13th August 2020, Dr Chee L Khoo
We all know the usefulness of highly sensitive troponin (hsTn) in diagnosing acute myocardial infarction in daily practice. hsTn has also been demonstrated to be strongly associated with recurrent events in patients with stable atherosclerotic cardiovascular disease (ASCVD) (1-7). However, hsTn is not routinely used in clinical practice in this population of patients. A recent study (8) in patients with hypertension suggests that hsTn could be used to refine risk categorisation and better identify who should receive anti-hypertensive therapies. Could we incorporate hsTn testing into clinical risk algorithms which can influence our management of patients who are otherwise considered to be stable and low risk for cardiovascular events?
Measurements of cardiac-specific troponins I and T are extensively used as diagnostic and prognostic indicators in the management of myocardial infarction and acute coronary syndrome. Cardiac troponins are a marker of all heart muscle damage, not just myocardial infarction. severe tachycardia, heart failure, myocarditis, pericarditis, various cardiomyopathies, Takotsubo cardiomyopathy and renal failure are some of the conditions which causes elevated troponin. Diagnostic criteria for raised troponin indicating myocardial infarction is currently set by the WHO at a threshold of 2 μg or higher.
Troponin, or the troponin complex, is a complex of three regulatory proteins (troponin C, troponin I, and troponin T) that is integral to muscle contraction in skeletal muscle and cardiac muscle, but not smooth muscle. Both proteins are now widely used to diagnose acute myocardial infarction. Both markers can be detected in patient’s blood 3–6 hours after onset of the chest pain, reaching peak level within 16–30 hours.
A recent (sub)study published in JAMA Cardiology investigated whether the addition of highly sensitive troponin I (hsTnI) to guideline-derived ASCVD risk can improve risk classification and guide downstream treatment recommendations. Marston N et al used the data from Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin–Thrombolysis in Myocardial Infarction 54 (PEGASUS-TIMI 54) trial (9) to evaluate hsTnI level for risk evaluation within the framework of the 2018 AHA/ACC cholesterol management guidelines (10).
Based on guideline derived risk categorisation, patients in the study were assigned to either very high ASCVD or lower risk ASCVD based on their CV history and co-morbidities in line with the 2018 AHA/ACC cholesterol management guidelines criteria (9). Patients were also classified on the basis of hsTnI level using cut points of 2 ng/L (limit of detection) and 6 ng/L (risk threshold). Participants were all patients who had an MI 1 to 3 years before enrolment, were at least 50 years of age, and had at least 1 high-risk feature.
Patients in the very high-risk ASCVD group had the following:
(1) at least 2 prior major CV events (acute coronary syndrome within the past 12 months, history of MI before the preceding 12 months, history of ischemic stroke, or peripheral vascular disease, as defined by revascularisation, amputation, or claudication, with documented ankle brachial index <0.90) OR
(2) a single prior major event plus multiple high-risk conditions (age ≥65 years, prior coronary revascularisation, diabetes, hypertension, current smoking, apolipoprotein B [apoB] level≥90mg/dL despite statin therapy, prior congestive heart failure, or chronic kidney disease [eGFR<60 mL/min/1.73 m2]).
Patients in the lower-risk ASCVD group
The remainder of patients qualified for the lower-risk ASCVD group because of their established atherosclerosis as evident by a previous MI.
End Points
The pre-specified primary end point of the trial was a composite of CV death, MI, or stroke. Secondary end points included the individual components of the primary outcome, as well as
death from coronary heart disease and death from any cause. Patients were followed up for a median of 33 months.
The results
Of the 8635 patients in this analysis, 610 (7.1%) experienced a primary end point event (CV death, MI, or stroke). Patients considered to be have very high-risk ASCVD according to guideline-derived risk assessment had a statistically significantly higher rate of CV death, MI, or stroke, with a 3-year event rate of 8.8% compared with 5.0% in the lower-risk ASCVD group (HR, 2.01; 95% CI, 1.58-2.57; P < .001) (Figure 1A). Statistically significant differences were also seen for each of the individual components, including CV death, MI, or stroke.
When they used hsTnI level instead of guideline-derived risk assessment, we get a much better stratification of patients achieving primary end points of CV events. 13.5% of patients with hsTnI > 6ng/L reached the primary end points. In patients with hsTnI of < 6ng/L, those whose hsTnI < 2ng/L had a 3 year event rate of 2.8% and those with hsTnI between 2-6ng/L had a 3 year event rate of 6.0% – see Figure 1B.
