Newer Pharmacological Management of Heart Failure

Dr. P.K Hazra

Heart Failure – The Disease of the Presidents

MI, CHF MI, CHF RR, Stroke CAD, Stroke,

CHF

MI, CHF Stroke,

MI, CHF

Stroke,

MI, CHF

CHF MI, CHF

14 arrest

MI, CHF,

SCD

CHF,

Stroke

MI, CHF AFib

MI, CHF

CABG

/

CAD

Obese

healthy

1985

EF WASBORN;BRAUNWALD

HFpEF vs HFrEF

Eur Heart J. 2014 Apr;35(16):1022-32.

COLOUR TEST

CLASS 1 IIa IIb III gap

ACEI.ARB.ARNI IV IRON

SGLT2

PA MONITOR

Jacc 121017

ROSIGLITAZON MITRA CLIP COAPT MR

BB METFORMIN CEN SLEEP APN

MRA IVABRADINE LVAD ALPHA BLOCK STITCH DATA

DIURETICS SILDENAFIL ICD IN ELDERLY

CILOSTAZOLE

QRS >150 QRS 130-150 QRS<130 Arni in 36 hrs

No ARNI

saxagliptin

.

Prematurely stopped trials

• JUPITER

• COPERNICUS

• FAME

• SPRINT

• PARADIGM

• PARAMI

• CREDENCE

Best P value in the medical history

BB(MERIT HF) ARNI(2 drugs)

ACM + HFH p= 0.0 0 0 0 0 0 8 0.0 0 0 0 0 0 4

Even then the effect of one drug isP=0.0008 ( my conclusion)

PARADIGM-HF: Primary outcomeCardiovascular death or heart failure hospitalization

40 HR: 0.80 (0.73, 0.87)

p = 0.0000004 Enalapril 1117

30 (n=4212)

914

By 30 days

0.65 ( 0.45, 0.93)

P=0.019

Sacubitril/valsartan

(n=4187)

10

00 180 360 540 720 900 1080 1260

At risk Days after Randomization

Enalapril: 4212 3883 3579 2922 2123 1488 853 236

LCZ696: 4187 3922 3663 3018 2257 1544 896 249

McMurray, Packer et al. N Engl J Med 2014; 371(11):993-1004

Cu

mu

lative

Pro

po

rtio

no

fP

atie

nts

with

Po

int

(%)

Cv death

• EPA ( FISH OIL) 20%

• ARNI=20%(over and above ACEI)

• VICTOZA=22%

• EPLERENONE=27%

• ALDACTONE=31%

• EMPA= 38%

• ACEI 18% SOLVD

25%(CONSENSUS)

• BETA BLOCKERS

• ICD

• CRT

• MITRA CLIP

• PRIMARY ANGIOPLASTY

PARADIGM HF NUMBERS nothing less than 15% over and above good dose of enalapril

Primary20% cv death or hospitalisation20% cv deaths21 %hospitalisationSecondary

16% all cause deathSuperior QOL ;improved NYHA class

Takes care of BB intolerance; more benefits with lower dose or no BB? BB blunting effect on ARNI

15%

21%

39%

Arni takes care of MRA NAIVITY

BONUS

1. Intensification of home medicine=16%

2. ED visits = 34%

3. First hospitalisn within 30 day =40%

4. RE Hospitalisation 2nd 3rd 4th

5. iv ionotropes ICU 31%

6. Need for TX/LVAD/CRT=22%7. IS THERE ANY HARM?

Arni benefits all1. Irrespective of Ef%2. Age3. PRO BNP4. Low or high Bp5. Diabetes no diabetes6. ICD NO ICD7. Full dose low dose BB no BETA BLOKERS 8. AF no AF unlike BB

/

Max dose

Bb s -arb )

Diu

retics t

o r

elie

ve s

ym

pto

ms a

nd s

igns

of congestion

If L

VE

F ≤

35%

despite O

MT

or

a h

isto

ry o

f

sym

pto

matic V

T/V

F, im

pla

nt

ICD

Still symptomatic and LVEF ≤ 35%

Class I

Class IIa

Still symptomatic and LVEF ≤ 35%

Add MRA

)

Yes

Able to tolerate ACEI

(or ARB)

Sinus rhythm, QRS

duration ≥ 130ms

Sinus rhythm, QRS

HR ≥ 70 bpm

ARNI to replace ACE-I Evaluate

CR

Ivabradineneed for

T

No

Yes

BB in all ; when we know now that bbDoes not work in AF; presumably All arein NSR = class1 for bb even in af!

