Diagnoses and Outcomes of Patients with Suspicion of Acute Coronary Syndrome and Raised High Sensitive Troponin I: A Single Center Study from Pakistan

Introduction

Cardiac troponin is one of the most common clinical laboratory tests to be ordered from the emergency department (ED). With the advent of high sensitivity troponin assays, detectable values are now seen in a greater proportion of patients. Troponin values are pivotal for the diagnosis of myocardial infarction, especially for non-ST elevation myocardial infarction (NSTEMI), in which typical electrocardiogram (ECG) findings of myocardial infarction are not apparent. The fourth universal definition of myocardial infarction warrants a rise or fall of troponin with at least one value above the 99^th percentile upper reference limit (URL), along with evidence of ischemia.^[1] Another hallmark of the high-sensitive troponin assays is the availability of sex-specific upper reference limits. As troponins are directly related to the myocardial mass, the values are generally higher in males. Raised troponin values are also indicators of a poorer outcome.^[2]

Troponins are classically raised in acute coronary syndrome (ACS) including both ST-elevation myocardial infarction (STEMI) and NSTEMI. However, as troponins are released from the myocytes in any preceding injury or trauma, they are also frequently raised in conditions other than ACS. Non-ACS causes of raised troponins include both cardiovascular disease (CVD) and non-cardiovascular etiologies, of which myocarditis, heart failure, arrhythmias, anemia, and renal disease are just a few.^[3] Serial testing can differentiate acute change versus a chronically elevated value due to a non-ischemic episode.

Here we sought to study the cohort of patients presenting with suspicion of ACS to the ED with Hs-Troponin I levels above the 99^th percentile sex-specific URL. We looked at the final diagnoses of these patients admitted to the cardiology unit and aimed to see the association between the Hs-Troponin I levels with the ED, ward, and 30-day outcomes in both genders. We also analyzed the predictors of ACS in our patient cohort.

Materials and Methods

This was a retrospective study with exempt approval granted by the Institutional Board Review. The study was undertaken following the principles of the Declaration of Helsinki. Data of all consecutive patients presenting to the ED between January 2019 and April 2021 with suspected ACS and Hs-Troponin I values above the sex-specific 99^th percentile URL were extracted from the electronic medical record (EMR). Patients less than 16 years of age, those with positive COVID-19 PCR and missing data were excluded from the study. The first ED visit was considered as the index visit for the data analysis. A fellow cardiologist reviewed the data of all patients admitted under cardiology specialty for ultimate diagnosis in view of angiography and ECG findings.

Results

There were a total of 5,982 patients (3,031 males, 2,951 females) who had a Hs-Troponin I above 99th percentile URL at index presentation to the ED. Subjects were divided into four groups according to the quartiles of their in years < 48.00 (first quartile), 48.01–61.00 (second quartile), 62.01–69.00 (third quartile), and >69 (fourth quartile). The characteristics of the study population stratified by gender and age were shown in ►Table 1. The median (IQR) age of the patients was 61 (52–70) years. The median (IQR) levels of Hs-Troponin I was significantly lower in females at 68 (31–304) ng/L as opposed to 166 (64–787) ng/L in males. The difference remained significant in all age groups. The median Hs-Troponin I values increased with age up to 69 years.

The ED outcome of the patients based on their Hs-Troponin I levels are shown in ►Table 2. Patients were categorized into two groups; those with Hs-Troponin I values between 99^th percentile sex-specific URL and up to ten times URL increase, and those with an increase of more than 10 times sex-specific URL. In patients with more than a 10-fold increase in Hs-Troponin I values above 99^th percentile sex-specific URL, significantly more males (40.7%) were referred for admission as compared to females (33.1%) while significantly more females (52.3%) were referred to an outside facility or referred to the outpatient clinic of the institute (4.9%). The ED mortality was higher in males at 3.4% and 6.1% compared to females i.e., 1.9% and 4.6% with Hs-Troponin I values below and above the ten times sex-specific URL, respectively (►Table 2).

