update in the management of heart failure – evidence based

Update in the Management of Heart Failure –Evidence Based Care in 2021

Freny Vaghaiwalla Mody, MD Director, Heart Failure and Preventive Cardiology Program

Division of Cardiology, VA Greater Los Angeles Healthcare System. Professor of Medicine

David Geffen School of Medicine at UCLA

Outline Definition Epidemiology &Prognosis Classification Pathophysiology Diagnosis Prevention Treatment

“Heart failure is a complex clinical syndrome that can result from any structural

or functional cardiac disorder that impairs the ability of the ventricle to fill with or eject blood.” ( reduced stroke volume is common

pathophysiology for both systolic and diastolic HF).

ACC/AHA Guidelines

DEFINITION OF HEART FAILURE

Outline

Definition Epidemiology & Prognosis Classification Pathophysiology Diagnosis Prevention Treatment

Heart Failure (HF) statistic in USA 6.5 million Americans > 20 years with HF

91M with CV disease (Therefore HF= 7% of all CV disease) 960 K new cases annually

#1 cause of hospitalization for Medicare

8.5 % of Heart disease deaths in USA, (~ 840K deaths/year) 36% of CV deaths in the world.

50% with HF have 5 year survival ( prognosis worse than many cancers) 10-20% with advanced HF have 1 year survival Sudden death in 40% of deaths.

Medical Cost $21B (2012) >> $53B in 2030 Total ( indirect included) $31B >> $70B

**New therapeutic advances not fully embraced** -especially in the Geriatric population!!

AHA ( heart.org) and HFSA (hfsa.org) 2018

Acute Heart Failure Statistics Acute Heart Failure – Definition:

Acute HF symptoms requiring unplanned office visit, ER visit or hospitalization.

Have We Made Progress? The good news:

– In-hospital mortality 5% (↓ 40% in 10 years) – Mean length of stay 5-6 days (↓ 30% in 10 years)

The bad news:

– Readmission rates remain high • 25% within 30 days and 50% within 6-12 months

-- High mortality rates persist 5-10% at 30 days and 20-40% at 6-12 months

Despite Medical Advances, Heart Failure Hospitalization is a Worsening Epidemic

1. NIH.gov, Accessed 2016.

2. Fang J, et al. J Am Coll Cardiol, 2008. se.

SIGNIFICANT REDUCTION IN CORONARY DEATHS1

050

100150200250300350400

1980 1985 1990 1995 2000 2005 2010

SIGNIFICANT INCREASE IN HF HOSPITALIZATIONS2

-

5,000,000

10,000,000

15,000,000

20,000,000

1980-84 1985-89 1990-94 1995-99 2000-2004

THE PROBLEM: Unless focused, dramatic measures are taken, the clinical and financial burden to society is only going to escalate.

Deaths/100,000 Population Number of HF Hospitalizations with HF as Primary or Secondary Diagnosis,

by 5-year Time Period

*Study projections assumes HF prevalence remains constant and continuation of current hospitalization practices

Heart Failure is a Growing Economic Burden

HOSPITALIZATIONS AND READMISSIONS COSTS

> 1,100,000hospitalizations

for HF1

> 3,000,000hospitalizations include HF as a contributor.2

Total medical costs for HF are projected to

increase to $70B

by 2030, a 2x increase from 2013.*

50% of the costs are

attributed to hospitalization.6~5 days

average length of hospital stay3

~25%all-cause readmission within 30 days; ~50% within 6 months.4,5

se.

Despite advances in medical therapies to treat heart failure, the hospitalization rate has not changed significantly from 2000. As a result, heart failure continues to be a MAJOR DRIVER OF OVERALL HEALTH CARE COSTS.

UNITED STATES

1. CDC NCHS National Hospital Discharge Survey, 2000-10.

2. Blekcer et al. J Am Coll Cardiol, 2013.

3. Yancy et al. J Am Coll Cardiol, 2006.

4. Wxler DJ, et al. Am Heart J, 2001.5. Krumholz HM, et al. Circ Cardiovas Qual Outcomes, 2009.

6. Yancy CW, et al. Circulation, 2013.

Decompensation Events Requiring More Intensive Therapy are Associated with Higher Mortality Risk

Okumura N, et al. Circulation, 2016;133:2254-2262. .

