Definition of HFPEF Reasons for Failure in HFpEF 2013 AHA ACC HF - - PDF document

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Definition of HFPEF Reasons for Failure in HFpEF 2013 AHA ACC HF - - PDF document

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9/30/16 Which patient below has HFPEF? Heart Failure with Preserved Ejection All four patients present with exertional dyspnea, Fraction LVEF > 50%, no valvular abnormalities, no CAD. What is it and What Should We Do About it? A. 55 WM w/

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Heart Failure with Preserved Ejection Fraction

What is it and What Should We Do About it?

James C. Fang, MD University of Utah Health Sciences Center Salt Lake City, UT

Which patient below has HFPEF? All four patients present with exertional dyspnea, LVEF > 50%, no valvular abnormalities, no CAD.

  • A. 55 WM w/ BMI 38, HTN, 1+ edema
  • B. 70 BF with BMI 35, HTN, DM, arthritis and LVH
  • C. 86 WF with afib, anemia, LAE
  • D. 70 BM with CKD, “COPD”, RVSP 50

Reasons for “Failure” in HFpEF

  • 1. Wrong patients
  • - Unclear definition of condition
  • 2. Wrong intervention
  • - Neurohormonal activation?
  • 3. Wrong endpoints
  • - Multiple comorbidities, QoL?

Definition of HFPEF

2013 AHA ACC HF Guidelines, EF >50%

  • “…also referred to as diastolic HF. Several

different criteria have been used to further define HFpEF. The diagnosis of HFpEF is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF. To date, efficacious therapies have not been identified."

Yancy CW, et al. Circulation 2013

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HFPEF: Diagnosis of Exclusion

  • Constriction
  • Restriction
  • Mitral valve disease
  • CAD
  • Chronotropic

incompetence

  • Aortic valve disease
  • Pulmonary
  • Thoracic
  • PAH
  • Deconditioning
  • Anemia
  • Neuromuscular
  • “Volume overload”

ESC HF Guidelines 2012

(LOE: C)

HFPEF in Clinical Trials

How do they define it?

Trial Age EF S/Sx Hosp? Data CHARM >18 40 Yes Y No I-PRESERVE >60 45 Yes Y or N X, E, K PEP-CHF >70 45 Yes N Echo TOPCAT >50 45 Yes Y or N BNP

Limitations of Ejection Fraction to Define HFPEF

  • What is a ‘Preserved’ EF is Not Clear
  • Assumes mutually exclusive domains of systolic

and diastolic function

  • Current guidelines define EF 41 – 49% as

intermediate cohort (Yancy, Circ 2013)

  • Patients with EF 40 – 55% more similar to patients

with EF <40% (Sweitzer, AJC 2008)

  • Misclassification common (e.g. ‘recovered EF’

patients) (Punnoose, JCF 2011)

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Misclassification of EF

Comparison to a Core Lab

Shah AM, et al. JACC CV Img 2012

Diastolic Dysfunction May Not Be Specific for HFPEF

Redfield MM, et al. JAMA 2003;289:194

HFPEF in TOPCAT

Heterogeneity of Structure and Function

  • Mean LVEF 59.3±7.9%
  • Concentric LV remodeling (34%) and hypertrophy (43%)
  • Left atrial enlargement (53%)
  • Diastolic dysfunction was present in 66% of gradable

participants

– associated with greater left ventricular hypertrophy and a higher prevalence of left atrial enlargement

  • Doppler evidence of PH was present in 36%
  • At least 1 measure of structural heart disease was

present in 93% of patients

Shah AM, et al. Circulation HF 2014

SYMPTOMS

(>1 at screening)

SIGNS

(>1 in the last 12 mos)

  • Paroxysmal nocturnal

dyspnea

  • Orthopnea
  • Dyspnea on mild or moderate

exertion

  • Any rales post cough
  • Jugular venous pressure

(JVP) ≥ 10 cm H2O

  • Lower extremity edema
  • Chest X-ray demonstrating

pleural effusion, pulmonary congestion, or cardiomegaly

TOPCAT

Definition of Heart Failure (LVEF > 45%)

