Critical Diagnostics announced today that results of a Massachusetts General Hospital biomarker-guided therapy study of chronic heart failure patients with left ventricular systolic dysfunction followed over a 10-month period (“Head-to-Head Comparison of Serial Soluble ST2, Growth Differentiation Factor-15 and Highly Sensitive Troponin T Measurement in Patients with Chronic Heart Failure”) just published in the Journal of the American College of Cardiology’s JACC: Heart Failure, demonstrated that of all biomarkers evaluated, only serial testing of ST2 enhanced prognostic information over baseline concentrations and predicted change in left ventricular function.
As a baseline value added to traditional clinical and biochemical characteristics including NT-proBNP, ST2 added independent information in predicting total cardiovascular events, but, more importantly, as a serial biomarker measured every three months during the treatment period of the study, only ST2 provided incremental prognostic information. Specifically, patients with persistently elevated ST2 levels were at more than three-and-a-half times the risk of experiencing a cardiovascular event, such as an unplanned hospitalization, than patients who had low ST2 levels.
“Beyond the baseline measurement, only sST2 appeared to provide incremental prognostic information and reflect changes in myocardial remodeling over time,” note the authors. “A novel biomarker’s dynamic ability to reflect the underlying HF [heart failure] biology makes it an ideal candidate for potentially monitoring and guiding HF management. In the present analysis, sST2 [soluble ST2) appeared to add prognostic information above the natriuretic peptides across multiple time points of measurement, and indicate significant dynamic change of the biomarker in parallel with risk for adverse events and myocardial remodeling.”
Furthermore, this study also shows there was a direct relationship between the percent of time spent with ST2 below its FDA-cleared threshold of 35 ng/mL and cardiovascular event rates. The time that patients spent with ST2 levels below 35 ng/mL was directly related to improving cardiac function as measured by decreasing left ventricular end diastolic volume index, even after adjusting for relevant baseline characteristics. These findings strongly suggest that managing patients to a ST2 level below 35 ng/mL may be an appropriate patient management strategy, versus managing patients to a specific dosing regimen.
Note the authors: “More time spent in sST2 response predicted decreasing LVEDi [left ventricle end diastolic volume index] after adjusting for relevant baseline characteristics.”
“Concentrations of sST2 are increasingly accepted to reflect important prognostic information not already revealed by natriuretic peptides,” remark the authors, “In the present analysis, sST2 appeared to add prognostic information above the natriuretic peptides across multiple time points of measurement, and indicate significant dynamic change of the biomarker in parallel with risk for adverse events and myocardial remodeling.”
Moreover, study further shows change in beta blocker dose in heart failure patients was directly associated with a change in subsequent levels of ST2. The findings reiterate those of another paper from this study just published that show that patients above 35 ng/mL who were taking low doses of beta blocker were almost seven times as likely to experience a cardiovascular event, such as an unplanned hospitalization, than patients who had low ST2 levels and were on high-doses of beta blocker.
“Notably, we found a significant relationship between β blocker [beta blocker] changes and sST2,” state the authors. “As β blockers have been shown to reverse myocardial remodeling, we are currently examining the potential link between this class of agents and sST2 in more depth . . . the link between β blockers dose changes and sST2 changes may be leveraged in identifying patients who may particularly benefit from aggressive β blocker titration.”
ST2 was recently included in the 2013 ACC/AHA Guideline For The Management of Heart Failure, recognizing ST2 as “not only predictive of hospitalization and death in patients with HF but also additive to natriuretic peptide levels in [its] prognostic value.” The guideline gives ST2 its highest classification (“A”) for the body of evidence supporting its recommendation.
Findings from the Massachusetts General Hospital study using an outpatient cohort of chronic heart failure patients, closely match those of a recently published three-and-a-half year University Hospital Baselstudy1 which showed that in-hospital serial testing of acute heart failure patients may help to identify a high-risk population with particular benefit from tailored therapy at discharge. The strongest effect in mitigating risk by intensified outpatient care was seen with addition of beta blockers but similar trends were observed with diuretics, and with renin-angiotensin-aldosterone system (RAAS) inhibitor drugs, the most common being ACE inhibitors.
Patients who didn’t show at least a 20 percent drop in their ST2 levels within 48 hours of admission had an alarming better-than-even (50/50) chance of dying within one year, whereas patients whose ST2 level decreased by at least 42% had only about a one in seven chance of dying within one year. Powerfully, it was also shown that if these high-risk patients received more intensive outpatient therapy their risk of adverse events was reduced to be comparable to that of the low risk group.
