MULTIPLE STUDIES SHOW SUPERIORITY OF CRITICAL DIAGNOSTICS’ ST2 OVER BNP, NT-proBNP AND OTHER HEART FAILURE BIOMARKERS.
SAN DIEGO, CA July 24, 2015 – Critical Diagnostics announced today that according to PubMed, an online repository of scientific literature maintained by the National Institutes of Health’s National Library of Medicine, in just the first six months of this year there have been as many citations and abstracts published on the cardiac biomarker ST2 than in all of 2014.
In the United States, Critical Diagnostics has received 510(k) clearance on the Presage® ST2 Assay, which is indicated for use as an aid in assessing the prognosis of patients diagnosed with chronic heart failure. The Presage ST2 Assay is also CE Marked with a broader indication for use than in the U.S. The Aspect-PLUS™ ST2 test is CE Marked and not currently available for sale in the United States.
RECENT PUBLICATIONS UNDERSCORE THE VALUE OF ST2 IN HEART FAILURE CARE:
- ST2 is highly prognostic in both acute and chronic heart failure patients.
- ST2 is equally prognostic in both HFpEF as HFrEF patient populations.
- Serial measurements of ST2 shows superior prognostic performance compared with BNP, NT-proBNP, highly sensitive troponin, and GDF-15.
- In a head-to-head comparison of ST2 and galectin-3, ST2 was superior.
- Where both natriuretic peptide and ST2 measurements were taken, ST2 improved prognostic accuracy.
- ST2 levels may interact with specific therapies, opening the door for possible guided heart failure therapy using ST2.
- Hospitalized heart failure patients whose ST2 levels failed to drop within 48 to 72 hours were more than 2-1/2 times more likely to die.
- Natriuretic peptides can be affected by confounding factors that complicate treatment decisions. There is no correlation between ST2 and age, body mass index, sex, or renal dysfunction.
1 IN 5 PEOPLE WILL DEVELOP HEART FAILURE; HALF WILL DIE WITHIN 5 YEARS
Heart failure is a condition in which the heart can't pump enough blood to meet the body's needs. One in five people will develop heart failure in their lifetime.[1] Half of all people diagnosed with heart failure will die within five years.[2] Heart failure is a global problem with an estimated prevalence of 38 million patients worldwide.[3] As the world’s population grows and ages, as rates of obesity, diabetes, smoking and alcohol consumption rise, as more nations adopt Western diets and sedentary lifestyles, that number will only grow.
NATRIURETIC PEPTIDES STILL UNPROVEN FOR PATIENT CARE
The global market for cardiac biomarkers was estimated at nearly $4 billion in 2013 and is predicted to reach $7.2 billion by 2018.[4] Natriuretic peptides, including BNP and NT-proBNP – widely adopted in diagnosing heart failure – are one reason for such growth. The value of natriuretic peptides, however, in the ongoing care and treatment of diagnosed heart failure patients, continues to be debated, because after at least 11 separate randomized clinical trials of natriuretic peptide-guided treatment,[5] several specialty societies[6] have concluded that the evidence is insufficient to support routine natriuretic peptide-guided treatment over conventional care.
ST2 OFFERS IMPORTANT ADVANTAGES OVER ESTABLISHED BIOMARKERS
Now one biomarker, ST2, is challenging natriuretic peptides as the go-to test for helping physicians manage their heart failure patients. The recent surge in published papers confirm earlier findings, showing the many clinical benefits of ST2 versus established cardiac biomarkers in treating heart failure patients.
ST2 IDENTIFIES TWICE AS MANY HEART FAILURE PATIENTS AT RISK
For instance, in a review paper published in March,[7] the authors evaluated data from a number of cardiac biomarker studies, noting, “In an analysis of 593 patients admitted to the Emergency Department with acute dyspnoea from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) study, sST2 (soluble ST2) was the strongest biomarker … with a hazard ratio of 4.6, compared with 2.3 for (Roche’s) NT-proBNP (OTC:RHHBY), and this observation was extended to outcomes at 4 years.” In other words, ST2 identified twice as many heart failure patients at risk for death as did NT-proBNP.
