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

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/ BMI 38, HTN, 1+ edema James C. Fang, MD B. 70 BF with BMI 35, HTN, DM, arthritis and LVH University of Utah Health Sciences Center C. 86 WF with afib, anemia, LAE Salt Lake City, UT D. 70 BM with CKD, “ COPD ” , RVSP 50 Definition of HFPEF Reasons for “ Failure ” in HFpEF 2013 AHA ACC HF Guidelines, EF >50% • “…also referred to as diastolic HF. Several 1. Wrong patients different criteria have been used to further -- Unclear definition of condition define HF p EF. The diagnosis of HF p EF is 2. Wrong intervention challenging because it is largely one of excluding other potential noncardiac -- Neurohormonal activation? causes of symptoms suggestive of HF. To 3. Wrong endpoints date, efficacious therapies have not been -- Multiple comorbidities, QoL? identified." Yancy CW, et al. Circulation 2013 1

9/30/16 (LOE: C) HFPEF: Diagnosis of Exclusion • Constriction • Pulmonary • Restriction • Thoracic • Mitral valve disease • PAH • CAD • Deconditioning • Chronotropic • Anemia incompetence • Neuromuscular • Aortic valve disease • “ Volume overload ” ESC HF Guidelines 2012 HFPEF in Clinical Trials Limitations of Ejection How do they define it? Fraction to Define HFPEF Trial Age EF S/Sx Hosp? Data • What is a ‘Preserved’ EF is Not Clear • Assumes mutually exclusive domains of systolic CHARM >18 40 Yes Y No and diastolic function I-PRESERVE >60 45 Yes Y or N X, E, K • Current guidelines define EF 41 – 49% as intermediate cohort (Yancy, Circ 2013) PEP-CHF >70 45 Yes N Echo • Patients with EF 40 – 55% more similar to patients with EF <40% (Sweitzer, AJC 2008) TOPCAT >50 45 Yes Y or N BNP • Misclassification common (e.g. ‘recovered EF’ patients) (Punnoose, JCF 2011) 2

9/30/16 Diastolic Dysfunction May Not Misclassification of EF Be Specific for HFPEF Comparison to a Core Lab Shah AM, et al. JACC CV Img 2012 Redfield MM, et al. JAMA 2003;289:194 TOPCAT HFPEF in TOPCAT Definition of Heart Failure (LVEF > 45%) Heterogeneity of Structure and Function SYMPTOMS SIGNS • Mean LVEF 59.3±7.9% (>1 at screening) (>1 in the last 12 mos) • Concentric LV remodeling (34%) and hypertrophy (43%) • Paroxysmal nocturnal • Any rales post cough dyspnea • Jugular venous pressure • Left atrial enlargement (53%) • Orthopnea (JVP) ≥ 10 cm H 2 O • Diastolic dysfunction was present in 66% of gradable • Dyspnea on mild or moderate • Lower extremity edema participants exertion • Chest X-ray demonstrating – associated with greater left ventricular hypertrophy and a pleural effusion, pulmonary higher prevalence of left atrial enlargement congestion, or cardiomegaly • Doppler evidence of PH was present in 36% • At least 1 measure of structural heart disease was At least one hospitalization in last 12 months for which HF was a major component OR present in 93% of patients Elevated BNP>100 pg/mL or N-terminal pro-BNP>360 pg/mL within the last 30 days Shah AM, et al. Circulation HF 2014 3

9/30/16 HFPEF: Abnormality of Systole 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 Norman HS, et al. J Card Fail 2011 Mohammed SF, et al. JACC-HF. 2014;2(2):113-122 HFPEF and chronotropic HFpEF and Obesity incompetence High Output HF? Borlaug BA, et al. Circulation 2006;114:2138-2147 Reddy Y, et al. JACC 2016 4