No Event

Intensification of Therapy

Emergency Department Visit

Heart Failure Hospitalization

All decompensation events were associated with a statistically significant increase in mortality risk.

All Cause Death

Kaplan-Meier cumulative mortality curve all-cause mortality after each subsequent hospitalization for HF.

Long-term Mortality Risk Increases with Multiple Hospitalizations

Setoguchi S, Stevenson LW, Schneeweiss S, Am Heart J, 2007;154:260-264. .

1st admission(n = 14,374)

2nd admission(n = 3,358)

3rd admission(n = 1,123)

4th admission(n = 417)

Heart Failure hospitalization in USA by age 1970-2005.

CDC/NCHS AHA: Heart , Stroke and Statistics Update

Outline Definition Epidemiology & Progosis Classification Pathophysiology Diagnosis Prevention Treatment

New Classification of Heart Failure

Marked symptoms at rest despite maximal medical therapy (eg, those who are recurrently hospitalized or cannot be safely discharged from the hospital without specialized interventions)

Refractory end-stage HFD

Known structural heart disease Shortness of breath and fatigue Reduced exercise tolerance

Symptomatic HFC

Previous MI LV systolic dysfunction Asymptomatic valvular disease

Asymptomatic HFB

Hypertension CAD Diabetes mellitus Family history of cardiomyopathy

High risk for developing heart failure (HF)A

Patient DescriptionStage

Hunt SA et al. J Am Coll Cardiol. 2001;38:2101–2113.

- Based on progressive HF pathophysiology and disease process -- These complement, but do not replace functional classes

New Definition and Classification of HF by LVEF

HFrEF – reduced LVEF < 40%

HF mrEF –mildly reduced/mid-range LVEF 41-49%

HFpEF– preserved LVEF > 50%

HFimpEF– improved LVEF defined as < 40% at baseline and with > 10-point increase and improved LVEF > 40%

Management of AHF and Chronic HFGO STEPWISE AND SYSTEMATICALLY !!!

Acute or Chronic LV dysfunction?

Exclude reversable etiologies if acute LV dysfunction ( ischemia, tachycardia mediated, aortic stenosis, etc. )

Congested or not congested ?

Identify precipitating causes of decompensation in WHF or chronic HF exacerbation.

Decongestion (diuretics/ mechanical) • Diuretics ( loop, thiazides, MRA (DCT), vasopressin inhibitor tolvaptan• Ultrafiltration (UNLOAD trial)

GDMT--• Betablockers, • ACEI/ARB or Saccubutril/valsartan (ARNI)• Mineralocorticoid receptor antagonists (MRA)

• Spironolactone, eplernone• Sodium-Glucose Co-Transporter 2 (SGLT2) Inhibitors

• Dapagliflozin, empagliflozin• Vericuagat

NYHA ClassificationBased on functional exercise capacity

Class I : No limitation of physical activity or only with severe exertion.

Class II : Slight limitation of physical activity

Class III: Marked limitation of activity/ or symptoms with ADLs

Class IV: Symptoms at rest

Outline Definition Epidemiology &Prognosis Classification Pathophysiology Diagnosis Prevention Treatment

Heart failure: a changing paradigm

Normal heart Failing heart

Development and Regression of End-stage Dilated Cardiomyopathy

RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; RAS, renin-angiotensin system.

↓ Systolic function↑ LV volumes↑ LV massShape→ rounder

RAS and SNS Blockade

Injury Leading to RAAS and SNS Activation

Hall et al. J Am Coll Cardiol. 1995;25:1154-1161.

Time Course of Changesin Ventricular Function

0.20

0.25

0.30

0.35

0.40

BSLN Day 1 1M 3M BSLN Day 1 1M 3M

Eje

ctio

nFr

actio

n P<0.0001

P<0.05

P=0.013 for metoprolol vs standard therapy

Standard Therapy Metoprolol

Outline Definition Epidemiology Classification Pathophysiology Prognosis Diagnosis Prevention Treatment

Symptoms Left Heart Failure = fluid buildup in lungs

Orthopnea (shortness of breath lying flat) Dyspnea on exertion

Right Heart Failure = fluid buildup in body Epigastric fullness (stomach bloating) Dyspnea or discomfort tying shoes Anorexia (loss of appetite) Early satiety (can only eat small meals)

Low Output Symptoms Fatigue and weakness Daytime somnolence (sleepy all the time) Nocturnal sleep disorder

THE GOAL:Predict gradual decompensation leading to acute decompensation

Current HF Management Tools Designed to Predict Decompensation

FACE-TO-FACE EVALUATION PARAMETER SURROGATE FOR:

Symptoms (PND, orthopnea, etc.) LVEDP, RAP

JVP RAP

HJR RAP

S3 LVEDP

Rales LVEDP

Daily weight Body volume (LVEDP, RAP)

BNP and NT-proBNP PCWP

Intrathoracicimpedance

PCWP

Heart rate variability Cardiac autonomic control

.