The breakdown of the eventual diagnoses of the patients admitted under Cardiology specialty with raised Hs-Troponin I from the ED is given in ►Table 2. Out of the total study cohort of 5,982 patients, 878 (14.6%) including 523 males and 355 females, were admitted under the Cardiology specialty. NSTEMI was the most frequent cause of raised Hs-Troponin I in these admitted patients (57.1%), followed by STEMI (16.6%), other non-ACS cardiovascular causes (12.6%), unstable angina (9.1%) and non-cardiovascular conditions (4.6%). Males had a significantly higher proportion of STEMI (68.5%) and NSTEMI (64.5%) compared to females, while females predominantly had a higher frequency of unstable angina (53.8%) and non-ACS cardiovascular conditions (61.3%). STEMI occurred in a relatively younger age group of patients with a median (IQR) of 56 (48–65) years, while NSTEMI and other cardiovascular and non-cardiovascular causes occurred in older age groups with a median of 59, 60, and 63 years, respectively. However, the median Hs-Troponin I was as expected the highest in STEMI (3085 ng/L), followed by NSTEMI (771 ng/L). In the ward, 11.6% of STEMI and 4.4% of NSTEMI patients expired. Further, the 30-day outcome of 818 (93.1%) discharged patients is shown in ►Table 2.

A total of 297 (4.96%) patients underwent serial Hs-Troponin I testing within 24 hours. The median(IQR) time between the serial testing was 4.14 (2.5–6.15) hours. The median (IQR) hospital stay was 2 (1–3) days for both STEMI and NSTEMI.

The demographics, diagnoses, and outcomes according to the rise of Hs-Troponin I in patients admitted under the cardiology specialty are shown in ►Table 3. In patients with more than a 10-fold increase in Hs-Troponin I values above 99th percentile sex-specific URL, NSTEMI was the most frequent cause of raised Hs-Troponin I, 70.8% in males and 70.1% in females. Comorbidities including diabetes mellitus (DM), hypertension (HTN), ischemic heart disease (IHD), and chronic kidney disease (CKD) were reported as depicted in ►Table 3. Angiography was done on a total of 377 males and 198 females. Mortality was higher in admitted females compared to males in the category of patients with Hs-Troponin I rise less than 10-fold (8.2% vs. 3.6%). The 30-day outcome also infers the higher death rates in females (►Table 3).

Of the 828 admitted patients, ACS was diagnosed in 727 (83%) cases, while 151 (17%) were diagnosed as non-ACS. Logistic regression analysis was carried out to assess the association of various demographic, clinical, and laboratory predictors with the risk of developing ACS. Univariate analysis showed that ACS was significantly associated with ages <48, 48–61, and >69 years, respectively. ACS was 1.5 and 1.9 folds higher among participants with age < 48 (OR = 1.53 95% CI: 0.9–2.3, p = 0.053) and > 69 (OR = 1.98 95% CI: 1.3–2.9, p = 0.001) years of age, respectively. Patients with ages 48 to 61 years demonstrated 50% (p ≤ 0.001) while male patients had 41% (p ≤0.0001) chance of getting ACS. ACS was 0.71 and 0.75 folds higher among patients with comorbidities, i.e., DM (p = 0.068) and HTN (p= 0.116), respectively. Patients with hypertriglyceridemia and high low density lipoprotein cholesterol (LDL-C) had 53% (p = 0.146) and 40% (p ≤0.025) chance of having ACS respectively. It was further observed that smoking was associated with a 55% risk of ACS (p = 0.086).

After adjusting for age, sex, comorbidities, smoking, and hypertriglyceridemia, the patients with high LDL-C were found to have 2.4 (p = 0.040) times higher odds of having ACS. Also, patients with diabetes mellitus were found to have 2.5 times higher odds of having ACS; however, the results were not statistically significant (p = 0.056, ►Table 5). Among hazardous predictors, the highest odds were by DM followed by smoking and high LDL-C; however, smoking failed to demonstrate significant association after controlling the effect of other predictors of ACS.