ST2 IS EQUALLY PROGNOSTIC IN HFpEF AND HFrEF PATIENTS
The investigators add, “sST2 is equally prognostic in patients with heart failure (HF) with preserved ejection fraction (HFpEF) as it is in those with reduced ejection fraction (HFrEF).”[8] They also write, “In a separate study,[9] those with elevated sST2 and NT-proBNP values experienced the highest risk of death at 1 year (>40%), whereas, importantly, in those with a low NT-proBNP, an elevated sST2 level reclassified likelihood of death considerably, suggesting that sST2 provides useful information even in those with low natriuretic peptide values. Similar results were reported in an ADHF (acute decompensated heart failure) cohort, where multimarker testing with highly sensitive (hs) troponin T, NT-proBNP, and sST2 accurately stratified subjects from low (<5% of death) to very high (>50%) risk.[10]
“In a large multinational meta-analysis of patients with ADHF,[11] sST2 provided value comparable with the strongest prognostic biomarkers for predicting death, improving reclassification of risk beyond a clinical model containing other biomarkers and clinical variables. Additionally, among patients with advanced HF, only sST2 was predictive of 90-day death or transplantation (hazard ratio 5.53), while NT-proBNP, renal biomarkers, hs troponin, and inflammatory biomarkers were not.”
SERIAL MEASUREMENTS OF ST2 ADD SUBSTANTIAL PROGNOSTIC INFORMATION
The same authors go on to say, “Rather than relying on a single measurement for prognosis in ADHF, emerging data suggest a role for using serial levels of sST2 to monitor patients.[12] In one study, sST2 values >76 ng/mL following hospitalization identified those with a 50% risk for mortality, transplantation, or rehospitalisation. In ambulatory patients with chronic HF, sST2 has comparably strong prognostic value, again additive to natriuretic peptides and equally useful for prognosis in subjects with HFpEF and HFrEF. Much as in ADHF, serial measurement of sST2 in chronic HF added substantial prognostic information, showing superior prognostic performance compared with all other markers, including hs troponin T, growth differentiation factor-15 (GDF-15), and NT-proBNP.”[13]
WHEN BNP AND ST2 LEVELS ARE HIGH, AN ADVERSE EVENT IS 7-1/2 TIMES AS LIKELY
In a study published in January, acute heart failure patients were followed prospectively for six months after discharge from hospital.[14] Where both BNP and ST2 plasma levels were above the median, ST2 improved prognostic accuracy. In such cases, HFrEF patients were more than seven-and-a-half times as likely to experience an adverse event, defined as all-cause death or hospital readmission for heart failure, and HFpEF patients were five times as likely to have such an occurrence.
“Soluble ST2 has been shown to risk stratify acute and chronic HF patients above and beyond the available information including traditional HF risk factors as well as current gold standard biomarkers such as NT-proBNP,” notes Hanna Kim Gaggin, MD, MPH, Assistant in Medicine, Massachusetts General Hospital, Assistant Professor of Medicine, Harvard Medical School, and one of the authors of the review paper. “Furthermore, studies have shown that soluble ST2 values change over time and may potentially be useful in serial measurement and tailoring HF treatment to the individuals in a personalized medicine model.”