No further action required

Consider reducing diuretic

Dose

STAY HAPPY BE LUCKY

No

ESC 2017

/

Max tolerated ACEi , BB)

Diu

retics t

o r

elie

ve s

ym

pto

ms a

nd s

igns

of congestion

If L

VE

F ≤

35%

despite O

MT

or

a h

isto

ry o

f

sym

pto

matic V

T/V

F, im

pla

nt

ICD

Still symptomatic EF<35Class I

Class IIa

Still symptomatic and LVEF ≤ 35%

Add MRA)

Yes

Able to tolerate ACEI

(or ARB)

Sinus rhythm, QRS

duration ≥ 130ms

Sinus rhythm, QRS

HR ≥ 70 bpm

ARNI to replace ACE-I Evaluate

CR

Ivabradineneed for

T

NoYes

BB in all ; when we know now

that bb

Does not work in AF; presumably

all are in NSR

ESC 2017

ESC2016 in symptomatic patients EUROPE

I1I B

ambulatory remain symptomatic despite s- ARB, BB then MRA= 3 drug(optimize)

ASYMPTOMATIC, STABLE NO ACTION REQUIRED!Adjust diureticsLet them die in awaiting of better drug ARNI!

.

Eur J Heart Fail. 2016 May 20. doi: 10.1002/ejhf.592.

I

/

Max tolerated ACEi , BB)

Diu

retics t

o r

elie

ve s

ym

pto

ms a

nd s

igns

of congestion

If L

VE

F ≤

35%

despite O

MT

or

a h

isto

ry o

f

sym

pto

matic V

T/V

F, im

pla

nt

ICD

Still symptomatic and EF≤ 35%

Class I

Class IIa

Still symptomatic and LVEF ≤ 35%

Add MRA

)

Able to tolerate ACEI

(or ARB)

Sinus rhythm, QRS

duration ≥ 130ms

Sinus rhythm, QRS

HR ≥ 70 bpm

ARNI to replace ACE-I Evaluate

CR

Ivabradineneed for

T

No

Yes

BB in all ; when we know now that bb

Does not work in AF; presumably all are in NSR

ESC 2017 Myths of sequence of pathwayActivation !!!First ACEI/ARB then BB then MRA

Second time unlucky!Missing the best drugARNI.Stay on inferior ACEIUnnecessarily on BBif some body in AF

PARADIGMERS continued to get benefits even after achievingStable asymptomatic status

STEP CARE DRUG SUGGEST step wise activation?

ACEI/ARB pathSYMPATHETIC SYSTEMMRA PATHNeprilysin pathFunny channel

Go through the parade of tolearnce in USA

I B-R

sympt. class II - III who tolerate an ACE/ARBI m, replace by an ARNI Go through the test of tolerance for 1 m.

2016 ACC/AHA/HFSA more LIBERAL /PRAGMATIC THAN ESC

Yancy CW, et al. Journal of the American College of Cardiology (2016), doi: 10.1016/j.jacc.2016.05.011

Substitute ACEi/ARB with ARNI

Trends in the Rate of Sudden Death across Trial Groups over Time.

Shen L et al. N Engl J Med 2017

NEJM

JULY 2017N=40,195N=40,1

95

N=40,195

N=40,195

Two Ancient disorders

DM CHF

Ebers papyrus (1550 BC), Egyptian medical reports1. Condition of "passing too much urine"

2. “When thou examinest the obstruction in his abdomen and thou findest that he is not in a

condition to leap the Nile, his stomach is swollen and chest asthmatic, then say thou to him:

it is blood that got itself fixed and does not circulate.”

