SHA24/060003

Alan Maisel MD Professor of Medicine, University of California, San Diego

Out of the Desert: Biomarkers in acute cardio-renal diseases

Director Coronary Care Unit And Heart Failure Program San Diego Veterans Hospital

“OK, now take a deep thought.”

The Ideal Biomarker

Maisel, JACC 2011

What is the major limitation of natriuretic peptide levels?

A First Warning • The use of Biomarkers for diagnosis is always secondary to clinical judgment

Excessive Shortness of Breath We Need Rapid and Accurate Diagnosis and treatment

THIS COULD BE YOUR MOTHER

Signs and Symptoms of HF • • • •

Shortness of breath Edema Neck vein Distension S-3

Francis G.S. A M J Med. 2001; 110 (suppl 7A): 375-465.

A chest x-ray can NEVER rule out acute heart failure!

•

Misses 20% of Echocardiogram proven cardiomegaly

•

Even worse if done portable

•

Diagraghm not well

How sure are we about the diagnosis of AHF??

Number of Cases

350

300

Significant Indecision Exists

250

43 %

200

Pretest Probability of CHF 150

100

50

0 0

10.0

20.0

30.0

McCullough, Maisel et al. Circulation. 2002;106:416−422.

40.0

50.0

60.0

70.0

80.0

90.0

100.0

What happens if we misdiagnose the acute breathless patient?

14

Dyspnea of respiratory origin mortality (%)

12

14

10

P<0,05

8

8

6

4

2

4

0

bronchodilators

Wuerz. Ann Emerg Med 1992;21:669-674

No therapy

CHF Therapy

Cardiorenal Axis ANP, ANP, BNP, BNP, and and CNP CNP • Natriuretic Natriuretic

• Diuretic Diuretic • Vasodilating Vasodilating • Renin Renin and and aldosterone aldosterone inhibiting inhibiting • Anti-fibrotic Anti-fibrotic

Renin-angiotensinRenin-angiotensinaldosterone aldosterone system system • Sodium Sodium retaining retaining • Antidiuretic Antidiuretic

• Vasoconstricting Vasoconstricting • Fibrosis Fibrosis

CP1030444-4

Pre-Pro-BNP1-134

Pro-BNP1-108

N-terminal Pro-BNP1-76

↑ WALL STRESS

BNP77-108 t1/2 = 18 min

Pro-BNP1-108

NT-proBNP? BNP?

Breathing Not Properly STUDY

Accuracy is 90% Optimal cut-off point determined @ 100 pg/mL 1.0 BNP=50 pg/mL BNP=80 pg/mL

0.8

Positive predictive value=75%

BNP=100 pg/mL BNP=125 pg/mL Sensitivity

0.6 BNP=150 pg/mL

0.4

Final Diagnosis Heart Failure

Final Diagnosis NOT Heart Failure

BNP 100 pg/mL “Test positive”

673

227

BNP <100 pg/mL “Test negative”

71 Sensitivity =90%

615 Specificity =73%

0.2

0.0

0.0

0.2

0.4

0.6 1-Specificity

Maisel AS et al. N Engl J Med. 2002;347:161-167.

0.8

Negative predictive value=90%

1.0

Clarification of Diagnosis & BNP BNP reduces clinical indecision by 74%

45%

Indecision

40% 35%

43%

30% 25%

* P <0.0001

20% 15% 10% 5% 0%

11% Clinical Evaluation

Clinical Evaluation and BNP

BNP levels adds to the physicianâ&#x20AC;&#x2122;s ability

McCullough, Maisel et al., Circulation 2002 106:416-422

BNP Levels in Patients Presenting With Either Systolic or Diastolic Dysfunction

BNP (pg/mL)

1000 500 300 200

Median= 413 pg/mL

Median= 821 pg/mL

100 50 30 20

Median= 34 pg/mL

10 5

Non CHF n=844

Diastolic n=165

Systolic n=287

Maisel et alJ Am Coll Cardiol 2003;410(11):2010-17.

