Update diagnostiek en behandeling van hartfalen · 2017-08-15 · BNP Levels in Patients Presenting...

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling

University Medical Center Groningen

Update diagnostiek en behandeling van hartfalen

Rudolf de Boer, MD PhD FESC Cardioloog, Universitair Medisch Centrum Groningen WCN Congres “Hart voor de Zaak”, 27-28 November, 2014 Mövenpick Hotel, Amsterdam

Thanks to: A.A. Voors, A. Mosterd & A.S. Maisel for sharing slides

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Update diagnose – ESC 2012

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


ESC: (nog?) géén “stage A & B”

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


The Short of Breath Pie

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Heart Failure

Pneumonia Pneumothorax

Anemia

Pulmonary Embolus

Musculoskeletal Pain

MetHgb Mondor’s Syndrome Tietze’s

disease

COPD exacerbation

Pneumomediastinum

Breast Cancer

Cyanide poisoning

FB Aspiration

Metabolic acidosis

Anaphylaxis

Chemical Exposure

Mediastinitis

Lung Cancer

Anxiety Panic Attack

DKA

Subdiaphrag Abcess

Empyema

Amniotic Fluid Embolus

IVDA Pulm Infarction

Asthma

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  Shortness of breath •  Edema •  Neck vein Distension •  S-‐3

Francis GS. Am J Med. 2001; 110 (suppl):375-‐465

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


How Good Is the History and Physical in AHF?

Variable Sensitivity (%) Specificity (%) Accuracy (%)

Hx of HF 62 94 80

Dyspnea 56 53 54

Orthopnea 47 88 72

Rales 56 80 70

S3 20 99 66

JVD 39 94 72

Edema 67 68 68

Dao Q, et al. J Am Coll Cardiol. 2001; 37:379-‐385.

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


BNP Levels in Patients Presenting With Either Systolic or Diastolic Dysfunction

J Am Coll Cardiol 2003; 410:2010-‐17.

1000

500

300 200

100

50

30 20

10

5

BN

P (p

g/m

L)

Non CHF Diastolic Systolic n=844 n=165 n=287

Median= 34 pg/mL

Median= 821 pg/mL

Median= 413 pg/mL

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Perceived NYHA Class in Patients Ultimately Admitted

374 93 168 103 10 ≥200 pg/mL

44 111 18 14 1 <200 pg/mL

Total IV III II I BNP

Singer AJ. Circ Heart Fail. 2009; 2:287-‐93

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9

1 P

roba

bilit

y (R

RT

)

Biomarker X

BM <xx

High NPV

BM >XX

High PPV R

ule

out

Rul

e in

Grey area

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


SegmenKng a Sub-‐type of Heart Failure Based on Underlying Disease

HF GENERAL POPULATION

de Boer RA, et al. Cardiovasc Drugs Ther. 2014; 28:237-‐46.

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling



BIOMARKER X MEDIATED HF HF GENERAL POPULATION

NON-‐BIOMARKER X MEDIATED HF


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling




•  AcVve disease process mediated by X (e.g. fibrosis), with adverse remodeling

•  Progressive

•  ~30-‐50% are at greatest risk of adverse outcome

•  Heterogeneous eVology

•  Not inherently progressive

•  ~50-‐70% are at lower risk of adverse outcome



Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling

University Medical Center Groningen Cappadocia

BNP

GDF-15 PCT

Gal-3

ST-2

HD profiles proteomics

phenomics

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Current and Future treatment of HF

•  ACE-inhibitor and beta-blocker as standard therapy: what next?

•  Role of ivabradine •  Future therapy for HFrEF •  Current and Future Treatment of HFpEF •  Current and Future Treatment of Acute Heart

Failure

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling

University Medical Center Groningen McMurray JJ, et al. Eur J Heart Fail. 2012; 14:803-‐69. ESC HF Guidelines 2012

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


MRAs in Severe HFrEF and post-MI

RALES: CHF NYHA III-IV 30% mortality reduction

EPHESUS: LV-dysfunction After AMI; 15 % mortality reduction

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling

University Medical Center Groningen Zannad F, et al. N Engl J Med 2011; 364: 11-‐21

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


EMPHASIS: primary outcome

Zannad F, et al. N Engl J Med 2011; 364: 11-‐21

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Recommendation MRA and ARB

McMurray JJ, et al. Eur J Heart Fail. 2012; 14:803-‐69. ESC HF Guidelines 2012

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  6558 HF patients; LVEF ≤ 35%, in sinus rhythm, with HR ≥ 70 BPM despite optimal beta blockade, HF hosp <1 year on stable background medication

•  randomized to (maximum) 7·5 mg twice daily or matching placebo

•  Primary endpoint was the composite of cardiovascular death or hospital admission for worsening heart failure

Swedberg K, et al. Lancet 2010; 376:875-‐85

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


SHIFT – main results

Swedberg K, et al. Lancet 2010; 376:875-‐85

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Recommendations Ivabradine

Teerlink JR. Lancet 2010; 376:847-‐9

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  ICD, class I indicaVon in eligible paVents

•  CRT-‐D, class I indicaVon in eligible paVents

•  Vagal Nerve sVmulaVon: mixed results!

