Sex-Specific 99th Percentile URLs for Cardiac Troponin Assays—Their Time Has Come

In 1543, astronomer Niccolò Copernico’s book De revolutionibus orbium coelestium proposed that the sun was the center of the universe and that other planets revolved around it, challenging the status quo that the earth was the center of the universe. That is the way progress is made. Health disparities in women with cardiovascular (CV) disease are well recognized (1). Outcomes in women are worse than in men. In our view, some of this problem is due to the lack of use of sex-specific cutoffs for cardiac biomarkers. High sensitivity cardiac troponin (hs-cTn) is the preferred biomarker for detection of myocardial injury (2,). Myocardial injury is diagnosed when hs-cTn is increased above the 99th percentile upper reference limit (% URL) (2,). hs-cTn assays allow for earlier diagnosis due to their increased sensitivity and greater precision (2,). They also identify those at risk after an acute cardiovascular event, in patients with chronic stable cardiovascular disease (3,) and for primary cardiovascular prevention (4,). Given the sex differences in cardiovascular physiology, it is not surprising that there are differences in cardiac troponin (cTn) values between men and women. Sex differences were analytically clear with creatine kinase MB, but were rarely used clinically. Similar data exist for cTn which support guideline recommendations for sex-specific URLs (5). Men have higher hs-cTn concentrations than women (5,). This has been hypothesized to be due to a greater cardiac mass and a higher incidence of subclinical coronary artery disease (CAD) in men (6,). This may be attributable to a greater body mass in men; however men also have higher blood pressure and higher sympathetic tone (7). In addition, when present, the degree of atherosclerosis, left ventricular (LV) hypertrophy, and cardiomyocyte apoptosis tends to be less in women (6,). These differences may be due to attenuating properties of estrogens, including the effects on atherosclerosis risk factors, thrombus formation, vasoreactivity, and vascular apoptosis (8,). Moreover, women have smaller epicardial coronary arteries despite adjustment for age, body habitus, and left ventricular mass (8,). This, together with a higher myocardial blood flow, results in greater endothelial shear stress which may inhibit focal lipid accumulation, reduce pathologic remodeling, and lower plaque instability (8). There are also differences in CAD pathophysiology. Plaque erosion is more often a cause of acute atherothrombosis than plaque rupture in women, particularly in premenopausal years (8,). Furthermore, women more often present with symptoms related to microvascular and endothelial dysfunction and/or diffuse coronary atherosclerosis, rather than a defined culprit plaque. This causes atypical symptoms such as neck pain, fatigue, dyspnea, or nausea (1,) and less marked increases in cTn, given the extent of myocardial injury is usually less in these situations (1,). Women also tend to wait longer from symptoms onset before they seek medical attention (8,). These aspects, plus lower cTn values generically, are thought to contribute to the higher number of delayed and incorrect diagnoses in females (1). Assay manufacturers provide sex-specific cutoffs for their hs-cTn assays as indicated on the IFCC website (Table 1). Analytical characteristics and reference values of available high sensitivity assaysa. LoB, limit of blank; LoD, limit of detection; NP, not provided; URL, upper reference limit. Data extracted from the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers v060617. http://www.ifcc.org/media/463453/HighSensitivityCardiacTroponinI_T_AssayAnalyticalCharacteristics_v060617.pdf. Analytical characteristics and reference values of available high sensitivity assaysa. LoB, limit of blank; LoD, limit of detection; NP, not provided; URL, upper reference limit. Data extracted from the IFCC Task Force on Clinical Applications of Cardiac Bio-Markers v060617. http://www.ifcc.org/media/463453/HighSensitivityCardiacTroponinI_T_AssayAnalyticalCharacteristics_v060617.pdf. The assay that a given institution uses will play an important role in deciding whether sex-specific cutoffs add clinical benefit. Some assays, such as the high-sensitivity cardiac troponin T (hs-cTnT) assay from Roche, do not yield high percentages of measurable values in women. This can lead to difficulties in precision with all lower values but especially for women who have such lower values. Depending upon which assay is being considered, the differences in measured cTn between men and women range from modest to large. The issue of how to determine 99th % URL values is controversial. To measure a true 99th % URL, one must ensure that the “healthy” population used is free of subclinical disease. Koerbin et al. (9,) showed that when the values were ‘coned’ by progressively excluding patients with abnormal renal function, increased NT-pro BNP, clinical history, and abnormal echocardiographic examinations, only patients < 55 years old showed marked sex differences in the 99th percentile. Thus, the quality of the screening procedures for normality has a marked impact on the values. However, it is unusual to find the rigorous procedures used by Koerbin et al. (9) employed by diagnostic companies; data derived from the literature therefore are a more reliable source. There are two settings to consider: a) primary and secondary prevention with stable or incipient cardiovascular disease, and b) acute coronary syndromes (ACS). For stable disease assessment, there is little controversy that sex-specific cutoffs improve prognostication. cTn concentrations provide useful prognostic information in the general population (4,). In a primary prevention study from Norway, the association between high-sensitivity cardiac troponin I (hs-cTnI) and cardiovascular death was stronger in women than in men (10). Likewise, there is good evidence