PATIENTS WITH HIGHEST ST2 VALUES AT 3-FOLD RISK OF AN ADVERSE EVENT
In a March review of several cardiac biomarkers,[15] the authors state that in a multivariable model that included traditional markers of risk in acute HF patients, ST2 had independent and additive prognostic information beyond NT-proBNP, regardless of left ventricular ejection fraction.[16] In a multimarker panel, patients whose ST2 value was in the highest tertile, had a more than three-fold greater risk of adverse outcomes (death or transplantation) than those in the lowest tertile.[17]
SERIAL MEASUREMENT OF ST2 SUPERIOR TO NT-proBNP
In addition, they note that serial measurement of ST2 after acute HF therapy provided incremental information beyond a single value, and was superior to that provided by NT-proBNP.[18] “ST2 levels may interact with specific HF therapies. Beta-blockers, angiotensin II receptor antagonists and mineralocorticoid receptor antagonists may influence ST2 values, opening the door for the possibility of guided HF therapy using serial measurement [of ST2].”[19]
“A new generation of heart failure drugs, such as LCZ696[20] and ivabradine,[21] have shown to improve outcomes of patients with heart failure, but questions still remain about their optimal application,” says James L. Januzzi, MD, PhD, Professor of Medicine at Harvard Medical School, an active clinician at Massachusetts General Hospital since 2000 and lead investigator on the PRIDE study, the first US-based prospective study of NT-proBNP for diagnostic evaluation for HF. “With increased emphasis on precision medicine techniques to approach the care of patients with chronic diseases like heart failure, biomarkers will play a pivotal role for such patients. In this respect, biomarkers will be used to assess therapy effectiveness, providing value for serially monitoring patients, and allowing physicians to adjust care to achieve the best results while being mindful of spiraling health care costs. For these applications, ST2 holds great promise.”
ST2 IMPROVES RISK STRATIFICATION
In the April publication[22], “ST2 Pathogenetic Profile in Ambulatory Heart Failure Patients,” investigators examined over 1,000 heart failure patients to determine whether ST2 levels improve risk stratification relative to other biomarkers, including NT-proBNP, high-sensitivity troponin T (hsTnT), galectin-3 from BG Medicine (NASDAQ:BGMD), and C-reactive protein (hsCRP). Soluble ST2 remained an independent prognosticator of risk at every tertile of each biomarker. This was observed even after adjusting for clinical parameters. Importantly, soluble ST2 remained a significant and independent risk predictor, regardless of the concentrations of NT-proBNP, hsCRP, galectin-3, and hsTnT.
ST2 IS SUPERIOR TO GALECTIN-3
As noted in the paper, in a study done by some of the same investigators published last year[23] in which ST2 and galectin-3 (Gal-3) were compared head-to-head for long-term risk stratification in an ambulatory heart failure population, in a cohort of 876 heart failure patients with a median follow-up period of 4.2 years, “In multivariate analysis, only ST2 remained independently associated with cardiovascular mortality. Incorporation of Gal-3 showed no significant increase in discrimination or reclassification and worse calibration metrics. On direct model comparison, ST2 was superior to Gal-3.”
HIGHER LEVELS OF ST2 ARE ASSOCIATED WITH INCREASED RISK OF DEATH
In an abstract reported at the American College of Cardiology Scientific Sessions in San Diego in March,[24] results from a cohort that was part of a large multinational, multi-center, prospective randomized study (ASCEND-HF) of hospitalized patients with acute decompensated heart failure, showed higher levels of ST2 were associated with increased risk of death. Moreover, patients whose ST2 levels failed to drop within 48 to 72 hours were more than two-and-a-half times as likely to die, compared to those whose ST2 levels fell.
CHANGES IN ST2 BETTER ABLE TO PREDICT HOSPITAL ADMISSIONS
In a study published in early January,[25] researchers followed heart failure patients with pharmacologically optimized heart failure and left ventricular ejection fraction [40% or less]. Clinical review, plus NT-proBNP and ST2 measurements took place at baseline, and one, three and six months, to analyze the prognostic utility of serial changes in these biomarkers. Renal profiles were measured on all samples as well as a 12-lead electrocardiogram performed at baseline.
COMPARED WITH NT-proBNP, ST2 “PROMISING CANDIDATE FOR MONITORING”
Investigators confirmed that percentage changes in sST2 were better able to predict cardiovascular admission (to hospital) with pharmacologically optimized heart failure than NT-proBNP. As the authors noted, “Receiver operator curve analysis of percentage change in sST2 from baseline to six months was strongly reflective of decompensation with area under the curve (AUC) of 0.778. This was significantly better than NTproBNP (AUC 0.425; p = 0.013).” They conclude by saying, “Compared with NTproBNP, sST2 appears to be a promising candidate for monitoring these patients.”