Weight Change is Not a Reliable Indicator of Rising Pressure or Impending Decompensation

1. Data based on Zile MR, et al. Circulation, 2008. Presented at FDA Advisory Panel, October 9, 2013.

2. Lewin J, et al. Eur J HF, 2005.

3. Abraham WT, et al. Cong Heart Failure, 2011.

WEIGHT GAIN SENSITIVITY SPECIFICITY

2 kg weight gain over 48-72 hrs2 9% 97%

2% weight gain over 48-72 hrs2 17% 94%

3 lbs in 1 day or 5 lbs in 3 days3 22.5% -

NO CORRELATION – Daily weights do not correlate with filling pressures

Clinical Examinations are not Reliable for Assessing Rising Pressure – Poor Sensitivity and Specificity

VARIABLE ESTIMATE OF SENSITIVITY (%) SPECIFICITY (%) PPV (%) NPV (%)

JVPEDEMA

RAP4810

7894

6055

6960

PULSE PRESS Cardiac Index 27 69 52 44

S3DYSPNEAORTHOPNEAPNDRALES

PCWP365013

817390

696760

545748

Table adapted from Capomolla S, et al. Eur J Heart Failure, 2005..

N = 366

Clinical examination has LIMITED RELIABILITY in assessing filling pressures.

Absence of Specific Signs, Symptoms, and CXR Findings Doesn’t Exclude High PCWP

Ability to predict PCWP >18–20 mm Hg in pts. with severe HF

Sens. Spec. PPV NPV

Dyspnea on exertion 66 52 45 27Orthopnea 66 47 61 37Pedal Edema 46 73 79 46JVD 70 79 85 62S3 73 42 66 44CXR

Cardiomegaly 97 10 61 ---Redistribution 60 68 75 52Interstitial edema 60 73 78 53Pleural effusion 43 79 76 47

Adapted from: Chakko S, et al. Am J Med. 1991;90:353.Adapted from: Butman SM, et al. J Am Coll Cardiol. 1993;22:968.

BNP Levels of Patients Diagnosed Without CHF, With Baseline Left Ventricular Dysfunction, and

With CHFM

ean

BN

P C

once

ntra

tion

(pg/

ml)

AsymptomaticCompensated LV

Dysfunction(n=14)

38 ± 4141 ± 31

1076 ± 138

No CHF(n=139)

Decompensated CHF

(n=97)

0

200

400

600

800

1000

1200

1400

Maisel A. et al. J Am Coll Cardiol 2001;37(2):379-85

P < 0.001

Plasma BNP in some cardiovascular diseases

Hypertension +Tachycardias ( eg Afib with RVR) +Isolated diastolic dysfunction ++Mitral stenosis ++Aortic stenosis ++Dialysis-dependent Renal Failure +++Dilated cardiomyopathy ++++Hypertrophic Cardiomyopathy ++++Acute Myocardial Infarction ++++

Large variation in “normal” or optimal level Obesity Age Gender

Confounders of Naturietic Peptide interpretation

Higher NP levels than expected Lower NP levels than expected

Increasing age* Obesity

ACS* Flash pulmonary edema

Renal insufficiency Pericarditis/Tamponade

RV dysfunction* Genetic polymorphisms

Atrial fibrillation “Burned-out” Cardiomyopathy

Pulmonary hypertension*

Pulmonary embolism*

Anemia/high output states*

Sepsis

Mitral Regurgiation*

* Delineates likely elevation from Ventricular stretch

BNP and Heart FailureLimitations

20% of patients with chronic HF reported to have BNP levels <100 pg/ml.

BNP may be elevated in AA patients, Renal failure, ACS, LV diastolic dysfunction, Aortic stenosis, COPD, PPH, PE .

BNP may be reduced in obese patients.

Biomarkers willMake bad doctors worse and good doctors better!

