Sex-Specific Biomarker Threshold Doubles MI Diagnosis in Women With Suspected ACS

Use of a high-sensitivity troponin I assay with a sex-specific diagnostic threshold substantially increases the diagnosis of MI in women with suspected ACS compared with a standard troponin test using a universal cutoff, according to a prospective studypublished online January 21, 2015, ahead of print in BMJ. Nonetheless, women whose diagnosis is upgraded to MI based on the new test are less likely than men to receive further workup and treatment for MI despite a worse prognosis.

The findings were originally presented at the European Society of Cardiology Congress 2013 in Amsterdam, the Netherlands.

According to the authors, the question of whether the sex-specific biomarker strategy will “improve outcomes through better targeting of treatments for coronary heart disease requires urgent attention.”

A team led by Nicholas L. Mills, MD, of the University of Edinburgh (Edinburgh, Scotland), looked at 1,126 consecutive patients (mean age 66; 45% women) who presented to the Royal Infirmary of Edinburgh with suspected ACS between August and October 2012.

The women were older than the men and at a higher mortality risk, although they had undergone less revascularization. Women were as likely as men to present with chest pain and to have ST-segment depression or T-wave inversion but less likely to have ST-segment elevation. On admission, women had lower median serum troponin concentrations (29 vs 69 ng/L; P = .025) and median peak troponin concentrations (50 vs 1,230 ng/L; P < .001) compared with men.

Serum troponin was measured on admission and at 6 or 12 hours after symptom onset with both a contemporary troponin I assay using a single diagnostic threshold (50 ng/L) and a high-sensitivity troponin I assay (both Architect_STAT; Abbott Laboratories) using both a common cutoff (26 ng/L) and sex-specific thresholds (34 ng/L for men; 16 ng/L for women).

Sex-Specific Threshold Affects Women More Than Men

Based on the conventional troponin test, 11% of women and 19% of men were diagnosed with a spontaneous type 1 MI. When the high-sensitivity assay was employed, the proportion of women diagnosed with type 1 MI increased to 16% using a common threshold and doubled to 22% with the sex-specific threshold (P < .001). In men, the high-sensitivity assay had less of an impact, increasing the diagnosis of type 1 MI to 23% using the generic threshold and to 21% using the sex-specific threshold (P < .021).

Four percent of both women and men were diagnosed with type 2 MI using the conventional troponin assay at a generic threshold. Use of the high-sensitivity assay with sex-specific thresholds led to a small but significant increase in the percentage of women, but not men, diagnosed with a type 2 MI.

Women Still Lag in MI Management

Looking at posttest management, however, women diagnosed with MI by either test were less likely than men with the same diagnosis to:

• Be referred to a cardiologist
• Receive angiography or PCI
• Be prescribed a statin on discharge

In fact, women whose MI was identified only by the sex-specific threshold were even less likely to undergo further workup and receive treatment for MI.

After adjustment for age, renal function, and history of diabetes, women whose MIs were diagnosed by the sex-specific test or results concordant with that assay faced a higher risk of death (adjusted OR 6.0; 95% CI 2.5-14.4) or recurrent MI (adjusted OR 5.8; 95% CI 2.3-14.2) at 1 year than those without MI. Similar results were observed when outcomes were compared for women diagnosed by the sex-specific vs the generic threshold of the high-sensitivity troponin I assay, indicating that the former cutoff is likely to correctly identify more women at increased risk of recurrent MI or death.

The findings suggest that the use of contemporary assays with a single threshold results in an underdiagnosis of MI in women and contributes to inequalities in treatment and outcomes between the sexes, the study authors say.

Smaller Hearts Require a Lower Threshold

Dr. Mills and colleagues note that the apparent underdiagnosis of women has usually been attributed to differences in presentation, with women more likely to have atypical symptoms and less reliable ECG changes. However, they report, recent research has questioned such differences, and the current data suggest another possible explanation: inappropriate, gender-neutral biomarker thresholds for diagnosis.

Women with MI typically have lower troponin levels than men, and the reason may be that the troponin concentration correlates with LV mass and women simply have less mass to be injured than men, the researchers point out. Thus, they say, it is “not surprising that sex-specific differences exist in the normal reference range for troponin.” To date, contemporary assays have not had the sensitivity and precision to determine sex-specific upper reference limits.

Dr. Mills and colleagues acknowledge concern that high-sensitivity assays may sacrifice clinical specificity. However, they observe, secondary causes of myocardial injury and infarction were present in only a few patients in the study cohort. And although such causes were more common in women than men, specificity was only slightly lower in women, suggesting that “improvements in diagnostic sensitivity will not be offset by reductions in specificity,” the authors argue.

In addition, to address the possibility that older age and differences in clinical presentation may play a role in the underdiagnosis of women, the researchers performed a sensitivity analysis controlling for these factors. The differences between women and men persisted, suggesting that the generic biomarker threshold contributes to the inequalities in diagnosis.

According to the investigators, the issue of whether implementation of high-sensitivity troponin assays with sex-specific diagnostic thresholds will improve outcomes through better targeting of treatment is being tested in the multicenter randomized High-STEACS trial.