Cost-Effectiveness of BNP at ED: The BASEL Study

$8000 P=0.001

$6000

$4000

â&#x201A;Ź1,545 Savings/Patient Biosite Triage BNP (in pg/mL)

$2000

0 Muller C, et al. N Engl J Med. 2004;350:647-654.

You can’t win them all (ask R.Federer) : Caveats to NP testing • • • • •

Dry versus wet BNP Gray Zone Renal dysfunction Obesity Heart Failure with normal levels

BNP level = baseline BNP(dry) plus change due to increased volume(wet)

BNP level (pg/ml)

Wet (Change due to volume overload) Dry ( NYHA Euvolemic state)

NYHA Class - Euvolemic (Dry) BNP

Grey Zone

PROGNOSTIC UNCERTAINTY

Grey area

Obesity â&#x20AC;˘

There appears to be a linear inverse relationship between BMI and NP levels

â&#x20AC;˘

Patients who are obese (BMI >35kg/m2) should have their NP doubled to use the standard cutpoints.

Maisel, Valle, Aspromente et Al EJHF 2009

The Differential Diagnosis of an Elevated Natriuretic Peptide • • • • • • • • • •

Unrecognized HF Prior HF LVH Valvular heart disease Atrial fibrillation Advancing age Myocarditis ACS Pulmonary hypertension Congenital heart disease

• • • • • • • • •

Anemia Pulmonary embolism Cardiac surgery Sleep apnea Critical illness Sepsis Burns Renal failure Toxic-metabolic insults

Heart Failure- Cause for Hospital Admission Other

Non compliance

Ischemia

Arrhythmia

Volume overload

0

10

20

% of Patients

30

40

Changes in BNP Mirror changes in PAW* During Treatment of Acute Heart Failure 1300

33 N = 15 (responders)

31

PAW

1200 1100

PAW (mm Hg)

27 25

1000

23

900

21

800

19 700

17

600

15 baseline *Pulmonary artery wedge.

4

8

12

Hours

Kazenegra, Maisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001

16

20

24

BNP (pg/ml)

BNP

29

BNP trends during hospitalization and subsequent prognosis upon hospital discharge

Highest baseline, greatest change; highest discharge level= worse prognosis

Lowest Predischarge BNP= best prognosis

Lowest Baseline BNP Level=second best prognosis

Serial BNP for Guiding Treatment During Hospitalization?

Courtesy of Damien Logeart.

BNP on Discharge Predictive of Events

Death or Readmission (%)

100

p<0.0001

Predischarge BNP >700 ng/L n=41, events=38

15.2

75 Predischarge BNP 350-700 ng/L n=50, events=30

50

p<0.0001

25

5.1 Predischarge BNP <350 ng/L n=111, events=18

0

1 0

30

60

90

120

150

Follow-Up (Days)

180

Hazard Ratios of 2nd and 3rd Versus 1st BNP Range

Logeart D et al. J Am Coll Cardiol 2004;43(4):635-41.

No w Now 55 Yea rs Years Di a gno s is o f Acute H F HF Diagnosis of Acute Fo l l oFollowing wi ng Pa ti ent i n H o in s pita l Patient Hospital Uti liUtilizing zi ng Di s cha rge BNP BNP Discharge Mo ni to ring BNP Po s t-di s cha rge Monitoring BNP Post-discharge Gui diGuiding ng OutpaOutpatient ti ent Rx Rx Us e Use a s PaasrtPart o f DxofCri a fo r Hfor FPEF Dxteri Criteria HFPEF Screen fo r LV Screen forDyfx LV Dyfx Outpa ti ent Ri s k Pro fi lProfiling i ng Outpatient Risk 0

0

75 25 25 50 50 75 Con fid e n c e u uptake p take (%) Confidence (%)

100 100

History Physical exam CXR

Sign on a bus in Melbourne Australia illustrating how Chest Pain can Present

High Sensitivity Troponin

Howâ&#x20AC;&#x2122;s your Cardiologist feel about this?

