitive Troponin Tests Rule Out MI, but Have No Impact on Hard Events

While the findings were “disappointing and surprising,” the study PI believes the trial gleaned new insights and validated the rule-out power of the test.

High-STEACS: Sensitive Troponin Tests Rule Out MI, but Have No Impact on Hard Events

MUNICH, Germany—Introduction of high-sensitivity cardiac troponin tests in Scotland led to the reclassification of one in six patients who had myocardial injury that was missed by standard troponin assays. Importantly, however, only a third of these patients were ultimately identified as having a myocardial infarction, and use of the newer tests had no impact on subsequent rates of cardiovascular death or MI over the next 12 months.

“We expected outcomes to improve, so we were surprised and disappointed,” lead investigator Nicholas Mills, MBChB, PhD (University of Edinburgh, Scotland), told TCTMD. “But reflecting on that and looking at the actual diagnosis of these patients, it is perhaps not so surprising. These patients with very small amounts of myocardial injury have not previously been included in randomized trials. Therefore, we don’t really know how effective treatments are in this group—they are a very mixed group of patients that have many other conditions [such as] microvascular disease, for example—where the outcomes maybe we can’t improve because we don’t have effective treatments.”

Mills presented results from the stepped-wedge, cluster-randomized, High-STEACS trial here at the European Society of Cardiology Congress 2018; they were published simultaneously online in the Lancet.

When the STEACS Are High

The study enrolled more than 48,000 consecutive patients presenting with chest pain to one of 10 Scottish hospitals, with all patients undergoing both tests during a validation phase and implementation phase. Ultimately, one in five patients with chest pain were found to have cardiac troponin I levels higher than the 99th centile of the normal range, stratified by sex, using either a standard troponin assay or the newer high-sensitive cardiac troponin I (hs-cTnI) tests. Of the 10,360 patients flagged as having abnormal values, 1,771 (17%) were reclassified on the basis of the newer test.

The primary outcome, rates of CV death or MI 1 year after presentation, were compared in the patients reclassified by the assay and found to be no different between the period when physicians were blinded to the new test (events occurring in 15% of patients) and the implementation phase when the newer test was in use (12% of patients; adjusted OR 1.10; 95% CI 0.75-1.61).

In important additional findings flagged by Mills, there was no evidence of misdiagnosis, inappropriate treatment, excess bleeding or other harms following the introduction of the high-sensitivity assays. Moreover, while length of stay was doubled for patients initially identified as having myocardial injury, the duration of hospital stays was halved for those in whom MI was ruled out. Overall, said Mills, length of stay “was reduced by one-third across the entire trial population, suggesting that clinicians were more confident ruling out myocardial infarction with potential benefits for healthcare systems.”

During a Tuesday morning press conference, moderator Sarah Clarke, MD (Papworth Hospital, Cambridge, England), asked Mills how stays could have been shortened, given that physicians were instructed to follow specific protocols.

In response, Mills explained that the growing confidence among treating physicians was palpable as their experience with the test increased. “During the conduct of the trial we did not recommend doing anything different than what the international guidelines recommended, but certainly I remember the first few months of using this test in clinical practice and it really struck me: I would have a 55-year-old patient with diabetes and a family history of heart disease who would come in with slightly atypical chest pain. I would always admit this [type of] individual, consider him high risk, do serial testing, and consider further investigation.”

When serial, hs-cTnI tests showed troponin levels of 1, three times in a row, Mills said he “quickly learned that a very low troponin concentration is extremely helpful and rules out the presence of structural heart disease or unstable coronary disease very effectively. And so, while we did not mandate it, clinicians learned very quickly during the conduct of this study that actually this test is very powerful to rule out heart disease. And I think that’s why in the 79% of patients who did not have a heart attack in our trial population, the length of stay halved.”

Investigators have not yet done cost-efficacy analyses, but Mills agreed that these are “critical” and underway.

Implications for Practice

A panel of 10 cardiologists adjudicated every index presentation and every primary outcome in High-STEACS, with two adjudicating every event and a third arbitrating if the two disagreed.