Etiology of Heart Failureo Coronary artery disease-

Chronic ischemia “Hibernating myocardium”**

o Hypertensiono Idiopathic cardiomyopathyo Myocarditis**o Valvular heart disease-

Aortic Stenosis**o Hereditaryo Other: toxic (Alcohol, adriamycin) , o metabolic -thyroid**o Tachycardia- induced CM**o Beriberi ( Vitamin B1 deficiency)

**=Reversible causes of LV Dysfunction

Hypertension is the No. 1 risk factor for HF

20

40

60

0HTN

Population-attributable

risk (%)

MI Angina VHD LVH Diabetes

Hazard ratio M 2.1 6.3 1.4 2.5 2.2 1.8W 3.3 6.0 1.7 2.1 2.8 3.7

Men Women

Levy D at al. JAMA. 1996;275:1557-62.VHD = valvular heart disease

Framingham Heart Study

-16-21

-38

-52-60

-50

-40

-30

-20

-10

0CHF Fatal/non-fatal

strokesCVD deaths Fatal/non-fatal

CHD events

Antihypertensive Drug Treatment Reduces CHF and other CV Events

*17 randomized, placebo-controlled treatment trials (48,000 subjects)—14 diuretic and 3 beta-blocker-based trials

**All differences are statistically significant.

Hebert P, Moser M, Mayer J, Glynn RJ, Hennekens CH. Arch Intern Med. 1993;153(5):578-581.Moser M, Herbert PR. J Am Coll Cardiol. 1996;27(5):1214-1218.

Per

cent

Management of Systolic And Diastolic Heart Failure

Precipitating Causes of Acute Decompensated CHF

P — Pulmonary embolus R — Renal failure/fluid overload E — Endocarditis C — compliance *** with diet and medications I — ischemia/infarct P — pregnancy I — infection T — tachycardia mediated /temperature/fever A — arrhythmia (a.fib) /anemia T — thyroid E — environmental toxins/COPD- emphysema S — systemic HTN out of control

Heart Failure ManagementMainstay of Therapy for Systolic HF

Diuretics ACE inhibitors (ARBs) β-Blockers Aldosterone antagonists (Spironolactone, Eplerone)

Digoxin ( increases mortality >> so use for refractory symptoms and cannot tolerate other GDMT)

Newly approved Therapy for Systolic HFo Ivabradine receptor inhibitor o Neprisylin Inhibitor / ARB o SGLT2 inhibitorso Vericuguat

Diuretics and Heart Failure Diuretics are a mainstay of therapy

for heart failure Relieve symptoms of dyspnea and

edema Associated with variety of problems:Electrolyte abnormalitiesActivation of RAAS and SNSDiuretic resistance Increased mortality?

Mortality and Diuretics in Chronic CHF: SOLVD

0%

10%

20%

30%

40%

50%

All Cause CV Arrhythmic

Mor

talit

y

DiureticsNo Diuretics

Cooper HA et al, Circulation 1999

The TRANSFORM-HF Trial

ToRsemide compArisoN with furoSemide FOR Management of

Heart Failure

Background and Rationale (3) Despite pre-clinical and clinical data supporting

several benefits of torsemide over furosemide, there are no large, definitive, randomized trials comparing these therapies.

X

Adams KF, et al. Am Heart J 2005 Buggey J, et al. Am Heart J 2015 Bikdeli B, et al. J Am Coll Cardiol 2013

Mortality With Torsemide Compared With Furosemide

Background and Rationale (2)

Potential Advantages of Torsemide More consistent oral bioavailability and longer

duration of action Anti-Aldosterone Effects Anti-Fibrotic Myocardial Effects Positive Ventricular Remodeling Favorable BNP Effects Functional Status Benefits Reduced HF Rehospitalization Potential Mortality Benefits

Cosin J, et al. Eur J Heart Fail 2002Buggey J, et al. Am Heart J 2015Murray MD, et al. Am J Med 2001

Primary Objective

To compare the treatment strategy of torsemide versus furosemide on long-term clinical outcomes among patients

hospitalized for HF

Primary Endpoint:All-cause mortality

Placebo(n = 126)

Enalapril (n = 127)

Placebo(n = 1,284)

Enalapril (n = 1,285)

CONSENSUS*NYHA Class IV

SOLVD** NYHA Class II–III

80

60

40

20

00 6 12 18 24 30 36 42 48

Perc

ent (

%)

MonthsRisk reduction 27% (P = 0.003) Risk reduction 16% (P = 0.0036)

*The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429–1435. **The SOLVD Investigators. N Engl J Med. 1991;325(5):293–302.

