BNP in Heart Failure Azam Hadi MD 9/17/2018

Outline BNP physiology Heart failure diagnosis Prognosis BNP guided therapy 9/17/2018

Natural History of Heart Failure 100 75 50 25 I II III IV 1 10 NYHA CLASS Annual Survival Rate Hospitalizations / year .1 Deceased Class IV Severe symptoms despite optimal medical therapy Sharp deterioration in survival Increase in hospitalizations This slide demonstrates the importance of treating heart failure in Stage III, since waiting until Stage IV leaves very few options for treatment. Admission of a heart failure patient to hospital is a warning sign that this patient requires intervention. Survival Rate Hospitalizations Adapted from Bristow, MR Management of Heart Failure, Heart Disease: A Textbook of Cardiovascular Medicine, 7th edition, ed. Braunwald et al.

Norepinephrine in HF Elevated Plasma Norepinephrine Concentration Predicts an Unfavorable Prognosis in Heart Failure Patients Cohn et.al., 1984

Neurohormonal Axis

CVP and Cardiac Outcomes Kaplan-Meier Analysis of Event-Free Survival According to Tertiles of CVP Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Damman, K. et al. J Am Coll Cardiol 2009;53:582-588 Curvilinear Relationship Between CVP and eGFR According to Different Cardiac Index Values Solid line = cardiac index <2.5 dashed line = cardiac index 2.5 to 3.2 dotted line = cardiac index >3.2 p = 0.0217 Central Venous Pressure Damman, K. et al. J Am Coll Cardiol 2009;53:582-588

Physiology Maisel A et al. Eur J Heart Fail 2008;10:824-839

BNP history 1988 – Sudoh et al isolate BNP from porcine tissue (“Brain”) 1991 Mukoyama et al. “cardiac hormone secreted by the ventricles” 1994 Davis et al – BNP in dyspneic patients 2001 Maisel et al. publish the first point of care BNP in ED and hospital setting 9/17/2018

Natriuretic peptides

BNP half life

Natriuretic peptide receptors

BNP and diagnosis 1994 – Davis et al. 52 patients with dyspnea admitted from ER. HF diagnosis by cardiologists blinded to BNP results Sensitivity 93% Specificity 90% Breath Not Properly (BNP) trial – Maisel et al. N=1586 patients in a multicenter trial

Breath Not Properly ER physicians were blinded to BNP results Mean age 64±17 Female 44% Cutoff of BNP=100 pg/ml – sensitivity of 90% and specificity of 76% 9/17/2018

Breath Not Properly 9/17/2018

Maisel AS et al. N Engl J Med 2002;347:161-167. Receiver-Operating-Characteristic Curve for Various Cutoff Levels of B-Type Natriuretic Peptide Figure 3. Receiver-Operating-Characteristic Curve for Various Cutoff Levels of B-Type Natriuretic Peptide (BNP) in Differentiating between Dyspnea Due to Congestive Heart Failure and Dyspnea Due to Other Causes. Maisel AS et al. N Engl J Med 2002;347:161-167.

The N-terminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study. Increased NT-proBNP was the strongest independent predictor of a final diagnosis of acute CHF (odds ratio 44, 95% confidence interval 21.0 to 91.0, p <0.0001). NT-proBNP testing alone was superior to clinical judgment alone for diagnosing acute CHF (p = 0.006); NT-proBNP plus clinical judgment was superior to NT-proBNP or clinical judgment alone. NT-proBNP measurement is a valuable addition to standard clinical assessment for the identification and exclusion of acute CHF in the emergency department setting AJC; Volume 95, Issue 8, 15 April 2005, Pages 948–954

BNP nomogram 9/17/2018

BNP and Diagnosis 9/17/2018

BNP – confounding conditions Renal failure – elevated BNP. Not only “decreased clearance” Age and gender – esp. elderly women Flash pulmonary edema – BNP, unlike ANP, not extensively stored – requires mRNA upregulation 9/17/2018

BNP – confounding conditions Obesity – lowers BNP levels (NPR-C receptors) RV dysfunction – Pulmonary Embolism, PH Constriction/Tamponade – BNP not elevated Diastolic dysfunction – lower BNPs Sepsis/ICU patient – modestly elevated BNP Nesiritide or Entresto Flash pulmonary edema – BNP, unlike ANP, not extensively stored – requires mRNA upregulation 9/17/2018