The fact is

• Troponin assays are getting better- so much so, in fact, that we as clinicians need to similarly evolve in our understanding of how we can use them most effectively.

• I have observed medical housestaff cast off the significance of elevated troponin levels in a patient by “troponinemia” and moving on, as if that were an explanation in and of itself.

Alsoâ&#x20AC;Ś. â&#x20AC;˘ The ever-improving sensitivity of troponin assays has engendered skepticism and caused confusion for many, but the reality is that the modern troponin assays truly are better. â&#x20AC;˘ They are providing accurate and precise information, and are providing it in abundance.

remember • Early troponin assays, intended to aid in the diagnosis of acute myocardial infarction, were generally easy to use, providing simple “yes/no” answers because of their relative lack of sensitivity.

• They worked well, and troponins became an integral part of the universal definition of myocardial infarction.

Once a Troponin is “elevated”, the cat is out of the bag “Cards to See for Elevated Troponin”

Most recently, “highly sensitive” troponin assays have emerged which can, by definition, detect troponin in over 50% of the general population. The most sensitive of these can detect troponin in almost everyone.

Because of this, troponin assays are no longer simple binary “yes/no” variables, but instead need to be interpreted as continuous variables, and within a greater context – with an understanding of the interplay of numerous factors such as age, sex, and renal function to name just a few.

IFCC Cardiac Biomarker TF Consensus Definition

• (1) The total imprecision at the 99th percentile value <10% CV • (2) Measurable concentrations below the 99th percentile should be attainable with an assay at a concentration value above the assay’s limit of detection for at least 50% (and ideally 95%) of healthy individuals

Reference: Apple, F.S., et al. Clin Chem, 2012; 58(1) :54–61 41 41

Why is Total Imprecision <10%CV at the 99th%ile Important?

•

Guidelines recommend that the cuff-off for clinical decision-making using cardiac troponin be at the 99th%ile of a healthy population.1-3 • Since healthy subjects have low troponin levels, an assay with poor precision at the cut-off could cause ‘false positives’ for myocardial infarction due to analytical imprecision.4 • Guidelines recommend the use of assays with good precision (<10%CV), although experts have suggested assays with imprecision up to 20% are still clinically useable.4

References: 1. Apple FS. Clin Chem. 2007; 53(4): 547-55 2 Hamm, C. et al. EHJ. 2011; 32: 2999–3054 3. Thygesen, K. et al. EHJ. 2012;33: 25512567 4. Apple, F.S., et al. Clin Chem, 42 2012; 58(1) :54–61

Comparison a Contemporary and hsTn Assay LoD 10%CV 99%ile % Detectable above LoD

ARCHITECT TnI* ng/L µg/L (ng/mL) (pg/mL) 0.010 10 0.032 32 0.028 28

ARCHITECT hsTnI** ng/L µg/L (ng/mL) (pg/mL) 0.002 1.9 0.005 4.5 0.026 26.2

<50% of normals

>50% of normals

*Representative data from package insert **Internal R&D Final Verification Data

• ~7x Improvement in precision without significant change to 99 th%ile • Increased percent detection rate of cardio-healthy or “normal” subjects

43

What is meant by % Detection above the LoD?

Frequency

Limit of Detection

Not Measureable!

Contemporary Assays:

10%CV Troponin level

Representative Cartoon for Contemporary Assays

99th%ile 44

Limit of Detection

Not Measureable!

Frequency

What is meant by % Detection above the LoD?

Contemporary Assays:

Troponin level

10%CV

Representative Cartoon for “hsTn” Assays

99th%ile © 2012-2013 Abbott

45

How do hsTnT assays compare to Contemporary TnI? n=718

Š 2012-2013 Abbott

46

Diagnostic Accuracy of Cardiac Troponin Assays at Presentation According to Time since Onset of Chest Pain