At least one hospitalization in last 12 months for which HF was a major component OR Elevated BNP>100 pg/mL or N-terminal pro-BNP>360 pg/mL within the last 30 days

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Mohammed SF, et al. JACC-HF. 2014;2(2):113-122

Amyloid in HFPEF

may be more common than you think…

OR 3.8 5% w wTTR amyloid 12% w/ mild wTTR deposition but severe fibrosis

HFPEF: Abnormality of Systole

Norman HS, et al. J Card Fail 2011

HFPEF and chronotropic incompetence

Borlaug BA, et al. Circulation 2006;114:2138-2147

HFpEF and Obesity

High Output HF?

Reddy Y, et al. JACC 2016

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Reasons for “Failure” in HFpEF

  • 1. Wrong patients
  • - Unclear definition of condition
  • 2. Wrong intervention
  • - Neurohormonal activation?
  • 3. Wrong endpoints
  • - Multiple comorbidities, QoL?

Clinical Trials in HFpEF

CHARM-PEF iPRESERVE PEP-CHF SENIORS (s) Therapy Candesartan Irbesartan Perindopril Nebivolol Age (yrs) > 18 (67) ≥ 60 (72) ≥ 70 (76) ≥ 70 (76) EF (%) ≥ 40 (54) ≥ 45 (59) ≥ 40 (65) ≥ 35 Patients (n) 3,023 4,128 850 752 Female (%) 40% 60% 55% 38% Death/HF hosp 0.89 (0.77- 1.03) 0.95 (0.86- 1.05) 0.92 (0.70- 1.21) 0.82 (0.63- 1.05)

HFpEF: Things That Don’t Work

A partial list…

  • ACEi
  • ARBs
  • Beta blockers
  • Calcium channel blockers
  • Nitrates
  • Sildenafil

TOPCAT

No difference in 1° endpt or all cause mortality

TOPCAT investigators, NEJM 2014

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Of 22 pre-specified, only 1 stratum showed a significant interaction with treatment

Enrolled by:

Spiro Placebo Hazard Ratio (95% CI) P-value Natriuretic peptide 78/490 (15.9%) 116/491 (23.6%) 0.65 (0.49-0.87) 0.003 Heart Failure Hosp 242/1232 (19.6%) 235/1232 (19.1%) 1.01 (0.84-1.21) 0.923 *p=0.013 for interaction

TOPCAT - Subgroups

0.00 0.10 0.20 0.30 0.40 0.50 Probability 12 24 36 48 60 72 Months

HR=0.82 (0.69-0.98) HR=1.10 (0.79-1.51)

Interaction p=0.122

US, Canada, Argentina, Brazil Russia, Rep Georgia Placebo: 280/881 (31.8%) Placebo: 71/842 (8.4%)

Exploratory (post-hoc): Placebo vs. Spiro by region

HFPEF and Vascular Inflammation

Comorbidities and the NO-sGC-cGMP axis

Paulus and Tschope, JACC 2013

HFPEF

A Microvascular Disease?

HFPEF n=124 Wgt 538 gm MVD 961 v/cc Controls n=104 Wgt 335 gm MVD 1316 v/cc Mohammed SF, et al. Circulation 2014

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Statins in HFPEF

The Vascular Hypothesis

n=17,985

Liu G, et al. Am J Cardiol 2014;113:1198-1204 Solomon SD, et al. Lancet 2012;380:1387-1395

Angiotensin receptor neprilysin inhibitor (ARNI) LCZ696 in HFPEF

PARAMOUNT Trial

Decrease LAVI Improved NYHA n=300 NT-proBNP >400 EF >45%

Borlaug BA, et al. JACC 2015

Eat More Beets?