•  Renal denervaVon: starVng all over again

•  Telemonitoring……………………………

Devices

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Guidelines are just Guidelines

•  Example:

•  ICD implantation

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Guidelines ICD in primary prevention of SCD

•  ICD implantation is reasonable (Class I Level A)

•  LV ejection fraction < 30-35%

•  Optimal medical therapy

•  Not within 40 days of infarction

•  90 year old woman, class II/IV, LVEF 28% should be

considered for ICD (in absence of contraindications)

McMurray JJ, et al. Eur J Heart Fail. 2012; 14:803-‐69. ESC HF Guidelines 2012

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Here is the truth ICDs for primary prevention

•  Your patient thinks: •  ICD: life saving for at least 50 of 100 patients receiving them

•  But you know: •  ICD: life saving for 7 of 100 patients receiving them

•  No such thing as immortality

•  Benefits only after 1 year

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling





Failure

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


X

Future therapy for HFrEF: LCZ696?

Beneficial physiological response Pathophysiological response

Vasodilation ! blood pressure ! sympathetic tone ! aldosterone levels !  fibrosis !  hypertrophy Natriuresis/Diuresis

HF symptoms/ progression

NPs Ang II

NEP

Damage

Inactive fragments

AT1 receptor X

RAAS NP system

Vasoconstriction " blood pressure " sympathetic tone " aldosterone "  fibrosis "  hypertrophy

Dual NEP/RAAS

inhibition (LCZ696)

Neurohormonal balance

X

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


LCZ696 (Valsartan and NEP inhibitor, AHU 377)

STUDY TERMINATED EARLY BY DSMB

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Primary endpoint: Death from CV causes or first hospitalization for HF

McMurray, et al. N Engl J Med 2014; ePub ahead of print: DOI: 10.1056/NEJMoa1409077.

Hazard ratio = 0.80 (95% CI: 0.73–0.87) p<0.001

Days since randomization No at risk LCZ696 4187 3922 3663 3018 2257 1544 896 249 Enalapril 4212 3883 3579 2922 2123 1488 853 236

Cum

ulat

ive

prob

abili

ty

1.0

0.6

0.4

0.2

0 0 180 360 540 720 900 1080 1260

Enalapril LCZ696

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Treatment of Diastolic Heart Failure

“No treatment has yet been shown, convincingly, to reduce morbidity and mortality in paVents with HF-‐PEF. DiureVcs are used to control sodium and water retenVon and relieve breathlessness and oedema as in HF-‐REF. Adequate treatment of hypertension and myocardial ischaemia is also considered to be important, as is control of the ventricular rate in paVents with AF.”

ESC HF Guidelines 2008/2012

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


RAAS-‐blockers in HFpEF: unsuccessfull

Charm-Preserved

PEP-CHF I-PRESERVE

Drug Candesartan 32 mg vs. Placebo

Perindopril 4 mg vs. Placebo

Irbesartan 300 mg vs. Placebo

Number 3023 850 4128

Age 67 years 75 years 72 years

% Female 40 55 60

LVEF >40% (54) >40% (64) >45% (60)

Primary Outcome

CV-death or HF-hosp

Death or HF-hosp

Death or CV-hosp

Follow-up 37 months 25 months 50 months

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  Objective: to determine effects of spironolactone on composite endpoint of CV-mortality, aborted cardiac arrest or HF-hospitalization in HFpEF patients

•  Inclusions: Symptomatic HF, Age ≥50, LVEF ≥45%, stratified according to: •  HF-hospitalization in past year

•  Elevated NPs (BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL)

•  Major exclusions: eGFR <30 ml/min/1.73m2, K+ ≥5 mmol/L, AF >90/min, recent ACS.