718 consecutive patients with chest pain 17% with myocardial infarction

Reichlin T et al. N Engl J Med 2009;361:858-867

Future Biomarkers: Triage, Diagnostics, Risk

Plaque • LDL • ox LDL • CRP • IL-6 • IL-10 • IL-18 • Fbg • TNF-

Unstable plaque • MMP-9 • MPO • ICAM • VCAM • LpPLA2

Plaque rupture • sCD40L • PIGF • PAPP-A • VCAM

Ischemic cascade with elevation of specific markers at different stages Circ, 2006

Thrombosis • PAI-1 • sCD40L • VwF • D-dimer

Ischemia • IMA Necrosis • FFA • cTNT • Choline • cTNI • BNP • CK-MB • ?IL-6/TF • Myg

LV remodeling • BNP • NT-ProBNP • MMP CP1267899-3

hsTn are being included into new guidelinesâ&#x20AC;ŚRule IN

49

Source: Thygesen et al. Eur Heart J. 2012;33:2252-7.

ADQI VII: Venice, Italy The Cardio-Renal Syndrome Proposed Consensus Definition: We defined the broad term “Cardio-Renal Syndromes” as “complex disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other.”

Ronco et al Eur Heart J 2009

Ronco et al Eur Heart J 2009

Clinical Characteristics of AHFS Patients Data on approximately 200,000 patients

Median age (years)

75

Hx of Atrial Fibrillation Preserved Ejection Fraction

30%

Women

>50%

Hx of CAD

60%

SBP >140 mm Hg

50%

Hx of Hypertension

70%

SBP 90-140 mm Hg

45%

Hx of Diabetes

40%

SBP <90 mm Hg

5%

Adams KF, et al. Am Heart J. 2005;149: 209.

Cleland JGF et al. Eur Heart J. 2003; 24: 442; Fonarow GC, et al. J Am Coll Cardiol. 2004; 844 â&#x20AC;&#x201C; 4A.

50%

Renal abnormalities 30%

CardioRenal Syndrome Type 1: Creatinine Increase in Acute HF Patients Creatinine is a measure of kidney function. An increasing Creatinine over time means that the kidney was injured and has lost function. The graph below shows how Cr increases in hospitalized HF patients.

100 80

% Cr

≥0.1

60

≥0.2

40

“Type 1 CardioRenal Syndrome ≥0.3 ” X

X≥0.4 Also know as: X X X X X X X X X X X X ≥0.5 X Worsening Renal Function (WRF) or Acute Kidney Injury (AKI)

1

3

20 0

5

7

9

11

Days Cr, serum creatinine.

Gottlieb SS et al. J Card Fail. 2002;8:136. Smith G, J Card Fail. 2003 Feb;9(1):13-25

13

15

Incidence WRF ~ 28%; 90% occurred within 7 days Outcome

No WRF (n=1212, 72%)

WRF (n=469, 28%)

Adj

Hospital Death (%)

3

7

2.72

30-d Death (%)

6

10

1.87

6-m Death

19

25

1.56

Hospital Stay (d)

6.9

9.1

2.3

Hospital Cost ($)

6,327

8,085

1,758

Krumholz et al Am J Cardiol 2000

Relation between CVP and eGFR in broad spectrum of patients with CV disease*

*p<0.001

Damman et al. JACC 2009

Iatrogenic causes of AKI in HF patients To much Diuretic ACE, ARB, Aldo Blockers Contrast Antibiotics

Approach in Acute Kidney Injury Identification of Risk patients

Primary prevention

Early detection of AKI Reduction of Morbidity and Mortality?

Secondary prevention

“Where are the biomarkers?”

AMI versus AKI Period

Acute Myocardial Infarction

1960s

LDH

1970s

CPK, myoglobin

1980s

CK-MB

1990s

Troponin T

2000s

Troponin I

Multiple Therapies 50% â&#x2020;&#x201C; Mortality

AMI versus AKI Period

Acute Myocardial Infarction

Acute Kidney Injury

1960s

LDH

SCr

1970s

CPK, myoglobin

SCr

1980s

CK-MB

SCr

1990s

Troponin T

SCr

2000s

Troponin I

SCr

Multiple Therapies 50% â&#x2020;&#x201C; Mortality

Supportive Care High Mortality

Need early biomarkers for better treatment of AKI

The promise of biomarkers for AKI

“The nephrologist‘s troponin“ Measured in urine or serum

Early management (goal-directed therapy)

