Heart Failure Risk Prediction in the Community Sharpened by hs-Troponins

March 12, 2020

A study of more than 48,000 people without a history of stroke, myocardial infarction (MI), or heart failure (HF) has bolstered and surpassed previous evidence that adding cardiac biomarkers to standard risk factors can sharpen long-term prediction of risk for incident HF.

Notably, sex-specific cut-off values for cardiac troponin I by high-sensitivity assay (hs-cTnI) that separated individuals by high vs low risk for new HF, especially when augmented by natriuretic peptide levels, were identified in a combined analysis of four large community-based cohorts.

The biomarkers, hs-cTnI and N-terminal pro-B-type natriuretic peptide (NT-proBNP), "add to the performance of risk-factor prediction alone, and the combination of both resulted in incremental value. We therefore think both markers may be useful for future risk prediction," senior author Dirk Westermann, MD, told theheart.org | Medscape Cardiology.

The analysis, "which is in line with others in this field, demonstrates that small increases of high-sensitivity troponin already are important and should be followed by some kind of testing," said Westermann, from the University Heart and Vascular Center Hamburg, Germany.

"This might include detailed recording of the medical history and asking for signs and symptoms of cardiovascular disease," or even performing echocardiography in persons deemed to be high risk, he said.

Whether biomarker screening is useful at a population level remains to be seen, "but higher-risk groups without established cardiovascular disease might be useful to test already, since preventive measures might reduce heart failure incidence," Westermann said. "Young high-risk patients might be the ones to go for. Following positive testing, strict preventive measures might help reduce the future risk."

Westermann is senior author on the analysis published March 11 in JACC Heart Failure, with lead author Isabell Yan, MD, from the same institution.

"It has already been demonstrated in numerous population studies that higher concentrations of NT-proBNP as well as high-sensitivity troponin both predict risk for onset of heart failure in apparently unaffected population-based patients," James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston, told theheart.org | Medscape Cardiology.

But the current study, he said, "does extend the understanding by providing data in a very large population of well-characterized patients, adjusting carefully for cardiac risk factors, and very importantly also providing unique information for the troponin that was evaluated in this study." Januzzi, who is not a coauthor on the publication, pointed out that "there are actually quite a few different high-sensitivity troponin assays out there."

He agreed that "it's the higher-risk patient populations where we are probably most likely to see the greatest return on investment, if you will, from screening populations with biomarker testing." However, "it's necessary to emphasize that we do not yet have an infrastructure or strategy in place for screening apparently healthy individuals for risk for heart failure."

Although that could happen in the future, "we lack, unfortunately, information about what to do next. We've got ample evidence that we can identify patients at risk," Januzzi said. "The question is: How do we reduce that risk? And that's where I think well-designed, prospective, longer-term trials are going to be necessary to really answer that question."

"The reported results are unparalleled in the size of the study, which was conducted at a population-based level," contend Hanna K. Gaggin, MD, MPH, and Andrew Abboud, MD, both from Massachusetts General Hospital, in an accompanying editorial.

"The authors from this study take the field a step forward by identifying the cut-off values for hs-cTn at which the risk of incident HF is much higher," they write.

"Uniquely, the large size of the trial published herein afforded the investigators the opportunity to provide distinct actionable cut-offs for screening and risk-stratifying men and women separately as risks have been shown to differ by gender."

The four population-based cohorts making up the analysis included 7,315 persons in DanMONICA from Denmark, 7,702 participants in FINRISK from Finland, 23,179 in Moli-sani from Italy, and 10,259 in Northern Sweden MONICA. The centers contributing those cohorts were members of the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) Consortium.

Persons with a history of stroke, HF, or MI were excluded from the total cohort of initially predominantly healthy adults, who averaged 51 years in age; 52% were women. They were followed for incident HF for a median of 6.6 years.

The rate of incident HF was 4.1%, the MI rate was also 4.1%, and 9.6% died from any cause.

At baseline, the median level for hs-cTnI was 2.3 ng/L and for NT-proBNP was 46.2 ng/L.

Incident HF hazard ratios (HR) per log-unit change in hs-cTnI were:

  • 1.42 (95% CI, 1.31 - 1.53; P < .001) after adjustment for standard cardiovascular risk factors, including body mass index, systolic blood pressure, diabetes, smoking status, antihypertensive therapy, low-density-lipoprotein levels, and renal function

  • 1.19 (95% CI, 1.09 - 1.30; P < .001) after further adjustment for NT-proBNP levels.

The steepest HRs for incident HF by biomarker levels in adjusted analysis was 1.63 (95% CI, 1.32 - 2.03; < .001) for hs-cTnI levels above 3.2 ng/L, and 2.48 (95% CI, 2.02 - 3.03; < .001) for NT-proBNP levels above 68.26 ng/L. The projected 10-year rate of incident HF at or above those hs-cTnI and NT-proBNP thresholds was 13.2%.

The concordance statistic (C-index), which is comparable to the receiver operating characteristic (ROC) curve reflecting best fit to a model, went from 0.843 for prediction of incident HF based on the standard risk factors to:

  • 0.848 based on those risk factors plus hs-cTnI

  • 0.862 for prediction based on the risk factors plus both hs-cTnI and NT-proBNP.

The optimal hs-cTnI cut-off values for indicating high risk of incident HF were 2.6 ng/L for women and 4.2 ng/L for men.

"One of the big limitations of this study is that we don't know whether the form of heart failure in these patients was reduced ejection fraction, or preserved ejection fraction," Januzzi said. "And moreover, we don't know the mechanism of onset of heart failure."

On the other hand, "it's absolutely fascinating to see that from concentrations of troponin and NTproBNP well within what would be viewed as the normal range, we're able to identify patients, with surprisingly good efficiency, at risk for heart failure onset," he said.

"And it implies, therefore, that the signals of heart failure are present well before symptoms of the diagnosis or signs of the diagnosis manifest."

Indeed, the current findings may shed light on early HF pathophysiology, which "we feel is an important part of this study," Westermann said. The added predictive power of hs-cTnI was independent of and additive to prediction based on NT-proBNP, he observed, suggesting that elevations in the two biomarkers come from different underlying causes.

In the case of hs-cTnI, "this is most probably not undiagnosed CAD, but very subtle structural changes that are reflected in small increments of troponin," Westermann said.

"Pathophysiology behind development of [HF with reduced ejection fraction] vs. [HF with preserved ejection fraction] is quite different, and preventative measures for each HF type are expected to be quite different," the editorial cautions.

Yan says she has nothing to disclose. Westermann reports receiving personal fees from Bayer, Boehringer-Ingelheim, Berlin Chemie, Astra Zeneca, Biotronik, and Novartis "outside the submitted work." Januzzi discloses prepublication involvement with the et al. manuscript as an editor at the Journal of the American College of Cardiology and JACC Heart Failure. He has previously disclosed receiving personal fees from the American College of Cardiology, Pfizer, Merck, AbbVie, Amgen, Boehringer Ingelheim, and Takeda; grants and personal fees from Novartis, Roche, Abbott, and Janssen; and grants from Singulex and Prevencio. Gaggin discloses receiving research support from Roche Diagnostics, Jana Care, Ortho Clinical, Novartis; consulting income from Merck, Roche Diagnostics, Radiometer; payments for clinical end point committees from Radiometer and Abbott. Abboud reports no conflicts of interest or financial disclosures.

JACC Heart Failure. Published online March 11, 2020. Full text, Editorial

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