Discovered in 1862 by George Ebers, German Egyptologist

Diabetes in hf trial ;otherside of same coin

HF

MERIT 24.5%

VAL-HEFT 25.4%

SOLVD 25.8%

CORONA 29.5%

EMPHASIS 31.4%

PARADIGM 34.7%GWTG –HF REGISTRY 44%

OPTIME hospitalised 44.2%

VMAC hospitalised 47%

Heart failure in diabetes trial EF

CVD REAL3%

CVD NORDIC 5%

EMPA 10%

SAVOR TIMI 13%

CANVAS 14%

TECOS/ LEADER 18%

EXAMINE 23%

sustain 6 23.6%

.

Pump pipe pee

Heart-Failure2nd Commonest Initial CV Presentation

in T2DM 1.9 million cohort

Shah D et al. Lancet. 2015 Feb 26;385 Suppl 1:S86.

AAASAHLess

PAD FIRST

evidence for hospitalized hf pt.

• ACEI or ARB: No trials

• MRA: Limited evidence from observational, single-center study (n=685);

patients

discharged after admission for AHF

o Delayed initiation of MRA therapy (30–90 days post-discharge)

is associated with a significant increase in 6-month and 1-year mortality vs.

initiation in hospital1

• Beta-blocker: Open-label IMPACT-HF study (n=363) showed trend for benefit

from in- hospital initiation of carvedilol vs. initiation of any beta-blocker >2

weeks after discharge

in patients hospitalized for AHF

ACEI, angiotensin converting enzyme inhibitor; AHF, acuteheart

failure; ARB, angiotensin receptor blocker; HF, heart failure;

MRA, mineralocorticoid receptor antagonist; RCT, randomized

clinical trial

1. Rossi et al. J Renin Angiotensin Aldosterone Syst 2015;16(1):119–25; 2.

Gattis et al. J Am Coll Cardiol 2004;43(9):1534–41

TRANSITION study designDown-titration or temporary discontinuation of sac/val is allowed in all groups at any time

Hospital

admission

for ADHF

3 strata

ACEI+OMT

ARB+OMT

36 hACEI

washout

Any OMT as

per treating

physician

PRE-discharge initiation

Open-label

Sac/val 50 mg 100 mg b.i.d. 200 mg b.i.d.

or

Sac/val 100 mg 200 mg b.i.d.

as per label and at investigator discretion

OMT continued throughout the study (excluding ACEI/ARB)

POST-discharge initiation

OMTbut

ACEI/ARB

naïve patients

Patient stabilized

36 hACEI

washout

Any OMT as

per treating physician

Discharge

max. 2 weeks

Open-label

Sac/val 50 mg 100 mg b.i.d. 200 mg b.i.d.

or

Sac/val 100 mg 200 mg b.i.d.

as per label and at investigator discretion

OMT continued throughout the study (excluding ACEI/ARB)

1–3 days’

screening period

Treatment period

10 weeks’ starting at randomization

16 weeks’ follow-

up period

ACEI, angiotensin converting enzyme inhibitor; ADHF, acutedecompensated heart failure; ARB, angiotensin receptor blocker; b.i.d,

twice daily; HF, heart failure; OMT, optimal medical treatment for HF;sac/val, sacubitril/valsartan

Pascual-Figal et al. ESC Heart Fail. 2018;5(2):327–36

Ran

dom

izati

on

toP

RE

-or

PO

ST

-dis

charg

e

Op

en-l

ab

elS

ac/

val

at

tole

rate

dd

ose

• Comparable proportions of patients met the primary and secondary endpoints in

the pre- and post-discharge initiation groups

• About half of HFrEF patients stabilized after an ADHF event achieved

the target dose of 200 mg sacubitril/valsartan b.i.d. within 10 weeks

• At week 10, more than 86% of patients in both groups were receiving any dose for

2 weeks or longer without interruption

• Incidence of adverse events and discontinuations due to AEs was similar

in in-hospital and ambulatory initiation groups

The initiation of sacubitril/valsartan in a wide range of HFrEF patients,

early after an ADHF event was feasible and overall well tolerated.