What they found speaks to the high sensitivity of the newer tests and a need to further refine testing protocols, Mills said. “We expected to identify principally patients who’d had a myocardial infarction, but in fact the majority were very complex patients with other causes of myocardial injury and only a small proportion had myocardial infarction. I think that was one of the principle reasons why we haven’t demonstrated a benefit in outcomes here.”

Many patients, he emphasized, fell into categories inadequately studied in clinical trials of ACS, including women (who made up 47% of High-STEACS) and the elderly. Mean age of patients reclassified was 75, he noted.

“This was an extremely heterogenous population—this trial enrolled everyone, so we had many patients over the age of 100, and we had every comorbidity you could possibly think of,” Mills told the press. “It is hard to say that there was one particular, favorite group of diagnoses, but the one that stuck out to me, and I adjudicated more than 10,000 index presentations, was atrial fibrillation. There were many patients who presented with tachyarrhythmias, stable HF, and small myocardial injuries picked up by the assay. So they did not have heart attacks, but they did have important cardiac conditions.

“Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th percentile derived from a normal reference population,” he concluded.

Our findings question whether the diagnostic threshold for myocardial infarction should be based on the 99th percentile derived from a normal reference population. Nicholas Mills

Speaking with TCTMD, Mills elaborated: “What we learned in the conduct of the trial is not to use the 99th percentile. The real value of high-sensitivity tests is as a rule-out test, and the optimal threshold—the best way to do that—is way below the 99th percentile where true normal is less than 5 nanograms per liter, and here we can be absolutely confident that the patient doesn’t have structural heart disease or unstable coronary disease.”

As a first step, however, is to use sex-specific thresholds, he added, noting that only one in five hospitals are currently doing this with troponin test results. “There’s major opportunity to educate and come up with an optimized approach that can lead, I hope, to further iterations of the universal definitions,” Mills said.

Patient sex also may play an important role in interpreting the High-STEACS results, he noted. “Eighty-three percent of patients who were reclassified were women. Now that’s because the 99th percentile is much lower in women than in men, and I think this also raises an important question because very few trials of acute coronary syndrome predominantly test treatment strategies in women—they haven’t been enrolled in these trials, particularly those with very small evidence of myocardial infarction. And therefore, there’s some uncertainty as to how effective our treatments are in this patient group.”

Following the main arena presentation of the High-STEACS trial, discussant Christian Hamm, MD (Universitätsklinikum Gieβen, Bad Nauheim, Germany), praised the investigators and predicted that hs-cTnI tests will ultimately improve outcomes, particularly as hospitals become better at singling out myocardial infarction from other types of myocardial injury. Longer duration of follow-up may also yield more positive outcomes.

“I’m convinced that this study population has much more potential to demonstrate, in the end, that a high-sensitivity troponin test really results in better outcomes for these patients,” Hamm said.

The audience, however, may have been less convinced. In an app-based poll prior to Mills’ presentation, 73% of people said they believed high-sensitivity troponin tests are “useful,” but that number fell to 62% by the time he’d finished. Of note, 8% of responders said they worried the test was “harmful” prior to seeing the High-STEACS results; that number fell to 4% at the end of the presentation.

Asked whether he worries the negative trial results will end up convincing skeptics that high-sensitivity troponin tests are not worth doing, Mills told TCTMD: “I would discourage them from drawing that conclusion. Yes, we don’t know necessarily how to improve outcomes in these patients, but high-sensitivity tests are a step change in diagnostic performance. The real value is going to be in ruling out myocardial infarction more confidently and reducing length of stay, and there will be real benefits for patients and healthcare systems. Can we improve outcomes in those who have injury? Not yet, but we’re still working on ways to do that.”

Disclosures
  • Mills reports receiving honoraria from numerous cardiac troponin manufacturers including Abbott Diagnostics, Singulex, Roche, and research funding from the British Heart Foundation, and reagents from Abbott Diagnostics.

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