for using sex-specific cutoffs in secondary prevention trials such as in patients with stable cardiovascular disease. In those undergoing elective percutaneous coronary intervention, pre-procedural hs-cTnT with the use of sex-specific cutoffs was found to be a strong predictor of mortality in both sexes (11,). In the Bypass Angioplasty Revascularization Investigation in Type 2 Diabetes (BARI 2 D) trial (12,), the lower concentrations of hs-TnT observed in women were associated with an increased risk of major CV events and death compared to men with similar levels. Furthermore, a recently published large study from a general population showed that increased hs-cTnI concentrations were independently associated with incident heart failure using different hs-cTnI cutoff values for women (2.6 ng/L) and men (4.2 ng/L) (13). The situation is more complex with acute disease. When the diagnosis of acute myocardial injury is made, cTn (especially hs-cTn) concentrations rise, and some have argued that the concentration differences between men and women with acute myocardial injury are harder to appreciate. In addition, women with coronary artery disease are about 10 years older (1,) and cTn values rise with age (2,), perhaps obscuring some of the differences. Women also tend to present to the hospital later than men which may also blunt differences. Studies from the Advantageous Predictors of Acute Coronary Syndromes Evaluation (APACE) group have found no benefit of using sex-specific cutoffs to predict major cardiovascular outcomes in patients with possible acute myocardial infarction (MI) (14,). The issue with many of these studies has been the population enrolled. Many studies recruited only patients in whom the primary question was MI or no MI instead of a more inclusive group. Thus, individuals who have presented atypically, such as women and the elderly, may have been less likely to be included. For example, in the APACE studies (14,), the mean age was in the early 60 s, whereas in the High-Sensitivity Troponin in the Evaluation of patients with suspected Acute Coronary Syndrome (High-STEACS study) (15), it was 10 years higher. The APACE investigators found that sex-specific cutoffs for the diagnosis of acute MI resulted in increased sensitivity but reduced specificity in women, whereas the opposite results were found in men. Thus, the authors concluded there was no overall benefit (14,). They argued that differences in age (women are older) compensated for sex differences (14). This argument ignored their own finding that with sex-specific cutoffs more women were diagnosed with increased cTn, and those patients, with or without MI, were at greater risk. Whether considering MI or myocardial injury, it is only with knowledge of a problem that treatments can be considered. Others found differences with a more inclusive approach. The High-STEACS study (15,) enrolled a more elderly population for both sexes. Sex-specific cut off values for hs-cTnI resulted in a sizable reclassification of myocardial injuries (17%) with a two-fold increase in women compared to men. There is a substantial literature documenting that increases in hs-cTn foreshadow a worse outcome; however without evaluation and treatment, no change in outcomes should be expected and that is what was observed. Indeed, in their subsequent analyses (15,), the group showed that despite increases in type 1 MI, type 2 MI, and myocardial injury, women were less likely to undergo evaluation for ischemia or receive antiplatelet therapy or secondary prevention strategies. Even in the group of patients with Type 1 MI, women underwent less coronary angiography (52% vs. 73%). Perhaps for that reason, the rate of primary outcome (recurrent myocardial infarction or cardiovascular death at 1 year) in men decreased by 3% (18% to 15%) while in women it remained unchanged (19%) (15). This is likely in part a result of the embedded gender disparities in attitudes, practice, and outcomes. Eggers et al. (6) studied hs-cTnI concentrations in patients with non-ST elevation acute coronary syndrome only. They found that gender-specific cutoffs did not improve risk prediction but did find that hs-cTnI above the sex-specific 99th percentiles, as determined locally, exhibited stronger prognostic information in women than in men. Overall, the clinical and prognostic benefits of the use of sex-specific cut points are clear in the chronic setting, but less secure in the acute setting. Sex-specific cut off values are necessary for risk stratification and their benefits in patients with acute coronary syndromes have likely been obscured by the populations some have chosen to study. Thus, an approach that uses sex-specific cut offs is one that will definitively help with stable disease and is likely to assist in acute cardiac care as well. Copernico turned out to be right but only once the world was willing to embrace a new paradigm. The time is now for sex-specific cut off values for hs-cTn. All authors confirmed they have contributed to the intellectual content of this paper and have met the following 4 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; (c) final approval of the published article; and (d) agreement to be accountable for all aspects of the article thus ensuring that questions related to the accuracy or integrity of any part of the article are appropriately investigated and resolved. Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest: None declared. A.S. Jaffe presently or in the past has consulted for most of the major diagnostic companies (Abbott, Beckman, Brava, Blade, Siemens, Sphingotec, ET Healthcare, Roche, Novartis, Quidel). None declared. None declared. None declared. None declared. None declared. cardiovascular high sensitivity cardiac troponin percentile upper reference limit cardiac troponin coronary artery disease left ventricular high sensitivity cardiac troponin T acute coronary syndromes high sensitivity cardiac troponin I myocardial infarction