Policy Guidelines
Background
HF is a complex clinical syndrome resulting from from any structural or functional impairment of ventricular filling or ejection of blood, including disorders of the pericardium, myocardium, endocardium, heart valves, or great vessels, or from certain metabolic abnormalities, but most patients with HF have symptoms due to impaired left ventricular (LV) myocardial function(Colucci, 2017a; Yancy et al., 2013). The most common symptoms of HF are dyspnea and fatigue, which may limit exercise tolerance, and fluid retention. Some patients have exercise intolerance but little evidence of fluid retention, whereas others complain primarily of edema, dyspnea, or fatigue. Heart failure is often a progressive condition, beginning with predisposing factors and leading to the development and worsening of clinical illness(Colucci, 2017b).
There is no single diagnostic test for HF because it is largely a clinical diagnosis based on a careful history and physical examination. However, biomarkers of cardiovascular diseases have been developed for diagnosis and prognosis, and the use of several biomarkers is now considered the standard of care. ST2 is a marker of cardiomyocyte stress and fibrosis that adds additional value to natriuretic peptides tests for risk stratification of patients with a wide spectrum of cardiovascular diseases (Bayes-Genis et al., 2015).
ST2 is the receptor of the IL-33 cytokine that can be secreted by living cells in response to cellular stress and mechanical strain. IL-33 binds the receptor complex of ST2L and IL-1R accessory protein and reduces myocardial fibrosis, prevents cardiomyocyte hypertrophy, reduces apoptosis, and improves myocardial function. The cardioprotective effects of IL-33 are specifically through the ST2L receptor. Soluble ST2 (sST2) binds IL-33 blocking the interaction between IL-33/ST2L(Pascual-Figal & Januzzi, 2015). Experimentally, this leads to cardiac hypertrophy, fibrosis, and ventricular dysfunction. In patients with acutely decompensated heart failure, elevated concentrations of sST2 are strongly associated with the presence and severity of the diagnosis and powerfully predict increased risk of heart failure complications including arrhythmia, pump failure, or death, independent of natriuretic peptides and other established or emerging biomarkers(Januzzi, Mebazaa, & Di Somma, 2015).
The 2013 American College of Cardiology and American Heart Association guidelines recommend measurement of ST2 for additive risk stratification in patients with acute or chronic ambulatory heart failure (HF)(Yancy et al., 2013).
Clinical Validity and Utility
Gaggin and Januzzi (2013) conducted a review on the role of emerging biomarkers like soluble ST2 (sST2) in the diagnosis of heart failure. The authors stated that sST2 could be a valid biomarker to be added to the natriuretic peptides for prognosis of heart failure. The clinical utility of sST2 could increase with more data emerging about the potential role of sST2 across a broader demographic of patients. The authors concluded that “a multi-biomarker approach to the HF patient is not far ahead, allowing the unique opportunity for specifically tailoring care to the individual.”
Ky et al (2011) conducted a multi-center prospective to evaluate whether plasma ST2 levels predict adverse outcomes in 1,141 chronic heart failure outpatients. Patients in the highest ST2 tertile had a markedly increased risk of adverse outcomes compared to the lowest tertile. The investigators concluded that “ST2 is a potent marker of risk in chronic heart failure and when used in combination with NT-proBNP offers moderate improvement in assessing prognosis beyond clinical risk scores.”
Broch et al (2012) studied the the association between sST2 and cause-specific outcome in 1449 patients enrolled in the Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA study). Soluble ST2 was measured in 1449 patients, ≥60 years of age with left ventricular ejection fraction ≤40% due to ischaemic heart disease. ST2 remained associated with death due to worsening HF, hospitalization due to worsening HF, and hospitalization due to any CV cause, even after full adjustment for N-terminal pro brain natriuretic peptide and C-reactive protein. The investigators concluded that “Soluble ST2 is associated with adverse outcomes in older patients with systolic, ischaemic HF. In particular, sST2 is independently associated with worsening HF.”
Wang et al (2012) studied the prognostic value of three novel biomarkers induced by cardiovascular stress. The investigators measured soluble ST2, growth differentiation factor-15, and high-sensitivity troponin I in 3,428 participants in the Framingham Heart Study. Multivariable-adjusted proportional hazards models were performed to assess the individual and combined ability of the biomarkers to predict adverse outcomes. The 3 new biomarkers were associated with death, major cardiovascular events, and heart failure, but not with coronary events. The investigators concluded that the findings demonstrated the prognostic value of the newer biomarkers in apparently healthy individuals.