The investigators in the Massachusetts General Hospital study, using the same cohort of patients, recently examined another biomarker, galectin-3 by BG Medicine. Those results were published earlier last year [“Serial measurement of galectin-3 in patients with chronic heart failure: results from the ProBNP Outpatient Tailored Chronic Heart Failure Therapy (PROTECT) study,” in the European Journal of Heart Failure, May 10, 2013].
While a September 23, 2013 press release from BG Medicine about this paper stated, “elevated levels of galectin-3 are predictive of adverse outcomes in chronic heart failure patients and suggest that the prognostic value of this non-invasive biomarker may be enhanced when serial measurements are made over time,” the study’s authors note in their paper, “In fully adjusted multivariate Cox proportional hazard models, however, neither baseline nor subsequent galectin-3 levels had a significant effect on the prediction of time to first CV [cardiovascular] event.”
The authors further state: “[W]e were not able to show that HF [heart failure] medications with symptom-related or mortality benefits had effects on galectin-3 levels . . . There have thus far been no studies in humans demonstrating that medications can lower galectin-3 levels, and one study reported that initiation of CRT [Cardiac Resynchronization Therapy, a type of pacemaker to treat symptoms associated with congestive heart failure] had no effect on galectin-3 concentrations.” Consequently, “in this study, HF therapies had no clear effects on galectin-3 levels.”
“Interestingly, in our study,” continue the authors, “drugs with beneficial effects on remodeling had no appreciable effects on galectin-3 levels. This finding suggests that, despite the role of galectin-3 in the development of fibrosis, currently applied HF therapies may not lower galectin-3 concentrations and galectin-3 effects may not be easily reversible.”
This is the fourth paper published in the last few months that permits direct comparisons between the biomarkers ST2 and galectin-3. An October 10, 2013 press release from the Company on results of the HF-ACTION study published in Circulation: Heart Failure (“Soluble ST2 in Ambulatory Patients with Heart Failure: Association with Functional Capacity and Long-Term Outcomes”), announced that levels of ST2 are predictive of long-term outcomes for people suffering with heart failure and identify those patients who may benefit from exercise.
“In this analysis of the HF-ACTION study, ST2 was significantly associated with long-term outcome even after an adjustment for clinical covariates,” stated the study authors. “To our knowledge, this is the most robust test of this novel biomarker [ST2] to date with regard to covariate adjustment in a large, multicenter cohort of ambulatory heart failure patients.”
In contrast, as the authors made note of in a separate paper published on the use of galectin-3 evaluating the same cohort of patients: “In a final model adjusting for all predictors of the primary endpoint in the HF-ACTION dataset as a whole . . . as well as NTproBNP, there was no evidence for an independent association between galectin-3 and outcomes . . . Given the unique nature of the randomized intervention in the HF-ACTION study (exercise training), we examined the interaction between baseline galectin-3 levels and treatment assignment. There was no significant interaction between galectin-3 levels and exercise training for any of the 3 study endpoints [all-cause death or hospitalization, cardiovascular death or cardiovascular hospitalization, and for cardiovascular death or heart failure hospitalization.]”
On September 30, 2013, Critical Diagnostics also announced that a head-to-head study published online in JACC (the Journal of the American College of Cardiology) comparing the company’s novel cardiac biomarker ST2 to galectin-3 (gal-3), found ST2 to be superior. In a rigorous multivariate analysis, only ST2 remained independently associated with all-cause and cardiovascular mortality. The incremental predictive contribution of gal-3 to existing clinical risk factors was, as the study authors pronounced, “trivial,” and when troponin was included, galectin-3 fell out of the model. The same study also showed that ST2 adds considerable prognostic value even when the commonly used biomarkers for heart failure patient care, Roche Diagnostic’s (OTC: RHHBY) NT-proBNP, as well as high-sensitive troponin are also considered.
Declared the authors: “This study highlights the importance of assessing the true value of emerging cardiac fibrosis biomarkers above and beyond clinical risk factors and natriuretic peptides particularly in light of the newly obtained ST2 . . . ACC/AHA class II recommendation for determination of prognosis in chronic HF. ST2 significantly refined discrimination and reclassification analysis while Gal-3 had negligible effects on performance metrics in risk prediction models.”
“In all studied cohorts with or without additional biomarkers, including natriuretic peptides, ST2 unambiguously emerged as a cardinal HF risk stratifier,” observe the authors. “These main findings suggest that the pathways identified by ST2 profoundly affect risk stratification in the context of chronic HF . . . The incorporation of ST2 into clinical practice for the prediction of all-cause and cardiovascular mortality should be readily contemplated by the practicing clinician.”