Pil B, et al. N Engl J Med 2014; 370: 1383-‐1392

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Primary outcome

Outcome Spironolactone Placebo HR (95%CI) and p-value

Primary Outcome 320 (18.6%) 5.9/100pt-yr

351 (20.4%) 6.6/100pt-yr

0.89 (0.77-1.04) P=0.138

Primary Components

CV Mortality 160 (9.3%) 2.8/100pt-yr

176 (10.2%) 3.1/100pt-yr

0.90 (0.73-1.12) P=0.354

Aborted Cardiac Arrest

3 (<1%) 0.05/100pt-yr

5 (<1%) 0.09/100pt-yr

0.60 (0.14-2.50) P=0.483

HF Hospitalization 206 (12.0%) 3.8/100pt-yr

245 (14.2%) 4.6/100pt-yr

0.83 (0.69-0.99) P=0.042

Mean follow-up 3.3 years


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Safety

Spironolactone Placebo P-value Hyperkalemia (≥ 5.5 mmol/L)

322 (18.7%)

157 (9.1%)

<0.001

Hypokalemia (< 3.5 mmol/L)

279 (16.2%)

394 (22.9%)

<0.001

Total number of SAE’s: spironolactone 835 (48.5%) placebo 855 (49.6%)

However… Doubling Creatinine above ULN HR=1.49 (1.18-1.87); P<0.001


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling

University Medical Center Groningen Pfeffer MA, et al. Circula>on. 2014; 131: 00-‐00 (ePub)

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  Target patient population: ∼4,300 patients with symptomatic HF (NYHA Class II–IV) and LVEF ≥45%

PARAGON-HFPEF: study design

*Valsartan 40 mg BID (up to 2 weeks) followed by valsartan 80 mg BID as an optional starting run-in dose for those patients being treated with less than the minimum dose of ACEI or ARB at Visit 1

up to 2 weeks ~240 weeks

Valsartan 160 mg BID

LCZ696 200 mg BID

LCZ696 100 mg BID

On top of optimal background medications for co-morbidities (excluding ACEIs and ARBs)

Primary outcome: CV death and total (first and recurrent) HF hospitalizations (anticipated ~1,721 primary events)

Valsartan 80 mg BID* Screening

3–8 weeks

Active run-in period

Double-blind treatment period

Randomization 1:1

•  Solomon SD, et al. Poster presentation at ESC-HF Congress, 25 May 2013; Clinicaltrials.gov NCT01920711;accessed March 2014

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Effect of ivabradine versus placebo on cardiac function, exercise capacity, and neuroendocrine activation in patients with Chronic Heart Failure with Preserved left ventricular

Ejection Fraction An 8-month, randomised double-blind, placebo controlled, international,

multicentre study

•  Primary objective± to assess the effect of ivabradine compared to placebo on the diastolic function, exercise capacity, and the neuroendocrine activation over an 8-month treatment period in patients with chronic HF-PEF

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling





Failure

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Drugs in AHF: current 1.  Diuretics

2.  Vasodilators (nitrates) ?

3.  Oxygen

4.  Morphine

5.  Ventilation

6.  Treat underlying condition(s)

Lille change in last ~30 years

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Drug Trials in AHF: unsuccessful 1.  PDE-inhibitors: Milrinone: OPTIME-CHF

2.  Endothelin antagonists: Tezosentan: VERITAS

3.  Ca-sensitizers: Levosimendan; SURVIVE/REVIVE

4.  AVP Antagonists: Tolvaptan; EVEREST

5.  Adenosine A1-Receptor Antagonist: Rolofylline; PROTECT

6.  Natriuretic Peptides: Nesiritide: ASCEND-HF

7.  Low dose Dopamine/Nesiritide: ROSE

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Relaxin

Hsu et al. Science 2002;295:671–674; Jeyabalan et al. Adv Exp Med Biol 2007;612:65–87; Dschietzig et al. Circ Res 2003;92:32–40

Relaxin

•  Naturally occurring hormone, discovered in 1929

•  Elevated in circulation in first trimester of pregnancy and throughout 9 months

•  Relaxin receptors, identified in 2002, localized in blood vessels

•  Mechanism of action involves activation of the endothelial endothelin type B receptor

•  Contributes to maternal hemodynamic adjustments to pregnancy

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


RELAX-AHF: Patients

•  1161 patients hospitalized for AHF, with elevated BNP/NT-proBNP levels and pulmonary congestion by chest X-ray

•  Systolic blood pressure >125 mmHg at the beginning and at the end of screening

•  Able to be randomized within 16 hours from presentation to the hospital

•  Impaired renal function defined as a eGFR on admission between 30–75 mL/min, calculated using the simplified Modification of Diet in Renal Disease (sMDRD) equation

Teerlink JR, et al. Lancet 2013; 381:29–39

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


1st Primary Endpoint: Change in dyspnea with VAS

2nd Primary Endpoint: Change in dyspnea with Likert

35

30

25

20

15

10

5

0

Cha

nge

from

bas

elin

e (m

m)

0 6h Day 1 Day 2 Day 3 Day 4 Day 5 Follow-up

12h

Serelaxin (n=581)

Placebo (n=580)