Feasibility and safety were similar if initiation was in hospital or shortly after discharge.

b.i.d., twice daily; HFrEF, heart failure with reduced ejection fraction

Transition in hospitalized pt.

ESESC Guidelines HF 2016 recommend consideration of i.v.FCM to t iron deficiency in HFrEF

ESC, European Society of Cardiology; FCM, ferric carboxymaltose; HF, heart failure;

HFrEF, heart failure with reduced ejection fraction; TSAT, transferrin saturation.

Ponikowski P, et al. Eur Heart J. 2016;37:2129–200.

Iron deficiency – predictor of poor response

to CRT

• 48 patients (age: 63 yrs, median LVEF: 26%, NYHA class II/III: 60/40% with CRT implanted

• A lack of response to CRT: a lack of reduction in the LVESVI by ≥ 15% at 6 months

Prevalence of iron deficiency

80

(% patients)

Multivariate analysis:

• iron deficiency: OR – 4.10 (1.02-15.61), p=0.0360

40

20

p=0.003• non-LBBB: OR – 5.84 (1.27-26.84), p=0.02

as independent predictors of non-response to CRT

CRT non-responders CRT responders

CRT, cardiac resynchronisation therapy; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction;

LVESVI, left ventricular end-systolic volume index; OR, odds ratio; NYHA, New York Heart Association Bojarczuk J et al. IJC 2016;222:133-134

Meta-analysis on individual patient data with FCM:efficacy outcomes

Rate ratio analysis (recurrent event analyses)

Recurrent event outcomesFCM*

(N=504)

Placebo*

(N=335)Rate Ratio (95%CI) p

hospitalizations and CVD 69 (23.0) 92 (40.9) 0.59 (0.40-0.88) 0.009

HFH and CVD 39 (13.0) 60 (26.7) 0.53 (0.33-0.86) 0.011

CV hospitalizations and ACD71 (23.7) 94 (41.8) 0.60 (0.41-0.88) 0.009

HFH and ACD41 (13.7) 62 (27.6) 0.54 (0.34-0.87) 0.011

All-cause hospitalizations and

ACD108 (36.1) 118 (52.5) 0.73 (0.52-1.01) 0.060

HFH 22 (7.3) 43 (19.1) 0.41 (0.23-0.73) 0.003

CV hospitalizations 52 (17.4) 75 (33.3) 0.54 (0.36-0.83) 0.004

All-cause hospitalizations 89 (29.7) 99 (44.0) 0.71 (0.50-1.01) 0.056

*Total number of events (incidence per 100 patient-years of follow-up)

CI, confidence interval; CV, cardiovascular; FCM, ferric carboxymaltose; HF, heart failure.

Anker SD et al. Eur J Heart Fail. 2017:doi:10.1002/ejhf.823.

41%47%

40%

ESCVDLessons learned…

Is it necessary?

Would you take a chance and drive without a seatbelt?

You never know whenyou”ll need protection!

ESCVDLessons learned…

Is it necessary?

Would you take a chance and drive without a seatbelt?

You never know whenyou”ll need protection!

Would you drive a while and then wear seat belt?

Can SGLT2i /GLP1 RA be started in hospitalized pt.?