CONSENSUS and SOLVD:Effect of ACE Inhibition on Mortality

ACE INHIBITORS - IN WHOM AND WHEN?Indications:• potentially all patients with heart failure

Contra-indications:• Angioedema, bilateral RAS, pregnancy

Cautions- but NOT contraindication (because ACEi are NEPHROPROTECTIVE!!:

• significant renal disease (creatinine > 2.5 or K+ > 5.0)• hypotension (SBP < 85 mmHg)Drug interactions to look out for:• K+ supplements/ K+ sparing diuretics (including

spironolactone)• NSAIDs* avoid!!!

Monitoring Cr and K+ with RAAS Blockade (cont.)

Changing ARB dose or discontinuing is usually NOT necessary

Persistent elevation of creatinine (>30% relative to baseline) suggests other factors: NSAID use? Volume depletion (try decreasing diuretic dose) Renal artery stenosis

Hyperkalemia can usually be corrected by restricting dietary potassium Up to 5.9 mg/dL can generally be tolerated Levels ≥6.0 mg/dL require attention, including

discontinuation of ARB, ACEI, aldosterone receptor blocker NSAID, non-steroidal anti-inflammatory drug.

ER, extended release.

Adapted from: MERIT-HF Study Group. Lancet. 1999;353:20012007.CIBIS-II Investigators. Lancet. 1999;353:913.

Packer M, et al. N Engl J Med. 2001;344:16511658.

Mortality Benefit of Beta Blockers in Heart Failure Due to Left Ventricular Systolic Dysfunction

Followup (months) Time (days)

CIBISII

Log rank P=0.00006

Bisoprolol

Placebo

n=2647

0 200 400 600 800

Prob

abili

ty o

f sur

viva

l

COPERNICUS

Surv

ival

(%)

34%Mortality: 34% 35%

Carvedilol

Placebo

P=0.00014 (unadjusted)

100

90

80

70

60

50P=0.0014 (adjusted)

n=2289

Months0 4 8 12 16 20 24 28

MERITHF

Cum

ulat

ive

mor

talit

y (%

) 20

15

10

5

0

P=0.0062 (adjusted)P=0.00009 (nominal)

Placebo

n=3991

.9

.8

.7

.6

.5

.4

.3

.2

.1

1.0

00 3 6 9 12 15 18 21

ER Metoprolol Succinate

CARMEN: Possible Mechanism of Benefit—Left Ventricle Remodeling Comparison of LVESVI

Between Treatments

-7

-6

-5

-4

-3

-2

-1

0

C & ECarvedilolEnalapril

Month 6 Month 12 Month 18

NS P<0.002

Baseline

LVES

VI (b

ipla

ne) [

ml/m

2 ]

Remme WJ. Cardiovasc Drug Ther. 2001;15:69-77.

LVESI = Left ventricular end-systolic volume index

Beta Blocker Withdrawal

Should beta blockers be stopped or the dose reduced when a heart failure patient is hospitalized for decompensated heart failure?

Contra-indications for Starting or Up-titrating a Beta Blocker

High-degree AV node block w/o pacemaker Symptomatic bradycardia Hx. asthma with active wheezing COPD with reactive component/ responsiveness to

bronchodilators (use and titrate with added caution based on risk:benefit ratio)

Bradycardic Patients: Practical Recommendations in the Use and Titration

of Beta Blockers

No data available Resting bradycardia NOT a contraindication, but

warrants caution and slower titration. Strategies frequently used by HF specialists:

– Titrate based on blunting of exercise-induced heart rate– Titrate cautiously in patients with resting heart rate <60– Titrate until symptoms occur

HFSA 2006 Practice Guideline Heart Failure in the Elderly

As in all patients, but especially in the elderly, careful attention is recommended to the following during therapy with ACE inhibitors and beta blockers:

- volume status- the possibility of symptomatic cerebrovascular disease- and the presence of postural hypotension

Strength of Evidence = C

In the absence of contraindications, these therapies are also recommended in the elderly, even the very elderly (>80 years old)

0 3 6 9 12 15 18 21 24 27 30 33 36

RALES: Randomized Aldactone Evaluation Study

From Pitt et al. N Engl J Med (in press).