"I order ST2 levels on every patient admitted with acute heart failure, one in the ED [Emergency Department] and one at the time of discharge,” remarks Alan S. Maisel, MD, Director of the Coronary Care Unit and Heart Failure Program at the VA Medical Center in La Jolla, California, as well as the principal investigator in the Breathing Not Properly study, which paved the way for BNP to become a diagnostic tool in congestive heart failure. “The patient’s ST2 level needs to significantly drop in hospital – at least 20% – if not, I try to see them earlier in clinic and sometimes even consider ratcheting up therapy before they go home. I also routinely get ST2 levels on all my chronic heart failure clinic patients when they come to see me. This is a great way to monitor patient stability, and the number 35 [ng/mL, the FDA cleared cut point for ST2] gives me something to shoot for with regards to titrating medications."
ST2 IS NOT AFFECTED BY TYPICAL CONFOUNDING FACTORS
One of the well-earned criticisms of popular cardiac biomarkers such as BNP and NT-proBNP is that they can be affected by confounding factors such as age, body mass index, history of heart failure, anemia and impaired renal failure – that can make interpreting results confusing, thus complicating treatment decisions.
For example, in a meta-analysis published last year of 11 studies of natriuretic peptide-guided treatment of heart failure versus standard clinically guided care,[26] data for patients 75 years or older – which makes up a large portion of heart failure patients – showed no survival benefit, indicating age can be a confounding factor in the use of natriuretic peptide biomarkers.
Co-morbidities frequently accompany heart failure. As a case in point, some 20 percent of heart failure patients are obese.[27] A study published in March showed significant differences in BNP levels in obese and normal weight patients.[28]
A study published this April[29] sought to assess the relationship between concentrations of ST2 and inpatients hospitalized with acute heart failure and renal insufficiency. ST2 levels were not changed with the degree of renal function, while BNP levels were much higher in patients with severe renal insufficiency.
The same study showed no correlation between ST2 and age, body mass index, sex, or NYHA functional class. Moreover, this study demonstrated that a single ST2 cut off value at discharge was independently associated with the development of death or HF readmission within three months after hospital discharge. As the authors noted, “These findings raised the questions whether sST2 might be superior to BNP in predicting prognosis in patients hospitalized with acute decompensated HF and severe renal insufficiency.”
Gender can be another confounding factor. While the hearts of women and men are structurally similar, they differ in their manifestations of cardiovascular disease, including symptoms, comorbidities, responses to treatment, and outcomes. Important sexspecific differences also exist in cardiovascular biomarkers. A paper just published on sex and biomarkers[30] pointed out the association between soluble ST2 levels and sex hormones was not significant and that “a cut‐off point of 35 ng/mL seems to be robust for prognosis in both sexes with heart failure.”
“ST2 is a great complement to the natriuretic peptides, providing insight into prognosis – without the confounding factors that affect the natriuretic peptides,” states Dr. Marc Goldschmidt, Director of the Heart Success Program at Morristown Medical Center, which provides specialized heart care for patients with advanced heart failure and other cardiovascular diseases. “ST2 has become an important tool in the management of heart failure patients across the continuum."
ST2 PREDICTS REVERSE REMODELING
One of the most thought-provoking studies published in 2015 involved the prediction of reverse remodeling (R2), meaning a positive structural improvement in left ventricular function of systolic heart failure patients, thus increasing ejection fraction – the amount of outbound blood pumped by the heart – an important determinant of the severity of systolic heart failure.[31]
REVERSE REMODELING PATIENTS HAD A 3-FOLD LOWER RATE OF EVENTS
In this study, investigators examined four biomarkers, ST2, NT-proBNP, highly-sensitive troponin T and galectin-3, to determine if one or more combined with standard clinical measurements[32] could be used to develop a score for predicting R2. As the authors conclude, “ST2 was the only biomarker that was independently associated with R2.” This is clinically important given that, as the study showed, patients with reverse remodeling had a 3-fold lower rate of clinical events, defined as cardiovascular death or HF hospitalization, during the six-year follow-up period.
18 EXPERTS FROM AROUND THE WORLD AUTHOR ST2 CONSENSUS PAPER
2015 also saw publication of a seminal 87-page consensus paper on ST2[33], authored by 18 leading experts in the field discussing the evidence base behind the evolving role of the cardiac biomarker ST2 and its appropriate uses in the management of patients with heart failure and related cardiac diseases.
