dr. p.k hazra · paradigm-hf: primary outcome cardiovascular death or heart failure hospitalization...
TRANSCRIPT
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!