Insuficiencia Cardíaca

Prof. Domingo A. Pascual Figal

Hospital Universitario Virgen de la Arrixaca

Facultad de Medicina, Murcia

Cambios en la Enfermedad Cardiovascular

en el último año

Implicaciones para la Práctica Clínica

2011 Top Game Changers in Cardiology:

………………………………

and the Top Game Changer Is...

Objetivo primario (Mortalidad CV u hospitalización por IC)

HR = 0,63 (IC 95% 0,54-0,74)

p < 0,001

100

0

60

50

40

30

20

10

0 1 2 3

Eplerenona

Placebo

Años desde la aleatorización

232 562 925 1.364 199 512 848 1.373

Mo

rtal

idad

CV

u h

osp

ital

izac

ión

po

r IC

(%

)

Eplerenona Placebo

Nº de pacientes en riesgo

Conclusiones

• En los pacientes con IC con disfunción sistólica y síntomas leves, la adición de eplerenona al tratamiento médico optimo:

– fue bien tolerada

– mejoró la supervivencia

– y previno hospitalizaciones

• NNT

– Objetivo primario, por año de seguimiento, es 19

– Para aplazar una muerte, por año de seguimiento, es 51

En el corto y

En el largo plazo

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Disposition of Patients

1373 Randomized to placebo

2737 Randomized

1364 Randomized to eplerenone

No AFF N= 911 (66.8%)

No AFF N= 883 (64.3%)

Median follow-up time 21 months,

AFF N= 453 (33.2%)

AFF N= 490 (35.7%)

No AFF N= 1794 (65.5%)

AFF N= 943 (34.5%)

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New Onset Atrial Fibrillation/Flutter (AFF)

0

2

4

6

8

10

0 1 2 3 4

New Onset AFF Cumulative Rate

(%)

Years from Randomization

Eplerenone

Placebo

No. at Risk

Placebo 883 611 345 133 1

Eplerenone 911 627 397 162 2

HR [95% CI] = 0.58 [0.35, 0.96]

P = 0.034

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Effects of eplerenone by baseline AFF:

without AFF

Total number of

subjects

Eplerenon

e

n = 911 (%)

Placebo

n = 883

(%)

Hazard

Ratio

P-value

Without AFF

CV death/HF

Hospitalization

160 (17.6%) 217 (24.6%) 0.70 <0.001

All-cause mortality or

HF hospitalization

175 (19.2%) 228 (25.8%) 0.72 0.001

All-cause

hospitalization

260 (28.5%) 294 (33.3%) 0.83 0.03

HF hospitalization 103 (11.3%) 150 (17.0%) 0.65 <0.001

All cause death or all

cause hospitalization

292 (32.1%) 341 (38.6%) 0.81 <0.01

HF death or HF

hospitalization

107 (11.7%) 156 (17.7%) 0.65 <0.001

CV hospitalization 201 (22.1%) 244 (27.6%) 0.77 <0.01

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Effects of eplerenone by baseline AFF:

with AFF

Total number of

subjects

Eplerenon

e

N = 453

N (%)

Placebo

N = 490

N (%)

Hazard

Ratio

P-value P-value for

interaction

with/withou

t AFF

With AFF

CV death/HF

Hospitalization

89 (19.6%) 139 (28.4%) 0.60 <0.001 0.41

All-cause mortality or

HF hospitalization

95 (21.%) 148 (30.2%) 0.60 <0.001 0.28

All-cause

hospitalization

148 (32.7%) 197 (40.2%) 0.70 <0.01 0.22

HF hospitalization 61 (13.5%) 103 (21.0%) 0.56 <0.001 0.49

All cause death or all

cause hospitalization

170 (37.5%) 228 (46.5%) 0.70 <0.001 0.26

HF death or HF

hospitalization

63 (13.9%) 106 (21.6%) 0.56 <0.001 0.49

CV hospitalization

103 (22.7%) 155 (31.6%) 0.63 <0.001 0.20

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CV death or HF hospitalization by

baseline atrial fibrillation/flutter (AFF)

0

10

20

30

40

0 1 2 3 4

CV Death / HF Hospitalization

Cumulative Rate (%)

Years from Randomization

Without Baseline AFF

With Baseline AFF

No. at Risk

With AFF 943 602 385 161 2

Without AFF 1794 1171 689 270 4

HR [95% CI] = 1.13 [0.96, 1.33]

P = 0.153

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Study outcomes by baseline AFF

AFF

(N=943)

N (%)

No AFF

(N=1 794)

N (%)

P-value

HF Hospitalization/CV Death 228 (24.2%) 377 (21.0%) 0.153

HF Hospitalization

164 (17.4%) 253 (14.1%) 0.059

CV Death 122 (12.9%) 210 (11.7%) 0.643

All-cause mortality or heart

failure (HF) hospitalization

243 (25.8%) 403 (22.5%) 0.153

All-cause mortality 139 (14.7%) 245 (13.7%) 0.789

All-cause hospitalization 345 (36.6%) 554 (30.9%) 0.019

All cause death or all cause

hospitalization

398 (42.2%) 633 (35.3%) 0.008

HF death or HF hospitalization 169 (17.9%) 263 (14.7%) 0.067

CV hospitalization 258 (27.4%) 445 (24.8%) 0.355

¡HIPOTENSIÓN¡

HeartWare

HeartMate II

DOT-HF trial

SMART-AV

Study Design

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

Minnesota Living With HF Questionnaire quarterly

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

Visits q3 months

Extra visits as needed for treatment goals

Close-out echocardiogram

Total cardiovascular events assessed

NT-proBNP Concentrations

Baseline Follow-up P

Overall 2118 [1122-3831] 1321 [554-3197] .02

By treatment allocation

Treatment Baseline Follow-up P

SOC 1946 [951-3488] 1844 [583-3603] .61

NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01

P = .03 for SOC follow-up versus NT-proBNP follow-up 44.3% of NT-proBNP subjects 1000 pg/mL