The authors of that paper also pointed to a recent transplant study in which serum galectin-3 levels were measured before and after a heart transplant. Galectin-3 levels stayed elevated even after patients received new hearts, leading the authors to conclude that galectin-3 is a systemic biomarker rather than being specific to heart disease. By comparison, ST2 has been shown to be directly involved in cardiac fibrosis, and ST2 levels change rapidly with changes in a patient’s condition, which makes ST2 an ideal biomarker for assessing ongoing patient status using serial testing.
An editorial published in JACC (“The Importance of Rigorous Evaluation in Comparative Biomarker Studies”) by James L. Januzzi, MD and Roland RJ. van Kimmenade, MD PhD, which specifically examined the findings of the head-to-head study of ST2 and galectin-3 mentioned above, noted, “While the results of this excellent study do not shut the door on galectin-3, they should make us take pause.”
Finally, on January 28, 2014, BG Medicine issued a press release on results of a clinical research study2 validating the analytical and clinical performance of the automated VIDAS® Galectin-3 assay by bioMérieux SA. (BIM.PA) declaring that elevated galectin-3 levels were predictive of fatal cardiovascular events and severity of heart failure among a cohort of patients diagnosed with chronic heart failure. Almost simultaneous with the release of that paper, though, was an editorial in the International Journal of Cardiology about a study by the same authors3 using the exact same cohort of patients, except in this case measuring ST2. In a side-by-side comparison from the two publications, ST2 significantly improved accuracy in predicting at-risk patients, identifying a meaningful number of patients missed by galectin-3 that would go on to die.4
“Cardiac biomarkers are helping make ‘personalized medicine’ a potential reality,” says David Geliebter, CEO of Critical Diagnostics. “The right treatment, for the right patient, at the right time. But just as all patients and treatments are not equal, all biomarkers are not equal. Some that have touted perceived benefits without the body of evidence to support those claims are now being tossed onto the scrapheap of failed promises. In study after study as demonstrated above, though, and now in every day use around the world, ST2 has demonstrated strong clinical utility, assisting healthcare professionals with risk assessment and treatment decisions, and by so doing, helping reduce cardiovascular event rates and improving quality of life for heart failure patients everywhere.”
About Heart Failure
Heart failure is a condition in which the heart can't pump enough blood to meet the body's needs. As the population ages, the prevalence of heart failure is growing, placing a serious burden on healthcare costs. Approximately 26 million people worldwide are currently diagnosed with heart failure. At a time when deaths from coronary heart disease and stroke are declining on a relative basis, mortality from heart failure is increasing. One out of every three people over the age of 55 will develop heart failure in his or her lifetime. Heart failure is the leading cause of hospitalization in people 65 or older and is responsible for more hospitalizations than all forms of cancer combined, and the prognosis for heart failure is worse, with as much as 40 percent of heart failure patients dying within a year of being diagnosed.
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. Unlike many other cardiac biomarkers, ST2 levels change quickly in response to changes in the patient’s condition—thus helping physicians make informed decisions on an appropriate course of action to take and, if needed, to quickly adjust treatment. All this makes ST2 an ideal serial biomarker for monitoring and treating heart failure patients.
The Presage® ST2 Assay from Critical Diagnostics is the only commercially available ST2 biomarker test in the world. The Presage ST2 Assay has been CE Marked and cleared by the U.S. FDA for use as in the risk stratification of chronic heart failure patients.
About Critical Diagnostics
Founded in 2004, Critical Diagnostics (www.criticaldiagnostics.com) develops novel biomarkers to help physicians optimize patient care in cardiovascular diseases, while containing healthcare costs. Critical Diagnostics has distribution partners for its Presage ST2 Assay in 45 countries, covering two-thirds of the world’s population.
1 “Heart Failure Therapy Induced Early ST2 Changes May Offer Long-term Therapy Guidance,” published in the Journal of Cardiac Failure in November 2013.
2 “Galectin-3 testing: Validity of a novel automated assay in heart failure patients with reduced ejection fraction,” Clinica Chimica Acta.
3 “Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction,” International Journal of Cardiology.
4 The areas under the receiver operating characteristic (ROC) curve, criteria defined as cardiovascular death at the end of the follow-up (of the 137 patients in the study, 86 died), were 0.76 (95% confidence interval) for ST2 and 0.69 (95% confidence interval) for galectin-3.
Contacts:
Dennis Dalangin, 877-700-1250
VP Marketing
ddalangin@criticaldiagnostics.com