META ANALYSIS OF 3 MUSKETEERS ;ATHOS ,PORTHOS ,ARAMIS

trial TOTAL MACE CVDTOTAL Pop

CVD/HHFTOTAL popln

EMPA 14% 38%

CANVAS 14% 13% 22%

DAPA 7% 2% 17%

CREDENCE 20 % DMS 22% p=ns credence 31%(cvd/hfh)39%(hfh) credence

ESCVD MACE ESCVDCVD

ESCVDCVD/HF

EMPA 14 % 38% 34%

CANA 18% 15% 23%

DAPA 10% 6% 17% co-primary

META-NALYSIS =14% =20% =24%

META ANALYSIS OF 3 MUSKETEERS ;ATHOS ,PORTHOS ,ARAMIS

trial TOTAL MACE CVDTOTAL Pop

CVD/HHFTOTAL popln

ACD Renal outcomecomposite

EMPA 14% 38% 32%

CANVAS 14% 13% 22%

DAPA 7% = 11% 2% 17% 7%

CANA CREDENCE

20 % DMS 22% p=ns credence

31%(cvd/hfh)39%(hfh) credence

17% p=ns Credence34%

ESCVD MACE ESCVDCVD

ESCVDCVD/HF

primaryCVD /HF

MI

EMPA 14 % 38% 34% NA 13%

CANA 18% 15% 23% 17% 21%

DAPA 10% 6% 17% co-primary 16% co-primary 13%

META-NALYSIS =14% =20% =24% =16% =15%

Rule of 3

• Canvas 1/3 rd primary

• Declare 1/3 rd secondary

• EMPAREG death reduced by 1/3 rd

• ACD reduced by 1/3 rd empa

• cvd or hfh reduced by 1/3 rd empa/credence

• Hfh reduced by 1/3 in empa /credence

• Worsening nephropathy reduced by 1/3rd

Rule of 1/3rd

• Metformin naivity =1/3rd in cvot trials

• Gfr cut-off so far= 1/3 rd of normal

• Renal death reduced by 1/3rd in credence

• HFH redu

• CVD REAL DEATH / HFH REDUCED BY 1/3 RD

• Diabetic population in PARADIGM HF =1/3rd

ARNI Adds life to years and Years to life

•1.5 to 2yrs all across

•much higher than any cancer therapy where this acturial methods asked by insurance .

•after age 45 survival . ARNI - ENAL (12.9-11.6)= 1.3yrs

•after age 65 , (11.4-10.0)= 1.4 yrs

•freedom from primary event 2.1 yrs after age 45 and 1.3 after age 65

STRatifying therapies based On NT-

proBNP and GDF-15 in Heart Failure

[STRONG-HF]

Finding the balance between costs and quality

in heart failure: a global challenge

2.5 5.0 Length of stay (d) 10 12.5

Cerlinskaite K et al. Eur J Heart Failure Aug 2018

All

-cau

sere

ad

mis

sio

nra

te(%

)

.

Guerra F et al. BioMed Research International 2017

Sakubitril/valsartan therapy prolongs

life free of primary composite eventEstimated lifetime free of primary composte endpoint according to age group and treatment arm

Difference betweentreatment arms

Enalapril LCZ696

0.3

14

12

10

8

6

4

2

LCZ696

Enalapril

1.2

1.5

1.6

1.6

2.2

2.5

0 40 50 60 70 80 1.2

Age (years)

Survival time (years)

Claggett et al. N Engl J Med. 2015 Dec 3;373(23):2289-90

Su

rviv

al

tim

e(y

esrs

)

Ag

e(y

ears

)

Hfref EF <40 % algorithm for next decade before discharge from ADHF or in officeor in clinicsClass 1 for NSR

1. EPLERENNONE2. ARNI3. CARVEDILOL4. SGLT2 in diabetics5. (valsartan/ enalapril in place of ARNI when

economically challenged)

a. Start low go slow except MRAb. Reassess after 4wks1 Symptomatic class2.Objective assessment3.Drug side effect4.Counselling for adherence5.Exercise6.treat co –morbidty7.Education on potassium care8.Reduce diuretics9. Gfr /10 = every n= monthly gfr10. Try to Accommodate ivabradine now

AF1.Can drop carvedilol if not hypertensive2.Can go for rate control with amiodarone3.Consider AF ablation4.Add noacs

IRON deficiencyIV megadose of FCM iron

CRT-p in all if QRS at 3 months of MGDMT =>140 ms and ef still <35%CRT-D in young and elderly ischemic DCM

Source dr pk hazra amri

Thanks for your attention!