0.950.900.850.800.750.700.650.600.55

1.00

0.500.450.00

No at riskPlacebo 841 775 723 678 628 592 565 483 379 280 179 92 36Spironolactone 822 766 739 698 669 639 608 526 419 316 193 122 43

30% Reductionin mortality

Months

Placebo

Spironolactone

What about Digoxin in Heart Failure?

No effect on mortality In the DIG Trial, digoxin reduced hospitalization

by 10% but increased arrhythmic deaths Digoxin can improve symptoms, exercise

tolerance in some patients Tips- Use low dose (.125 mg) and monitor carefully

When symptoms persist on ACE-i + diuretics + B-blockers, consider Digoxin

AHA / ACC Guidelines 2005

NITRO0010 — AHeFT Slides — v11

Days Since Baseline Visit Date

Hydralazine + Isosorbide dinitrateAHeFT: Trial Summary

0 100 200 300 400 500 60085

90

95

100

Surv

ival

(%)

P=.01

Fixed-dose HYD/ISDN

Placebo

Hazard ratio=0.57

Adapted from Taylor AL, et al. N Engl J Med. 2004;351:2052.

43% Decrease in Mortality

PARADIGM -Results

Ivabradine- sinus node If current inhibitor of HCN channel

SHIFT trialReduction in HF hospitalizations

Indications: LVEF < 35%, sinus rhythmn, and HR > 70bpm on max Beta-blocker tolerated doses or cannot tolerate beta-blockers

Hazard ratio (95% CI) P value

Primary composite endpoint* 0.86 (0.74-0.99) 0.04

Secondary composite endpoint† 0.89 (0.78-1.01) 0.08

Death from any cause 0.68 (0.57-0.82) <0.001

CV death 0.62 (0.49-0.77) <0.001

Fatal or nonfatal MI 0.87 (0.70-1.09) 0.23

Hospitalization for HF 0.65 (0.50-0.85) 0.002

Hospitalization for HF or CV death 0.66 (0.55-0.79) <0.001

Clinical Outcomes with Empagliflozin

61

EMPA-REG OUTCOME Pooled Analysis(N=7020)

*CV death, nonfatal MI (excluding silent MI), or nonfatal stroke; †CV death, nonfatal MI (excluding silent MI), nonfatal stroke, and hospitalization for unstable angina.

CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; MI, myocardial infarction.

Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

Favors empagliflozin

DAPA-HF Primary Outcome

Dapaglifozin vs Placebo in HFrEF with and without T2DM. Presented 9/1/19 by John McMurray At ESC , Paris, France

DAPA-HF Components of Primary Outcome


DAPA-HF Outcomes for DM vs no DM


DAPA-HF QOL Score


SGLT2 mechanism of action.

DAPA-HF adverse events


GDMT Benefits

Relative Risk 2-Year MortalityNone -- 35%ARNI 28% 25.2%Beta Blocker 35% 16.4%MRA 30% 11.5%SGTL2i 17% 9.5%

Drugs to discontinue doxazosin (probably all alpha blockers) verapamil diltiazem nifedipine Most antiarrhythmics all NSAIDS, including COX-2 agents all Alcohol in non-CAD cardiomyopathy any drug not helping is probably hurting

Hamid EG, Butler J. Timely Management of New-Onset Heart Failure The Other Vulnerable Phase doi.org: 10.1161/CIRCULATIONAHA.118.035452. Circulation. 2019;140:621–623

Evidence based therapies for HFpEF

Spironolactone for HF with Preserved EF (HFpEF) – TOPCAT trial-

SD Solomon et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1908655

PARAGON STUDY : Saccubutril/Valsartan vs Valsartan in HFpEF: Primary Composite Outcome.

Hosp for HF/Death from CV

PARAGON Result slide 2.pptPARAGON Result slide 2.pptHosp for HF

Death from CVCauses

SD Solomon et al. N Engl J Med 2019. DOI: 10.1056/NEJMoa1908655

PARAGON Study: Primary Outcome in Prespecified Subgroups.

The CHAMPION Trial Design TRIAL HYPOTHESIS

In addition to basing treatment on signs and symptoms, adjusting medications based on PA pressures will reduce HF-related hospitalizations.

.