Primary Endpoint

0

20

40

60

80

100

120

Total CV Events

Nu

mb

er

of

even

ts

100 events

58 events

P =.009 SOC

NT-proBNP

*Logistic OddsNT-proBNP= 0.44

(95% CI= .22-.84; P =.019)

*Adjusted for age, LVEF, NYHA Class, and eGFR

Individual Endpoints

0

10

20

30

40

50

60

Worsening

HF

HF hosp ACS VT/VF CV death

Nu

mb

er

of

even

ts

P =.001

NB: 0 cerebral ischemia events in either arm

NB: 3 of 4 CV deaths in NT-proBNP arm

occurred after elective withdrawal from study

P =.002 P =.72 P =.41 P =.52

SOC

NT-proBNP

Age and outcomes

0

0,2

0,4

0,6

0,8

1

1,2

1,4

1,6

1,8

Age ≥ 75 years Age < 75 years

Mean

nu

mb

er

of

even

ts

SOC

NT-proBNP

P =.008 P =.005

*No interaction between age and NT-proBNP guided care was found (P =.11)

Safety

0

1

2

3

4

5

6

7

8

Acu

te re

nal fa

ilure

Diz

zines

s

Hyp

o/hyp

erka

lem

ia

Hyp

otensi

on

Synco

pe

Adverse event

% w

ith

even

ts

Acute

renal failure Dizziness

Hypo or

hyperkalemia Hypotension Syncope

Adverse events

P =.72 P =.70 P =.32 P =.08 P =.47

SOC

NT-proBNP

Minnesota Living with Heart

Failure Questionnaire

Variable SOC NT-proBNP P

Global Scale -5.0 [-18-0] -10.0 [IQR -17-7] .05

≥10 point 38.8% 61.2% .03

NT-proBNP patients had larger QOL improvements

than SOC, and were more likely to have large

(≥10 point) improvements in their MLWHF scores

Selected echo results

-20

-15

-10

-5

0

5

10

15

20

% c

han

ge

LVEF

Absolute

LVEF

Relative

LV end-systolic

volume index

LV end-diastolic

volume index

SOC (N= 56)

NT-proBNP (N=60)

P <.001 P =.008

P =.06 P =.01

sST2

Acute HF: Other Tools are Inadequate…

ST2 Most Predictive of Mortality

ST2 predicted mortality

better than other

demographic variables

and biomarkers

ST2 provides valuable

information not

available from existing

tools Hypertension, CAD,

Diabetes, Ejection Fraction,

and Smoking were not

significant predictors of

mortality, but were

evaluated.

72

Rehman S, et al.. Characteristics of the Novel Interleukin Family Biomarker ST2 in Patients with Acute Heart Failure. J. Am. Coll. Cardiol. 2008;52(18):1458-1465.

Januzzi JL Jr, et al. Importance of Biomarkers for Long-term Mortality Prediction in Acutely Dyspneic Patients. Clin Chem. 2010 Dec; 56(12):1814-21. Epub 2010 Oct 4.

*HR shown if p<.05; univariate HRs are given. ST2 HR is forST2>35 ng/mL from

PRIDE dataset; additional data provided by investigators to Critical Diagnostics.

For ST2 > median, HR is 2.85.

0

0,5

1

1,5

2

2,5

3

3,5

4

ST2 > 35ng/mL

NT-proBNP> median

BNP >median

PriorCongestive

HF

NYHASeverity

(perfunctional

class)

Age (peryear)

Hazard Ratio

ST2 in Acute Heart Failure

ST2 values associated with: – More symptomatic HF – Lower EF – Higher NP levels

Not affected by age, sex, BMI, etiology of HF, AF, anemia (unlike NP’s)1

Strong association between ST2 levels at presentation and 1-year mortality – Cut-point of 30 ng/ml

1Shah et al. Circ Heart Fail 2009

73

74

Isn’t an Earlier Signal By Definition A More Clinically Useful Signal?

Acute (Pooled Acute)

ST2 Give an Earlier Signal For

Short Term Adverse Events than NPs

ST2 Relationship to Time of All Cause Mortality

in Stable, Ambulatory HF Patients

75

Cumulative Adverse Event Rates ST2 Value >35 ng/ml

for Death, Transplant or Cardiovascular Hospitalization

76

ST2 Predicts Response to Aldosterone

Blockade

ST2 predicts which patients will

benefit most from aldosterone

blockade.

Eplerenone attenuates remodeling

more in patients with a higher

baseline ST2

ST2 not only predicts outcomes but

also predict which patients will

benefit most from intervention.

77

Weir AP, et al. J. Am. Coll. Cardiol. 2010;55;243-250.

High and low ST2 separated at median.

Implicaciones

• Incuestionable beneficio del bloqueo de la

aldosterona en pacientes con disfunción

sistólica.

• La reducción de la FC con ivabradina reduce

síntomas (estabilidad) y el remodelado

ventricular.

• El uso inicial de dosis altas de diuréticos en

bolos ev es seguro y puede mejorar la

evolución en pacientes con IC aguda

Implicaciones

• En pacientes con IC y FE preservada la

mejora sintomática debe ser el objetivo, sin

olvidar un enfoque periférico

• El beneficio de la resincronización queda

claro incluso en estadíos poco sintomáticos

o asintomáticos.

• La monitorización con dispositivos de

presión o de impedancia queda relegada,

mientras que la expansión de la asistencia

ventricular es imparable.