Felker et al (2013) studied the association of ST2 level with long-term clinical outcomes in ambulatory heart failure patients enrolled in the HF-ACTION study – a multicenter, randomized study of exercise training in HF. ST2 was analyzed in a subset of 910 patients with evaluable plasma samples and correlations and Cox models were used to assess the relationship among ST2, functional capacity, and long-term outcomes. The investigators concluded that “ST2 was modestly associated with functional capacity and was significantly associated with outcomes in a well-treated cohort of ambulatory HF patients, although it did not significantly affect reclassification of risk.”
Anand et al (2014) evaluated the association between soluble ST2 and patient outcomes. sST2 was measured at baseline (n=1650), 4 months (n=1345), and 12 months (n=1094) in Valsartan Heart Failure Trial. The authors observed that baseline sST2 was nonlinearly associated with patient outcomes but did not provide substantial prognostic information when added to a clinical prediction model that included N-terminal probrain natriuretic peptide. An increase but not decrease in sST2 was independently associated with outcomes. The authors concluded that additional research is needed to determine whether monitoring ST2 levels can improve patient outcomes.
Januzzi et al (2013) conducted a retrospective study to assess soluble ST2 as a prognostic marker after orthotopic heart transplantation (OHT) and as a test to predict acute cellular rejection. sST2 concentrations were measured in 241 patients following OHT. Elevated sST2 was associated with cellular rejection, with highest rates of cellular rejection in the 4th sST2 quartile. No significant association between sST2 and antibody-mediated rejection or allograft vasculopathy was found. The investigators concluded that sST2 levels are associated with the presence of cellular rejection and predict long-term mortality following OHT.
Stojkovic et al (2018) published a study which found that GDF-15 is superior to sST2 in prediction of fatal arrhythmic events and all-cause mortality in DCM. Assessment of GDF-15 could provide additional information on top of LVEF and help identifying patients at risk of arrhythmic death.
Applicable Federal Regulations
The Presage® ST2 Assay kit received 510(k) marketing clearance from FDA in December 2011. The assay also received Conformite Europeenne (CE) Mark in January 2011. According to the FDA 510(k) Summary, the Presage® ST2 Assay is to be used in conjunction with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic HF.
The Presage® ST2 Assay kit is provided in a microplate configuration. The kit contains a ready-to-use 96-well microtiter plate coated with mouse monoclonal antihuman sST2 antibodies; a recombinant human sST2 standard calibrator (lyophilized); a standard diluent; an anti-ST2 biotinylated antibody reagent (mouse monoclonal antihuman sST2 antibodies) in phosphate-buffered saline; a sample diluent; a tracer concentrate and tracer diluent; a wash concentrate; a tetramethylbenzidine reagent; a stop solution; and 2 levels of controls provided in a sealed, lyophilized format (high and low control).
Two other research products are available to assay sST2: the MBL ST2 ELISA kit (Medical and Biological Laboratories, MA) and the Human ST2/IL-1 R4 DuoSet® (R&D Systems, MN). They use different standards, different antibodies, different reagents and buffers and, thus, results are not comparable between them and the Presage® ST2 Assay.16 Furthermore, neither the MBL ST2 ELISA nor the Human ST2/IL-1 R4 DuoSet® assay has received FDA marketing approval. These assays are not considered in this Policy.
Guidelines and Recommendations
Practice Guidelines and Position Statements
American College of Cardiology/American Heart Association (ACC/AHA)
In 2013, the ACC and AHA jointly published evidence-based guidelines for the management of heart failure (Yancy et al, 2013). The ACC/AHA stated that “biomarkers of myocardial fibrosis, soluble ST2 and galectin-3 are not only predictive of hospitalization and death in patients with HF but also additive to natriuretic peptide levels in their prognostic value.” In the ambulatory/outpatient setting, ACC/AHA recommended that “measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with chronic HF. (Level of evidence: B).” In the hospitalized/acute setting, ACC/AHA recommended that “measurement of other clinically available tests such as biomarkers of myocardial injury or fibrosis may be considered for additive risk stratification in patients with acutely decompensated HF (Level of evidence: A).”