EXPERTS DECLARE ST2 “A RELIABLE TOOL FOR PATIENT CARE”
In their introduction, the guest editors state, “There is plenty of room for improvement in the way we evaluate and risk-stratify patients with or at risk for HF [heart failure] using biomarkers. Although a large number of candidate biomarkers have been evaluated to help fill this gap, few have survived the rigorous studies that are a prerequisite to allow for translation into the clinical realm. It now appears clear that ST2 is a biomarker that has successfully navigated this course and is recently emerging as a reliable tool for patient care.”
To access the ST2 consensus paper, go to: http://www.ajconline.org/issue/S0002-9149(15)X0003-8.
"The recent literature, combined with growing real-world clinical experience, establish ST2 as a useful biomarker in the care of cardiovascular patients,” notes Lori Daniels, Director, Coronary Care Unit and Associate Professor of Medicine at UCSD Division of Cardiology and one of the authors on the consensus paper. “ST2 is clinically indicated for establishing prognosis in hospitalized patients as well as in outpatients, and has exciting potential for guiding therapy, reducing hospital readmissions, and improving outcomes."
“More and more evidence show that elevated levels of ST2 are related to a higher risk of adverse outcomes, such as death and hospitalization in HF patients,” remarks Qi-Zhu Tang, of the Cardiovascular Research Institute of Wuhan University (China) and author of “Soluble ST2 may possess special superiority as a risk predictor in heart failure patients,” in the International Journal of Cardiology“ published in May of this year. “Importantly, clinical trials including head-to-head studies, suggest that sST2 may possess special superiority in providing prognostic information compared with other predictors including NT-proBNP, galectin-3, GDF-15 and hsTnT. Furthermore, the relationship between sST2 levels and beta blockers, ARBs or MRAs treatment indicate that sST2 measurement may be used to monitor pharmacologically therapy in HF patients.”
“As the impressive body of evidence for ST2 grows, so too does clinical interest,” says David Geliebter, CEO of Critical Diagnostics, makers of regulatory-cleared ST2 assays. “While a diagnosis of heart failure can be a life changing event, there are innovative therapy approaches available, like measuring ST2 levels to help with risk assessment, that can aid in treatment decisions and may lead to better outcomes.”
NOT FOR DISTRIBUTION IN THE UNITED STATES.
ABOUT ST2
ST2 is a soluble protein expressed by the heart in response to disease or injury. It is reflective of ventricular remodeling and cardiac fibrosis associated with heart failure. ST2 is not adversely affected by confounding factors such as age, body mass index and impaired renal function. ST2 levels change quickly in response to changes in the patient’s condition. The Presage™ ST2 assay is CE marked and FDA cleared, has a unique CPT code, CMS (Medicare/Medicaid) reimbursement, and is in the ACC/AHA Guidelines as “not only predictive of hospitalization and death in patients with HF but also additive to natriuretic peptide levels in their prognostic value.” The Aspect-PLUS ST2 test, the world’s first and only rapid quantitative ST2 test, where results are reported in under 30 minutes, is CE marked. The Aspect-PLUS ST2 test is not available in the United States.
For a free downloadable copy of the White Paper, “The Pandemic Called Heart Failure,” go to: http://www.criticaldiagnostics.com/hfpandemicwhitepaper/
ABOUT CRITICAL DIAGNOSTICS
Critical Diagnostics (www.criticaldiagnostics.com) develops novel biomarkers to help physicians optimize patient care in cardiovascular diseases, while containing healthcare costs. The company has an intensive international patent portfolio. Critical Diagnostics has distribution partners in some 50 countries, covering two-thirds of the world’s population. For information about Critical Diagnostics and ST2 testing, please visit our website: www.criticaldiagnostics.com
FOR MORE INFORMATION, CONTACT:
Dennis Dalangin, VP Marketing & Operations
Telephone: +1 (877) 700 1250
Email: ddalangin@criticaldiagnostics.com
