G. Michael Felker, MD Duke University

1. Biomarkers in Ambulatory HF:
What to Test and How Often?
G. Michael Felker, MD, MHS, FACC, FAHA, FHFSA
Professor of Medicine
Vice-Chief for Clinical Research, Duke Cardiology
Director, Cardiovascular-Metabolism Therapeutic Area, DCRI
Duke University School of Medicine

2. 10 Minutes
3 Take Home Points
Multiple Dad Jokes
G. Michael Felker, MD, MHS, FACC, FAHA, FHFSA
Professor of Medicine
Vice-Chief for Clinical Research, Duke Cardiology
Director, Cardiovascular-Metabolism Therapeutic Area, DCRI
Duke University School of Medicine

3. Disclosures
 Employment: Duke University
 Grant Support: NHLBI, CSL-Behring, Novartis, Merck, Bayer,
Cytokinetics, BMS, Daxor
 Consulting: Novartis, Amgen, Medtronic, BMS, Cytokinetics,
Regeneron, Sanofi, Abbott, Cardionomic, Innolife, Whiteswell
 Endpoint Adjudication Committees/DSMBs: Merck, EBR Systems, V-
Wave, LifaNova, Rocket Pharma
 Board of Directors and President-Elect, Heart Failure Society of America

4. What Is a Biomarker: NIH Definition
“A characteristic that is objectively measured and evaluated as an
indicator of normal biologic processes, pathogenic processes, or
the response to a therapeutic intervention.”
Atkinson et al, Clin Pharmacol Ther 2001

5. Alternate Definition
“If it costs less than 20 bucks, it’s a lab test. If it costs more than 20
bucks, it’s a biomarker.”

6. Biomarkers in Ambulatory HF
 What to Measure?
 Why to Measure?
 When to Measure?

7. What Biomarkers in Ambulatory HF?

8. Ahmad T et al Nat Rev Cardiol. 2012
Candidate Biomarkers in Heart Failure
 BNP/NT-proBNP
 Troponin
 sST2
 Galectin-3
 GDF-15
 Bio-ADM
 Fibrosis markers
 Many others…

9. Natriuretic Peptides Reflect Ventricular Wall Stress
Iwananga, JACC 2006

10. Take Home Point #1
Natriuretic peptides (BNP or NT-proBNP) most reflect
ventricular wall stress not “volume overload” or “EF”

11. Why to Measure Biomarkers in Ambulatory HF?

12. Why Do We Need Biomarkers Anyway?
Because things are not
always as they seem!

13. Biomarker Use Cases in Ambulatory HF
 Diagnosis: Does this patient have heart failure?
 Risk Stratification: What is the prognosis of this patient?
 Guiding Therapy: Should I keep doing what I am doing or should I do something else?

14. Diagnostic Algorithm for Suspected Heart Failure
McDonagh T et al, Eur Heart J, 2021

15. Confounders of NP measurements
 “False positive”
– Pulmonary embolus
– Pulmonary HTN
– Renal dysfunction
– Rapid lowering of PCWP
– Age/Gender
– ACS
 “False negative”
– Obesity
– Acute MR
– Flash pulmonary edema

16. Effect of Sacubitril/Valsartan on NPs
0 2 4 6 8
0
100
200
300
400
500
600
700
800
900
1000
1100
1200
1300
1400
0
50
100
150
200
250
300
350
400
450
500
NT-proBNP
Months
BNP
Sac/Val
Enalapril
NT-proBNP
BNP
Packer M. et al. Circ 2015

17. Natriuretic Peptides: Diagnosis
In ambulatory patients with dyspnea, measurement of BNP
or N-terminal pro-B-type natriuretic peptide (NT-proBNP) is
useful to support clinical decision making regarding the
diagnosis of HF, especially in the setting of clinical
uncertainty.
Measurement of BNP or NT-proBNP is useful to support
clinical judgment for the diagnosis of acutely
decompensated HF, especially in the setting of uncertainty
for the diagnosis.
I IIa IIb III
I IIa IIb III
Heidenreich, P et al. Circulation 2022

18. Natriuretic Peptides are the Strongest Prognostic
Biomarkers in Heart Failure

19. Natriuretic Peptides and Prognosis Across the Spectrum of HF
Anand, I. et al, Circ 2003, Januzzi, Arch Int Med, 2006, Van Veldhuesin JACC 2013, Wang NEJM 2004
HFrEF
0.6
0.7
0.8
0.9
1
0 100 200 300 400
Days after Presentation
Age-adjusted
Survival
NT-proBNP  986 pg/mL
NT-proBNP > 986 pg/mL
P=0.001
Acute HF
Pre-HF
HFpEF