ACC/AHA Guidelines Class 1 Recommendation 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 (Level of Evidence: A) 9/17/2018

BNP and prognosis 9/17/2018

Predischarge B-type natriuretic peptide assay for identifying patients at high risk of re-admission after decompensated heart failure Kaplan-Meier curves showing the cumulative incidence of death or re-admission according to predischarge B-type natriuretic peptide (BNP) cut-off value of 350 ng/l in the validation study; p = 0.0001. J Am Coll Cardiol. 2004;43(4):635-641. doi:10.1016/j.jacc.2003.09.044 Date of download: 11/10/2013

BNP and prognosis 9/17/2018

Val-HeFT (Valsartan Heart Failure Trial) Prognostic Value of Changes in N-Terminal Pro-Brain Natriuretic Peptide Val-HeFT (Valsartan Heart Failure Trial) J Am Coll Cardiol. 2008;52(12):997-1003. doi:10.1016/j.jacc.2008.04.069

Val-HeFT (Valsartan Heart Failure Trial) Prognostic Value of Changes in N-Terminal Pro-Brain Natriuretic Peptide Val-HeFT (Valsartan Heart Failure Trial) J Am Coll Cardiol. 2008;52(12):997-1003. doi:10.1016/j.jacc.2008.04.069

BNP and prognosis Fonarow GC et al. J Am Coll Cardiol 2007; 49(19):1943-1950 9/17/2018

BNP and prognosis 9/17/2018

ACC/AHA Guidelines Class 1 Recommendation Measurement of BNP or NT-proBNP and/or cardiac troponin is useful for establishing prognosis or disease severity in acutely decompensated HF (Level of Evidence: A) 9/17/2018

Protect Trial Patient with Class II-IV symptoms, EF  40%, recent HF event Randomization echocardiogram Standard of Care Minnesota Living With HF Questionnaire quarterly Standard of Care + NT-proBNP Therapy adjusted to achieve optimal drug targets Visits q3 months Extra visits as needed for treatment goals Therapy adjusted to achieve optimal drug targets PLUS NT-proBNP  1000 pg/mL Close-out echocardiogram Total cardiovascular events assessed

Protect Trial- Office visits *908 visits overall; mean follow-up 10 ± 3 months Median number of visits: NT-proBNP 6.0 vs SOC 5.0; P =.05 SOC NT-proBNP P = .001 1-4 visits 5 visits 6-7 visits ≥8 visits Visit number

Protect Trial- Primary End Point SOC NT-proBNP 100 events 58 events *Logistic OddsNT-proBNP= 0.44 (95% CI= .22-.84; P =.019) *Adjusted for age, LVEF, NYHA Class, and eGFR

Kaplan-Meier Analysis 1.0 Log rank P =.03 0.8 0.6 Event free survival 0.4 Standard-of-care (N=76) NT-proBNP (N=75) 0.2 73 146 219 292 365 Days from enrollment

GUIDE-IT The aim of the GUIDE-IT study is to randomize approximately 1,100 high-risk patients with chronic HF who have a left ventricular EF ≤40% to either optimized guideline-recommended therapy or a strategy of adjusting therapy with the goal of achieving and maintaining a target NT-proBNP level of <1,000 pg/ml. Patients in either arm of the study are followed up at regular intervals and after treatment adjustments for a minimum of 12 months

BNP guided therapy Serial BNPs still controversial, but increasingly used… 9/17/2018

ACC/AHA Guidelines Class IIa Recommendation BNP or NT-ProBNP guided therapy is useful to achieve optimal dosing of GDMT in select clinically euvolemic patients followed in a well structured HF disease management program (Level of evidence: B) 9/17/2018

Conclusions BNP is a very useful diagnostic test Use clinical assessment along with BNP – not clinical assessment versus BNP… Trending BNP for a specific patient is more accurate than the absolute value itself Pre-discharge BNP is helpful Serial BNPs for management/decisions (obesity, critically ill, heart transplant patients, renal failure) 9/17/2018