High-Sensitivity Troponins Address MI Underdiagnosis in Women

Pam Harrison

January 28, 2015

GLASGOW, SCOTLAND and TRURO, UK — Use of a high-sensitivity troponin (hs-Tn) assay and sex-specific diagnostic thresholds doubles the number of MI diagnoses in women presenting with ACS, according to a prospective study that also suggested women are less likely to receive evidence-based treatment than men despite the same diagnosis[1].

"Our research shows that there is value in improving diagnostic accuracy, particularly in women, using a high-sensitivity troponin assay with sex-specific thresholds," senior author Dr Nicolas Mills (University of Edinburgh, Scotland) told heartwire . "It also demonstrates that there is inequity in how we treat women with MI and that by using these assays, we may be able to address that imbalance."

Also, a new meta-analysis suggests that only a single baseline measurement using a different hs-Tn assay provides effective criteria for ruling out acute MI in the emergency department, provided fairly low cut-off values are used[2].

Both studies were published online January 21, 2015 in the BMJ.

hs-Troponin I in the Prospective Study

The investigators prospectively studied 1126 consecutive patients presenting to a single center with suspected ACS. About 45% of them were women. Serum hs-TnI concentrations were measured on admission and repeated 6 or 12 hours after symptom onset using both a conventional TnI assay and an hs-TnI assay (ARCHITECT STAT, Abbott Laboratories). Sex-specific thresholds for the high-sensitivity assay were established at 34 ng/L for men and 16 ng/L for women.

"Using the [standard] troponin I assay with a threshold of 50 ng/L, 55 women (11%) and 117 men (19%) were classified as having type-1 myocardial infarction," according to the investigators, referring to the class of MI caused by coronary plaque rupture and thrombus formation.

With the high-sensitivity assay, the number of women classified as having a type-1 MI increased to 16% using a generic threshold of 26 ng/L and to 22% using a sex-specific threshold of 16 ng/L (P<0.001). But diagnosis of type-1 MI using the same high-sensitivity assay increased only slightly to 23% in men using the sex-specific threshold of 34 ng/dL.

In no case were patients were identified as having an MI by the conventional assay without also showing an MI by the high-sensitivity assay, the authors point out.

As investigators observe, women diagnosed with a MI on both assays were less likely than men to be referred to a cardiologist, undergo coronary angiography or PCI, or be prescribed a statin on discharge.

Disposition of Women and Men Following a Troponin-Based MI Diagnosis

Outcome Men (%) Women (%) P
Referred to a cardiologist 95 80 0.004
Coronary angiography 74 47 0.001
PCI 64 29 <0.001
Statin on discharge 85 60 0.001

'Women identified as having myocardial infarction using only the high-sensitivity assay with sex-specific thresholds were least likely to undergo investigations and treatment for myocardial infarction," investigators add.

Women with an MI identified by either the high-sensitivity assay with sex-specific thresholds or both that assay and conventional assay had the highest risk of death or recurrent MI at 12 months.

"In my personal practice, I don't differentiate between men and women in the treatment of ACS, so this finding surprised me a little, because I like to think I treat everyone the same," Mills told heartwire .

However, he observed, women in the study were about 7 years older than men at the time of presentation. "When you are older, you may have additional comorbid conditions, and sometimes we make decisions, particularly about invasive treatment of ACS, based on age and comorbid conditions, and these factors might have influenced the decision-making in this study."

Mills also emphasized that women in the study were just as likely to present with chest pain as men and to have myocardial ischemia by ECG, but their peak troponin levels were substantially lower than those in men. "I think this reflects differences in the pathophysiology of coronary disease in men and women."

For example, women are more likely to have plaque erosion rather than plaque rupture and have smaller MIs than men. "But even small MIs are important," Mills emphasized. "One in four women with very small MIs only identifiable using the high-sensitivity test returned within 12 months with a recurrent infarct or had died. . . . So these are high-risk individuals despite having been considered to have had a small MI."

Whether treatment of women with MI identified only by a high-sensitivity assay will improve survival is not yet known but is currently the subject of a large multicenter trial funded by the British Heart Foundation, observed Mills. "Once we have the answer to this question from the trial, we [may] be able to change the guidelines."

Are Two Assays Needed for an MI Diagnosis?

In their meta-analysis, Zhelev and colleagues observed that a single baseline hs-TnT reading (Elecsys, Roche Diagnostics) can be used to rule out acute MI in the emergency department, provided low cut-off values of either 3 ng/L or 5 ng/L are used. Their conclusion was based on 23 studies in which the performance of the hs-TnT assay was used at presentation in the emergency department with suspected ACS.

Using a 14-ng/L threshold, the majority of the papers showed an assay sensitivity of 89.5% (95% CI 86.3%–92.1%) and specificity of 77.1% (95% CI 68.7%–83.7%). A smaller number of papers showed a sensitivity using a 3- to 5-ng/L threshold of 97.4% (95% CI 94.9%–98.7%) and specificity of 42.4% (95% CI 31.2%–54.5%).

That, according to the authors, means that if 21 of 100 consecutive patients present with an MI, 21% being the median prevalence across the studies, then two of the 21 patients will be missed (false negatives) if 14 ng/L is used as a cut-off value, and 18 of 79 without MI be false positives. If, on the other hand, a much lower threshold of 3 to 5 ng/L is used as the diagnostic threshold, less than a single patient with acute MI out of 100 presenting with suspected ACS will be missed, while there will be 46 false-positive tests.

The authors caution, however, that the proportion of patients with acute MI might be higher if they present within 3 hours of symptom onset.

Commenting on both of these studies[3], Dr Adam Timmis (Queen Mary University of London, UK) noted that the ability now to reliably detect minor increases in troponin makes the diagnosis of small MIs—previously branded as unstable angina—a possibility. "High-sensitivity assays also have the potential to rule out myocardial infarction earlier and with greater confidence if diagnostic thresholds are not met," Timmis adds.

On the other hand, he proposed that ruling out NSTEMI with a single blood test may not be ready for "prime time," given the many limitations to a single baseline test discussed by Zhelev and colleagues. Still, "in patients judged to have a low probability of infarction, the case could be made for ruling out NSTEMI with one test using, for example, the 5-ng/L threshold of the Elecsys troponin T high-sensitive assay."

Timmis also wrote that the ability of sex-specific diagnostic thresholds to identify high-risk women with previously undetectable increases in troponin levels is "particularly exciting."

"If treatment can be shown to protect these women against cardiac events or even death, it will go some way toward redressing sexual inequalities in outcomes of myocardial infarction first reported in the BMJ more than 20 years ago," he states.

NICE recently published guidelines that recommend the new high-sensitivity TnI and TnT tests.

The prospective study was funded in part by the British Heart Foundation. The meta-analysis was supported by the South West Academic Health Science Network and the National Institute for Health Research. Mills declared that he has acted as a consultant for Abbott Laboratories and Beckman-Coulter. Disclosures for the coauthors are listed in the article. Zhelev declared having no financial relationships with any organization that might have an interest in the submitted work in the previous 3 years. Disclosures for the coauthors are listed in the article. Timmis had no relevant financial relationships.

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