Compared with patients with hsTnI <2ng/L, patients with hsTnI between 2-6ng/L were at 2 times higher risk of reaching primary end points and patients with hsTnI >6ng/L were at 5 times higher risk of reaching primary end points. In fact, among the 10.7% (920 of 8635) of patients with an undetectable hsTnI level, there were no CV deaths during the approximate 3-year follow-up in this study.
hsTnI is complementary to the 13 clinical risk factors in the guideline-based ASCVD framework. For example, the very high-risk patients with ASCVD and an undetectable hsTnI level have an annualized CV event rate of less than 1% (2.7% divided by 3) per year, reclassifying them as very low risk. In contrast, lower-risk patients with ASCVD and hsTnI level exceeding 6ng/L carry an annualized CV event risk similar to that of the very high-risk ASCVD group.
Implications of this study
Refining the risk category of patients with ischaemic heart disease is useful because it help guide us in determining how aggressive to treat these patients. However, in practice, many of these patients are already on maximal therapy. Well, not quite. The newer class of lipid lowering agents, PCSK9 inhibitors, have been shown to reduce CV events in patients on maximal oral therapy in a number of clinical trials.
The result of this study doesn’t mean that we should be ordering hsTnI in all patients with IHD. In Australia, access to these novel agents are still quite restricted under the PBS. This study represents one of many studies which may help pave the way for our funders to come to the party if we can demonstrate the sub-group of patients who will benefit most from the new class of agent.
References:
- de Lemos JA, Drazner MH, Omland T, et al. Association of troponin T detected with a highly sensitive assay and cardiac structure and mortality risk in the general population. JAMA. 2010;304(22): 2503-2512. doi:10.1001/jama.2010.1768
- Omland T, de Lemos JA, Sabatine MS, et al; Prevention of Events With Angiotensin Converting Enzyme Inhibition (PEACE) Trial Investigators. A sensitive cardiac troponin T assay in stable coronary artery disease. N Engl J Med. 2009;361 (26):2538-2547. doi:10.1056/NEJMoa0805299
- White HD, Tonkin A, Simes J, et al; LIPID Study Investigators. Association of contemporary sensitive troponin I levels at baseline and change at 1 year with long-term coronary events following myocardial infarction or unstable angina: results from the LIPID Study (Long-term Intervention With Pravastatin in Ischaemic Disease). J AmColl Cardiol. 2014;63(4):345-354. doi:10.1016/j.jacc.2013.08.1643
- Omland T, Pfeffer MA, Solomon SD, et al; PEACE Investigators. Prognostic value of cardiac troponin I measured with a highly sensitive assay in patients with stable coronary artery disease. J AmColl Cardiol. 2013;61(12):1240-1249. doi:10.1016/j.jacc.2012.12.026
- Everett BM, Brooks MM, Vlachos HE, Chaitman BR, Frye RL, Bhatt DL; BARI 2D Study Group. Troponin and cardiac events in stable ischemic heart disease and diabetes. N Engl J Med. 2015;373(7):610-620. doi:10.1056/NEJMoa1415921
- Cavender MA, White WB, Jarolim P, et al. Serial measurement of high-sensitivity troponin I and cardiovascular outcomes in patients with type 2 diabetes mellitus in the EXAMINE Trial (Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care). Circulation. 2017;135(20):1911-1921. doi:10.1161/CIRCULATIONAHA.116.024632
- Bonaca MP, O’Malley RG, Jarolim P, et al. Serial cardiac troponin measured using a high-sensitivity assay in stable patients with ischemic heart disease. J AmColl Cardiol. 2016;68(3):322-323. doi:10.1016/j.jacc.2016.04.046
- Pandey A, Patel KV, VongpatanasinW, et al. Incorporation of biomarkers into risk assessment for allocation of antihypertensive medication according to the 2017 ACC/AHA high blood pressure guideline: a pooled cohort analysis. Circulation. 2019;140(25):2076-2088. doi:10.1161/CIRCULATIONAHA.119.043337
- Bonaca MP, Bhatt DL, Cohen M, et al; PEGASUS-TIMI 54 Steering Committee and Investigators. Long-term Use of Ticagrelor in Patients With Prior Myocardial Infarction. N Engl J Med. 2015;372(19):1791-1800. doi:10.1056/NEJMoa1500857
- Grundy SM, Stone NJ, Bailey AL, et al. 2018 HA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Circulation. 2019;139(25):e1082-e1143. doi:10.1161/CIR.0000000000000625
- Marston NA, Bonaca MP, Jarolim P, et al. Clinical Application of High-Sensitivity Troponin Testing in the Atherosclerotic Cardiovascular Disease Framework of the Current Cholesterol Guidelines. JAMA Cardiol. Published online August 05, 2020. doi:10.1001/jamacardio.2020.2981