Placebo: mean AUC (SD)=2,308 (3,082) mm*h Serelaxin: mean AUC (SD)=2,756 (2,588) mm*h

p=0.007

100

80

60

40

20

0

–20

–40

–60

–80

–100

Pat

ient

s (%

)

p=0.113 p=0.051 p=0.086

31.4 35.8 44.6 50.3 63.1 67.9

8.7 9.8 16.6 16.4 26.7 25.8

42.1

21.1 7.3

36.4

22.8 7.8

33.9

32.9

14.5

28.0

35.0

16.4

26.0

37.4

24.7

22.7

37.5

26.4

Dyspnea Likert Scale

Moderately improved Markedly improved

Minimally improved No change Minimally worsened Markedly worsened

Placebo Serelaxin Placebo Serelaxin Placebo Serelaxin 6 h 12 h 24 h

SD=standard deviation

Teerlink JR, et al. Lancet 2013; 381:29–39

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


•  (Cardiovascular) mortality was not the primary endpoint of the study

•  In order to get EMA/FDA approval/registration for reduction of mortality, a follow-up study needs to be done

However….

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


RELAX-‐AHF-‐2: study design Please note that the study design informa3on for RELAX-‐AHF-‐2 is subject to change

Discharge#

Placebo i.v.

Serelaxin 30 µg/kg/d i.v.*

0 6 12 24 48 72 96 120 h 14 60 120 180 d

48 h study drug infusion (i.v.) period

*Same weight range-‐adjusted dosing as in RELAX-‐AHF; ‡Standard HF therapy permiied at physician’s discreKon; #If discharge visit coincides with a scheduled visit, only the discharge visit will be performed. AHF=acute heart failure; CV=cardiovascular; d=day; h=hour; i.v.=intravenous; SBP=systolic blood pressure Clinicaltrials.gov: NCT01870778; NovarVs, data on file 2013

In addiKon to standard HF therapy‡

Screening

Double-‐blind randomized treatment period

Screening occurred aner ≥40 mg i.v. furosemide

PresentaKon <16 h

RandomizaKon 1:1

Target patient population: 6,375 patients hospitalized with AHF, presenting with dyspnea, normal to elevated SBP (≥125 mmHg) and mild-to-moderate renal impairment

Primary outcome: Kme to CV death

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Conclusions

HFrEF: ACEi (or ARB) and beta-blocker

Still NYHA II or more: aldosterone blocker

In selected patients: ivabradine

Big bang: LCZ696

Still no evidence based therapy for HFpEF •  Maybe MRAs? •  Maybe ARNI?

Still no evidence based therapy for AHF •  Maybe Serelaxin?

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling




•  AcVve scarring (fibrosis) and adverse remodeling

•  Inherently progressive

•  ~30-‐50% are at greatest risk of adverse outcome

•  Heterogeneous eVology

•  Not inherently progressive

•  ~50-‐70% are at lower risk of adverse outcome


Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Hypertension Blood Pressure

Diabetes Glucose, HbA1c

Lipids Cholesterol,LDL

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


So everyone is supposed to be on the same dose of heart failure medications.

That cannot be “personalized medicine”

Har

tfale

n: U

pdat

e di

agno

stie

k en

beh

ande

ling


Comparison of Trials BNP-‐Guided Therapy

Adapted from Felker M, et al. Am Heart J. 2009; 158: 422

Troughton

STARS-BNP

TIME-CHF

BATTLE-SCARRE

D

PRIMA SIGNAL-HF

Berger et al.

PROTECT

n 69 220 499 364 345 252 278 151

Blinding No No Single Double Single Single ? No

Marker NT-BNP BNP NT-BNP NT-BNP NT-BNP NT-BNP NT-BNP NT-BNP

Aim (ng/l) 1692 100 400/800 1270 discharge 50% red. 2200 1000

Control HF score Usual care

≤class II 2 groups Usual care

HF spec. 2 groups Usual care

1° EP Death, CV

hosp., HF

HF death,

HF hosp.

Death, all-cause

hosp.

All-cause mortality

d alive out hosp.

d alive out CV hosp.

HF hosp., death

CV events

Age 70 66 77 76 72 77 71 63

NT-BNP 1981 350 4328 2008 2940* ~2500 ~2350 2118

1˚ EP Pos Pos Neg Neg Neg Neg Pos Pos Mortality p=0.06 7/11, ns p=0.06 Identical p=0.21 Identical Identical p=0.52

Update diagnostiek en behandeling van hartfalen · 2017-08-15 · BNP Levels in Patients Presenting...

Documents

Transcript of Update diagnostiek en behandeling van hartfalen · 2017-08-15 · BNP Levels in Patients Presenting...