20. Take Home Point #2
Natriuretic peptides (BNP or NT-proBNP) are the single
most useful biomarker in ambulatory heart failure for
making a diagnosis and for estimating prognosis

21. Can We Use Biomarkers to Guide our Therapy in HF?

22. Can Biomarkers Help Us Make Better Choices Caring for HF
Patients?

23. How Are We at Optimizing GDMT in HF?
Greene S et al JACC 2018

24. Despite our best intentions, we do a poor job
optimizing GDMT in patients with HF!

25. Guided Therapy Combined Analyses: Mortality
Meta analysis of publication data Pooled patient data from all available trials
66.6
.015
Better Treatment Better Control
1
Study ID
BNP-guided therapy
Anguita
Beck de Silva
STARBRITE
STARS-BNP
UPSTEP
Subtotal (i-squared = 0.0% p = 0.823)
NT-proBNP-guided therapy
BATTLESCARRED
Berger
PRIMA
PROTECT
SINGAL-HF
TIME-CHF
Troughton
Subtotal (i-squared = 0.0%, p = 0.692)
Overall (i-squared = 0.0%, p = 0.896)
Note: weights are from random effects analysis
OR (95% CI) % Weight
0.45 (0.04, 5.39) 0.74
0.32 (0.03, 3.19) 0.87
0.61 (0.23, 1.64) 4.68
0.95 (0.54, 1.68) 13.94
0.81 (0.52, 1.28) 22.27
1.00 (0.23, 4.43) 2.05
0.95 (0.53, 1.70) 13.27
0.64 (0.26, 1.16) 13.25
0.72 (0.45, 1.14) 21.22
0.66 (0.18, 2.43) 2.66
0.98 (0.33, 2.89) 3.92
0.67 (0.42, 1.05) 22.32
0.13 (0.62, 1.12) 0.96
0.72 (0.56, 0.91) 77.73
0.74 (0.60, 0.91) 100.00
Savarese G, et al. PLoS ONE. 2013
Troughton RW, et al. Eur Heart J. 2013

26. Felker, GM et al. JAMA, 2017

27. 446 405 376 355 331 315 293 272 254 242 225 218 202 185 175 166 152 135 128 128 128 100 93 85 78
448 401 381 359 330 301 278 263 257 243 227 210 199 185 175 169 153 138 138 138 115 104 90 90 77
Number at risk
Biomarker-guided
Usual care
0 2 4 6 8 10 12 14 16 18 20 22 24
0.00
0.10
0.20
0.30
0.40
0.50
0.60
Probability
of
HF
hospitalization
or
CV
death
P value = 0.875
HR (CI) = 0.983 (0.791, 1.222)
Usual care: 15 (7, 24)
Biomarker-guided: 15 (7, 24)
Duration of follow-up: Median (25th, 75th)
Months since randomization
Usual Care
Biomarker-Guided
GUIDE-IT: CV Death or HF Hospitalization
Felker, et al. JAMA 2017

28. “Optimal” GDMT:
BB, RAAS, MRA at ≥ 50% Target Dose
0%
5%
10%
15%
20%
25%
Biomarker-Guided Usual Care
P<0.001 P<0.01
Baseline
12 months
Felker, et al. JAMA 2017

29. Potential Explanations for GUIDE-IT Results?
 Patients in both arms were seen more frequently and had more adjustments to
therapy than routine clinical care
 GUIDE-IT sites tended to have a high level of HF expertise which may have
diminished differences between arms
 Provider and patient “inertia” and concern over perceived adverse effects may
limit aggressive up-titration of GDMT even in a clinical trial
 ”Strategy trials” are highly influenced by patient population and providers/sites
(more than traditional drug studies)

30. GUIDE-IT: Risk Related to Achieved NT-proBNP levels
Januzzi J et al. JACC 2019
Persistently high levels
of NPs despite titration
of GDMT are a very
poor prognostic sign

31. Trajectory of NT-proBNP and Prognosis

32. Biomarkers and Guided Therapy
BNP- or NT-proBNP guided HF therapy can be useful to
achieve optimal dosing of GDMT in select clinically
euvolemic patients followed in a well-structured HF disease
management program.
The usefulness of serial measurement of BNP or NT-
proBNP to reduce hospitalization or mortality in patients with
HF is not well established.
I IIa IIb III
I IIa IIb III
Heidenreich, P et al. Circulation 2022

33. Take Home Point #3
Interpretation of biomarkers must always be guided by
clinical context and clinical judgement

34. Thank you!