Development of New therapeutic strategies

Candidate Biomarkers CysC NGAL KIM-1 γ-GT IL-18 L-FABP NAG Hepcidin etc…

NGAL Physiology and Clinical Relevance • Member of the lipocalin superfamily • Normally expressed at very low levels in kidney, lungs, stomach, and colon • Increased after injury • Increased after ischemia – One of the most highly induced proteins in kidney after ischemic or nephrotoxic AKI in animal models

• Protective role – Murine models of renal ischemia-reperfusion showed amelioration of morphologic and functional injury when treated with NGAL

• Early diagnostic biomarker for AKI

64

Devarajan P. Nephrol Dial Transplant. 2008;23:3737-3743.

Parikh CR, Devarajan P. Crit Care Med. 2008;36(suppl):S159-S165.

Mishra J, et al. J Am Soc Nephrol. 2004;15:3073-3082.

Heart Failure

Cardiac surgery

Radiocontras t

Trauma

ICU Kidney transpla nt

NGAL IgA nephropa thy

CKD

Urine NGAL 2 hr post CPB: AuROC 0.998

Mishra et al Lancet 2005

Aghel et al. J. Card. Fail. 2010 - Summary • • • •

91 patients admitted to hospital with Acute HF Serum NGAL measured at admission using a research ELISA Type 1 CardioRenal syndrome (also known as WRF or AKI) was determined over a 5 day period by physician adjudication 38% developed Type 1 CRS

• Serum NGAL was a more powerful predictor of Type 1 CRS than BUN or eGFR • An admission serum NGAL >140 ng/mL had a 7.4-fold

CONFIDENTIAL

Diagnosis of AKI ~ NGAL >130 µg/g Sensitivity 0.90 (0.73-0.98) Specificity 0.99 (0.99-1.00) NGAL >130 µg/g – 32.3% required RRT OR 24.7, 95% CI, 7.7-79.4

n=635, AKI defined according to RIFLE criteria

Nickolas et al Ann Internal Med 2009

What can NGAL detect?

NGAL

Creatinine

• Marker of Renal Injury • High Sensitivity for Injury • Moderate Specificity for underlying nephropathy

Clinical Scenario: Year 2013

NGAL level

Diagnosis

Intervention

<100 ng/mL

No AKI

Routine care

NGAL level

Diagnosis

Intervention

<100 ng/mL

No renal injury

Routine care

150-300 ng/mL

High risk for AKI

Hold ACE Hold ARB Hold Aldo blockers No contrast No renal toxic antibiotics No NSAIDS Judicious diuretics

NGAL level

Diagnosis

Intervention

<100 ng/mL

No renal injury

Routine care

150-300 ng/mL

High risk for AKI

Hold ACE Hold ARB Hold Aldo blockers No contrast No renal toxic antibiotics No NSAIDS Judicious diuretics

>350 ng/mL

High risk for AKI, dialysis and death

ICU admit Consider ultrafiltration

Discharge levels of markers

Maisal et al Eur J Heart Fail 2011

Group

HR

p

NGAL <100 BNP <330

1.00

-

NGAL <100 BNP >330

3.23

0.3

NGAL >100 BNP <330

9.95

0.04

NGAL >100 BNP >330

16.85

<0.001

Maisal et al Eur J Heart Fail 2011

Find the “Sweet Spot” Prior to Hospital Discharge BNP

Unlikely to discharge Improved but ready?

Start Diuretics

SCr

Have you over diuresed?

New AKI/ WRF?

Find the “Sweet Spot” Prior to Hospital Discharge BNP Stop diuretics?

Vasodilators?

Start Diuretics NGAL SCr

AKINESIS: Acute Kidney Injury N-gal Evaluation of Symptomatic heart failure Study

Biomarkers will Make bad doctors worse and good doctors better!

Thank You