76

1. Abraham W, et al. Lancet, 2011.2. Abraham W, et al. Lancet, 2016.

CardioMEMS™ PA SENSOR IMPLANTED n = 550

TREATMENT GROUPn = 270

CONTROL GROUPn = 280

TRANSITION TO FORMER TREATMENT

GROUPn = 177

TRANSITION TO FORMER CONTROL

GROUPn = 170

PART 1: RANDOMIZED ACCESS1

Study exitN = 110

Study exitN = 93

PART 2: OPEN ACCESS2

Previously hospitalized patients (past 12 months) with NYHA Class III HF for at least 3 months, regardless of LVEF

575 consented. 25 could not be implanted due to anatomy, comorbidities, etc.

All took daily readings.

Randomization

Primary Efficacy Endpoint Met with Significantly Reduced Heart Failure Hospitalization

PART 1: RANDOMIZED ACCESS

Abraham W, et al. Lancet, 2016. .

00.20.40.60.8

11.21.41.61.8

2

0 90 180 270 360 450 540 630 720 810 900 990 1080

Cum

ulat

ive

Haza

rd R

ate

Days From Implant

33% RELATIVE RISK REDUCTION IN HF HOSPITALIZATIONS:TREATMENT GROUP VS. CONTROL GROUP

TREATMENT

CONTROL

No. at RiskCONTROL 280 267 254 241 210 175 131 101 62 27 12 5 0TREATMENT 270 262 246 235 197 164 125 105 75 38 8 3 0

p < 0.0001

CARDIOMEMS – Most proven device for outcomes benefit.

HFpEF

HFrEF

79

The CardioMEMS™ HF System is indicated for HF patients who are NYHA Class III, regardless of ejection fraction, who have been hospitalized for heart failure in the previous year.

.

INDICATIONS

Incidence of Sudden Death

0 5 10 15 20 25 30 35

Overall incidencein adult population

High coronary risksubgroup

Any prior coronary event

Percent/year

EF <30% HF

Out-of-hospital cardiac arrest survivors

Convalescent phaseVT/VF after MI

Myerburg RJ, Castellanos A. Cardiac arrest and sudden death. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia, PA: WB Saunders; 1997:742-779.

0 5 10 15 20 25 30 35

Mortality Benefit of ICD Trials in Symptomatic HF

Population Follow up RR vs standard therapy

MIRACLE III–IVLVEF ≤35%

6 months 27%

MADIT II II–IIILVEFV ≤30%

2 years 31%

SCD-HEFT II–IIILVEF ≤35%

5 years 23%

Abraham, et al. NEJM. 2002;346:1845-1853.Brady, et al. NEJM. 2005;352:225-237.

Zareba, et al. Am J Cardiol. 2005;95:1487-1491.

Therapies Demonstrated to ReduceMortality in Heart Failure

• ACE Inhibitors (ARB)

• Beta Blockers

• Aldosterone Antagonists

• Hydralazine-Isosorbide dinitrate

• Neprisylin Inhibitor-ARB combination LCZ696

• ICD (LVEF < 35, Class II or II)

• Cardiac Resynchronization (LVEF < 35, QRS > 120 ms, Class III or IV)

• SGLT2 Inhibitors1. The CONSENSUS Trial Study Group. N Engl J Med. 1987;316:1429–1435.2. Packer M et al. N Engl J Med. 1996;334:1349–1355.3. Pitt B et al. N Engl J Med. 1999;341:709–717.4. Moss A et al. N Engl J Med. 1996;335:1933–1940.5. Abraham WT et al. N Engl J Med. 2002;346:1845–1853.6. Zinman B, et al. N Engl J Med. 2015;373:2117-2128.

Intravenous Inotropes & Antiarrhytmics

All appear to increase mortality

Use only in refractory Heart Failure

NOT for use as chronic therapy

Conclusion Physicians should identify and aggressively treat

patients with CV risk factors or early HF- HTN most important.

BNP very helpful due to reduced accuracy of Sx and PE

Beta blockers, ACEI, and spironolactone should be routinely prescribed to clinically stable patients with HF (NYHA Class II to stable Class IV) who have LVEF <40% and are on standard therapy with ACE inhibitors (with or without digoxin or diuretics).

Role of new drugs (LCZ696 and ivabradine) to evolve.

Stem cell regeneration hold most promise in chronic heart failure

update in the management of heart failure – evidence based

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