The Intersection of HFrEF, HFpEF and Sex

Jonathan Howlett

Libin Cardiovascular Institute

CV Resp SCN

Speaker DisclosureDr. Jonathan Howlett

Relationships with commercial interests:

• Grants/Research Support: AstraZeneca, Merck, Servier, Pfizer, Novartis, CVRx, Medtronic

• Speakers Bureau/Honoraria: Otsuka, Bayer, Forrest.

• Consulting Fees: General Electric, Government of Canada, Alberta

• Other: Nil

I ALWAYS TALK ABOUT OFF-LABEL USE

OF MEDS – ESPECIALLY TODAY!!

2

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes

2. Response to therapy

3. Implications

Daubert, JACC HF 2019

Improving Case Fatality for HF Over Past 10 Years

5

Men Women

12%

8%

4%

0%

2004 2006 2008 2010 2012

Calendar years

2004 2006 2008 2010 2012

Type 2

Type 1

No diabetes

12%

8%

4%

0%

J Am Coll Cardiol HF 2019;7:239–49

Data from the Swedish Heart Registry (n= 42,987)

Higher unadjusted male survivalExcept HFrEF

But lower adjusted rateAt all EF values

J Am Coll Cardiol HF 2019;7:239–49

J Am Coll Cardiol HF 2019;7:239–49

• 12,058 men and 3,357 women enrolled in 2 large HF with reduced ejection fraction(HFrEF) trials

• PARADIGM-HF (ACEi v. ARNi) and ATMOSPHERE (DRI v. ACEi v. Both) trials

• Both with nearly identical inclusion criteria

• Outcomes adjusted for prognostic variables including NT-pro-BNP

J Am Coll Cardiol 2019;73:29–40

J Am Coll Cardiol 2019;73:29–40

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes

1. Women present later, with more comorbid conditions, HF driven by BMI, lack of activity, HTN, DM and with higher LVEF.

2. Women are treated less aggressively with respect to ACE and Device therapy

3. Women experience greater symptom burden, with more symptoms, yet have lower mortality, and hospitalizations.

2. Response to therapy

3. Implications

• “98 percent of us will die at some point in our lives.” • Will Ferrell Talladega nights

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes

2. Response to therapy

3. Implications

Studies of ACE, ARB, MRA, BB, ICD, CABG have shown no

interaction with sex in any trial with HFpEF

HFrecEF (> 10% improvement) in Alberta

Early Survival Benefit

Influence of sex on outcomes

A post-hoc analysis of the TOPCAT study

Dashed lines represent 95% CI; primary outcome: composite of CV death, aborted cardiac arrest, or hospitalization for HF

Treatment effect of spironolactone

in TOPCAT for men (blue) and

women (red) (patients with LVEF

≥45% [range 44% to 85%]; N =

3444)

8060 70

Ejection fraction (%)

Primary outcome

4

3

2

Fa

vo

rsp

lace

bo

Fa

vo

rssp

iro

nola

clo

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5040

Tre

atm

en

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ffect

incid

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ce

rate

rati

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1

Solomon S, et al, Eur Heart J. 2016;37:455–462 25

Men

Women

MED/ENT/0430

Merrill- TOPCAT

Miranda Merrill et al. JCHF 2019;7:228-238

Phenotypes and outcomes in TOPCAT

Jordana B. Cohen et al. J Am Coll Cardiol HF 2020;j.jchf.2019.09.009

HF hospitalizations and CV Death

55

50

45

40

35

30

25

20

15

10

5

0

Me

an

Cu

mu

lati

ve

Eve

nts

pe

r 1

00

pa

tie

nts

0 1 2

Years3 4

0.55

0.50

0.45

0.40

0.35

0.30

0.25

0.20

0.15

0.10

0.05

0.00

Pro

po

rtio

n

0 1

Heart Failure Hospitalizations*

2Years

3 4

Cardiovascular Death*

Valsartan

Sacubitril/Valsartan

212 (8.9%)

204 (8.5%)

Hazard Ratio 0.95 (0.79, 1.16), P = 0.62†

Valsartan 797

Sacubitril/Valsartan 690

*Semiparametric LWYY method†p-values not included in manuscript, but were included in the ESC Hotline presentation

Solomon S, et al. N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908655

Rate Ratio 0.85 (0.72, 1.00) , P = 0.056†

PatientsEvents

29

MED/ENT/0430

Primary endpoint:Ejection fraction and gender are significantlyheterogeneous in multivariate analysis

In a multivariable model incorporating all interaction terms and

covariates, only interactions for sex and ejection fraction

remained nominally significant (p < 0.003 for both)

CI, confidence intervals; LVEF, left ventricular ejection fraction

30

Solomon S, et al. N Engl J Med. 2019 Sep 1. doi: 10.1056/NEJMoa1908655MED/ENT/0430

Outcomes in PARAGON HF according to sex

Circulation. 2020;141:338–351. DOI: 10.1161/CIRCULATIONAHA.119.044491

Outcomes in PARAGON HF according to sex

Circulation. 2020;141:338–351. DOI: 10.1161/CIRCULATIONAHA.119.044491

Outcomes in PARAGON HF according to sex

• No sex interaction with (or change in)• BNP level

• Weight

• BP & pulse pressure

• NYHA class

• Potassium

• Sides effects

• Discontinuation of study drug

Circulation. 2020;141:338–351. DOI: 10.1161/CIRCULATIONAHA.119.044491

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes

2. Response to therapy1. HFrEF- Women are treated less aggressively, experience greater symptom burden,

lower event rates and demonstrate better reverse remodelling to EBMT

2. HFpEF- Women are older with higher LVEF and more comorbidities, experience lower event rates and may derive benefits from medications

3. Is this chicken or egg? Should EF (like anemia) be defined differently according to sex.

3. Implications

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes

2. Response to therapy

3. Implications

Exercise activity over time and incident HF risk

Volume of Exercise and Risk for Clinical Events after 90 Days

Risk Reduction Per 1 MET-hr/wk

HR (CI) * 2 p-value

All-Cause Death or

All-Cause Hospitalization

0.95

(0.92-0.98)8.8 0.003

CV Death or

CV Hospitalization

0.95

(0.92-0.99)6.8 0.009

CV Death or

HF Hospitalization

0.89

(0.84-0.94)16.7 <0.0001

* Adjusted Cox proportional hazards model

Objectives

Describe FH, specific to women and EF in terms of:1. Risk factors, presentation, outcomes2. Response to therapy3. Implications

1. Like HFrEF and HFpEF, which are not the same, men and women are also meaningfully different

2. Due to numerous differences between M/F in HF, Sex must be an a priori stratified variable; adequate numbers of women must be included to allow for sex-based analysis

3. Increased awareness of presentation features of women in HF especially activity level, BMI and QOL

4. Increased use of EB Therapies of all types, since women respond them, if anything, BETTER