Discussion

Troponin I values above the sex-specific URL along with evidence of ischemia are essential for the diagnosis of myocardial infarction. Our study cohort consisted of all patients presenting in ED with suspected ACS and Hs-Troponin I values above the sex-specific 99th percentile URL. Patients with ST-elevation typically are diagnosed on ECG and their troponins were often not requested. This accounts for the significantly higher NSTEMIs seen in this study.

In our cohort, out of 5,982 patients seen in the ED with raised Hs-Troponin I, 727 were admitted with an ultimate diagnosis of ACS. Out of these, 237 (32.5%) patients had Hs-Troponin I values less than 10 times sex-specific cutoffs on index ED visits. It is thus crucial to have a high index of suspicion and subject patients with suggestive symptoms to serial troponin testing. However, limitations of space and personnel are some of the practical factors involved in on-the-ground management strategies. Fast rule-in/rule-out protocols for ACS have been evaluated for quick diagnosis.^[5] Our center is a free-of-cost, high-quality, tertiary care setup located near a rural populace. The majority of our patients, therefore, come from the underprivileged sector of society and the ED is a busy place with a per-day flux of 700 to 1000 patients. The ED environment is highly volatile and the physicians are under constant stress for faster turnover of patients. The limitation of in-patient beds is the key factor involved in the huge number of referrals seen in our study.

Although several studies have been done on the white population, literature on South Asians is relatively scarce. As diagnostic cut points are generally made on the 99th percentile URL, and a number of variables affect the biological variation in troponin value; therefore, the cut-off has to have a basis in the community. Studies in the local setting are somewhat preliminary.^[6,7] Troponin has also been shown to be an independent predictor of all-cause of hospital mortality but should be measured only in those in whom there is a clinical indication,^[8] as there are a number of non-ACS and non-cardiovascular causes of raised troponins. Hs-Troponin I values should be interpreted along with the clinical scenario in outlining management plans to safeguard against unnecessary therapeutic interventions with consequent multi-faceted implications for both the patient and institute.

It is typically recommended that blood specimens for the measurement of cardiac troponin should be collected on initial assessment and repeated 3 to 6 hours later (1–3),^[9] although as mentioned, there are faster rule-in and rule-out algorithms for high-sensitive troponin assays.^[5,10,11] In our study, 297 (4.96%) patients underwent serial monitoring within 24 hours. The time difference median (IQR) was 4.14 (2.5–6.15) hours. Wassie et al^[12] claims that there is no difference in 30-day outcome between patients who have been tested once for troponin in the ED with negative results and those who underwent serial testing. Their study was done on a large cohort of nearly 28,000 patients over 15 ED facilities. They concluded that physicians' clinical judgment should be trusted to define the ordering of troponin in individual patients.

There is evidence to show that high-sensitive troponin I levels, even below the 99th percentile, have predictive power for future cardiovascular events and mortality.^[13] There is a positive association with age regardless of history of any cardiovascular disease.^[13] Our study shows rising Hs-Troponin I value with age up to 69 years. As anticipated, patients with ACS had higher Hs-Troponin I value than patients with other cardiovascular conditions, and more so in STEMI compared to NSTEMI. This has also been shown by other researchers.^[9]

We noted increased ED mortality with higher Hs-Troponin I values. A study has shown that a higher troponin result, greater than the 99th percentile URL, resulted in a 3-year higher mortality hazard of 3.2 (95% CI 3.1–3.2). Mortality varied with age, with a hazard ratio of 10.6 (8.5–13.3) in 18- to 29-year-old, and 1.5 (1.4–1.6) in those older than 90 years.^[14] The high mortality was predominantly seen in the first few weeks of the sentinel event. We observed a similar trend with the maximum mortality seen in the ED or during the initial admission days although the patients were followed for their 30-day outcome. Lee et al have found elevated troponin levels in patients attending ED to be associated with increasing age, compromised physiological functions, comorbidities, and increased mortality.^[15]