Blind Men and the Elephant: HFpEF?

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HFpEF

A Kidney Disorder?

Renal Dysfunction is Clinical Risk For Incident HFPEF but not HFREF

Risk factor HFrEF HFpEF Pcr value (<0.10) Age 1.61 (1.24-2.09) 2.53 (1.93-3.30) 0.018 Male 2.43 (1.49-3.95) 0.56 (0.31-1.01) <0.001 MI 2.77 (1.73-4.43) 1.25 (0.64-2.45) 0.058 Smoking 1.51 (0.96-2.36) 0.80 (0.46-1.41) 0.086 Atrial fibrillation 0.42 (0.19-0.93) 3.79 (1.64-8.77) <0.001 Cystatin C 0.98 (0.86-1.11) 1.45 (1.03-2.04) 0.033 UAE 0.96 (0.84-1.09) 1.21 (0.98-1.48) 0.061 NT-proBNP 1.85 (1.42-2.41) 1.35 (1.06-1.72) 0.082 TnT 1.38 (1.18-1.60) 1.10 (0.90-1.36) 0.091

Brouwers FP, et al. European Heart Journal 2013;34:1424-1431

PREVEND (8592 subjects, 11 yr fu, age 28-75, UAE>10 mg/L vs control)

Chlorthalidone decreases incident HFPEF (but not HFREF) relative to lisinopril

Davis BR, et al. Circulation 2008;118:2259-2267

SGLT2 decreases HF in DMII

The EMPA REG Trial

Zinman B, et al. NEJM 2015

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Reasons for “Failure” in HFpEF

  • 1. Wrong patients
  • - Unclear definition of condition
  • 2. Wrong intervention
  • - Neurohormonal activation?
  • 3. Wrong endpoints
  • - Multiple comorbidities, QoL?

Henkel, Redfield, et al. Cir Heart Fail 2008

Causes of Death in HFPEF

More non-CV related

And, of course, diet and exercise

Kitzman DW, et al. JAMA 2016

Summary

  • Diagnosis may be difficult

– Consider differential – Multiple mechanisms – consider BNP to confirm ‘diastolic dysfunction’

  • Consider use of spironolactone (cautiously)
  • A RenoCardiac syndrome?
  • Strongly consider enrollment in clinical trials
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Extra Slides Effects of IV Nitrite in HFpEF

Borlaug BA, et al. JACC 2015

Catheter Ablation for AF in HFPEF

Improvements in Functional Capacity…but variable

Jones DG, et al. JACC 2013;61(18):1894-1903

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Embracing Heterogeneity in HFpEF

Shah S, et al. Circ 2016

Intracardiac Shunt for HFpEF

REDUCE-LAP

Hasenfuss G, et al. Lancet 2016

Salt Restriction for HFPEF?

50 mmol (1150 mg)/2100 kcal in DASH diet for 21 days Parameter Before After P value Clinic BP 155/79 mmHg 138/72 <0.05 Ambulatory BP 130/67 mmHg 123/62 0.02 Car-Fem PWV 12.4 m/sec 11.0 m/sec 0.03 Urinary F2-Isoprostanes 209 pmol/mmol Cr 144 pmol/mmol Cr 0.02 Urinary Aldosterone 7 ng/24 hr 12 ng/24 hr 0.01

Hummel SL, et al. Hypertension. 2012;60:1200-1206

Why are we talking about it?

  • Compared to systolic HF, increasing in

prevalence

  • Disease of the elderly in a population that

is aging

  • No improvements in outcomes in past

twenty years in contrast to systolic HF

  • All cause mortality is high and comparable

to systolic HF

Owan, NEJM 2006; Borlaug, JACC 2009; Lee, Circulation 2009

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Lam CSP . JACC-HF 2014;2(5):541-543 Cheng S, et al. Circ CV Imaging 2009;2:191-198

EF Changes Over Time

MESA cohort