Comorbidities including DM, HTN, CKD, dyslipidemias as well as smoking have been associated in the past with cardiovascular events. Vidali et al have reported higher troponin I value in patients with hypertension, diabetes, and CKD.^[9] They have demonstrated that age, hypertension, diabetes, kidney disease, absence of chest pain, tachycardia (> 100 bpm), and ECG changes are significantly associated with troponin I positivity in univariate analysis. However, only age, tachycardia, and ECG changes remained independently associated with troponin I positivity at admission in multivariable analysis.^[9] Another study has shown age, CKD and smoking to be independent predictors of STEMI.^[16] Omidi suggests that age, gender, DM, HTN, family history and dyslipidemia have significant effects on the severity of CAD.^[17] We too demonstrated that raised LDL-C had a high likelihood of ACS in multivariable analysis although male gender, age group 49 to 61 years, age greater than 69 years, DM, and HTN were also additionally significant in univariate analysis. South Asians are more prone to the early development of atherosclerotic cardiovascular disease and a reduction in LDL-C improves the outcome of ACS patients. This has also prompted the Lipid Association of India to recommend aggressive lipid-lowering management in these patients after ACS.^[18]

We observed approximately equal numbers of male and female patients presenting to ED with Hs-Troponin I levels above the 99th percentile URL. The median (IQR) age of males and females was 61 (51/52–70) years. Higher Hs-Troponin I values were associated with a worse ED outcome in both males and females; however, the overall ED mortality was higher for males. In patients less than 48 years of age, significantly more males than females presented to the ED with raised Hs-Troponin I values, while there were more females than males with raised Hs-Troponin I in the older age group. However, amongst all age quartiles, more males than females were admitted to the Cardiology specialty.

It was noted in our study that a significantly higher percentage of males compared to females with Hs-Troponin I values greater than 10-fold sex-specific URL were processed for admission within the institute, while a greater percentage of females with these values were referred to other institutes for admission or to the out-patient facility. The in-patient mortality rate of females was higher than that of males when the Hs-Troponin I values were less than 10-fold higher than the sex-specific URL and similar when the troponin values were greater than 10-fold. It was also seen that angiography was performed in a lower percentage of women than men in both categories of Hs-Troponin I, which could account for possibly missed diagnoses in some females. This is also alarming considering that a greater majority of female with raised Hs-Troponin I were referred to out-patient clinics or other centers from ED. Shah et al suggest that there is under-diagnosis of AMI in women.^[19] They claim that women are less likely to be referred to a specialist cardiologist or for interventional measures than men. There is the general impression amongst medical and non-medical communities alike that women have a cardiovascular protective element due to the presence of estrogen which partly accounts for more complacent management.^[20] However, physical inactivity, increased central obesity and BMI with the ultimate development of metabolic syndrome increases the risk of morbidity and mortality in women, more so in the post-menopausal stage. In our study cohort too, the frequency of diabetes and hypertension was higher in women. Menyar et al,^[21] in their review, have also noted that gender difference exists in all stages of coronary artery disease diagnosis and intervention. These could be due in part to the more atypical presentation of ACS in women. The pathophysiology behind the possible unstable atherosclerotic plaques or hypercoagulability in women could be genetic, hormonal, or inflammatory as they have, in general, thinner and less pliable coronary arteries than men. Alabas et al^[22] have found higher mortality in women with STEMI and NSTEMI at 1 and 5 years and propose that stricter adherence to myocardial infarction management guidelines in women may alleviate premature cardiovascular-related mortality in them. We concur with their suggestion that following standardized clinical guidelines may help to reduce premature cardiovascular mortality in females.

To the best of our knowledge, there are no large-scale studies available as yet from our part of the world on the use of highly sensitive cardiac troponin I in the diagnoses of ACS. However, our study had certain limitations. Data were extracted from the EMR department and patients with missing or incomplete data were excluded. The study relied on the existing data in the EMR and lost to follow-up patients were not called in person.

Conclusion

Increased Hs-Troponin I values were strongly associated with a worse ED outcome in both genders; however, in-patient mortality was higher in females with values up to 10 times URL. High LDL-cholesterol was associated with significant odds of developing ACS, highlighting the crucial role of lipid and lifestyle management in the prevention of ACS.