9/30/16 Clinical Trials in HFpEF Reasons for “ Failure ” in HFpEF CHARM-PEF iPRESERVE PEP-CHF SENIORS (s) 1. Wrong patients Therapy Candesartan Irbesartan Perindopril Nebivolol -- Unclear definition of condition Age (yrs) > 18 (67) ≥ 60 (72) ≥ 70 (76) ≥ 70 (76) 2. Wrong intervention EF (%) ≥ 40 (54) ≥ 45 (59) ≥ 40 (65) ≥ 35 Patients (n) 3,023 4,128 850 752 -- Neurohormonal activation? 3. Wrong endpoints Female (%) 40% 60% 55% 38% -- Multiple comorbidities, QoL? 0.89 (0.77- 0.95 (0.86- 0.92 (0.70- 0.82 (0.63- Death/HF hosp 1.03) 1.05) 1.21) 1.05) HFpEF: Things That Don’t Work TOPCAT A partial list… No difference in 1° endpt or all cause mortality • ACEi • ARBs • Beta blockers • Calcium channel blockers • Nitrates • Sildenafil TOPCAT investigators, NEJM 2014 5

9/30/16 Exploratory (post-hoc): TOPCAT - Subgroups Placebo vs. Spiro by region 0.50 Placebo: Of 22 pre-specified, only 1 stratum showed a significant interaction with US, Canada, 280/881 (31.8%) treatment Argentina, Brazil 0.40 HR=0.82 (0.69-0.98) Hazard Ratio Enrolled 0.30 Probability Spiro Placebo (95% CI) by: P-value Interaction p=0.122 0.20 Natriuretic 78/490 116/491 0.65 (0.49-0.87) peptide (15.9%) (23.6%) 0.003 0.10 Heart Failure 242/1232 235/1232 1.01 (0.84-1.21) Placebo: Hosp (19.6%) (19.1%) 0.923 Russia, Rep Georgia 71/842 (8.4%) 0.00 HR=1.10 (0.79-1.51) *p=0.013 for interaction 0 12 24 36 48 60 72 Months HFPEF and Vascular Inflammation HFPEF HFPEF Comorbidities and the NO-sGC-cGMP axis n=124 A Microvascular Wgt 538 gm MVD 961 v/cc Disease? Mohammed SF, et al. Circulation 2014 Controls n=104 Wgt 335 gm MVD 1316 v/cc Paulus and Tschope, JACC 2013 6

9/30/16 Angiotensin receptor neprilysin Statins in HFPEF inhibitor (ARNI) LCZ696 in HFPEF The Vascular Hypothesis PARAMOUNT Trial n=300 NT-proBNP >400 EF >45% Decrease LAVI Improved NYHA n=17,985 Liu G, et al. Am J Cardiol 2014;113:1198-1204 Solomon SD, et al. Lancet 2012;380:1387-1395 Blind Men and the Elephant: Eat More Beets? HFpEF? Borlaug BA, et al. JACC 2015 7

9/30/16 HFpEF Renal Dysfunction is Clinical Risk For Incident HFPEF but not HFREF A Kidney Disorder? PREVEND (8592 subjects, 11 yr fu, age 28-75, UAE>10 mg/L vs control) Risk factor HFrEF HFpEF P cr 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 SGLT2 decreases HF in DMII Chlorthalidone decreases incident HFPEF (but not HFREF) relative to lisinopril The EMPA REG Trial Davis BR, et al. Circulation 2008;118:2259-2267 Zinman B, et al. NEJM 2015 8

9/30/16 Causes of Death in HFPEF Reasons for “ Failure ” in HFpEF More non-CV related 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 And, of course, diet and Summary exercise • 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 Kitzman DW, et al. JAMA 2016 9

9/30/16 Extra Slides Catheter Ablation for AF in HFPEF Effects of IV Nitrite in HFpEF Improvements in Functional Capacity…but variable Borlaug BA, et al. JACC 2015 Jones DG, et al. JACC 2013;61(18):1894-1903 10

9/30/16 Intracardiac Shunt for HFpEF Embracing Heterogeneity in HFpEF REDUCE-LAP Shah S, et al. Circ 2016 Hasenfuss G, et al. Lancet 2016 Why are we talking about it? Salt Restriction for HFPEF? 50 mmol (1150 mg)/2100 kcal in DASH diet for 21 days • Compared to systolic HF, increasing in prevalence Parameter Before After P value Clinic BP 155/79 mmHg 138/72 <0.05 • Disease of the elderly in a population that Ambulatory BP 130/67 mmHg 123/62 0.02 is aging Car-Fem PWV 12.4 m/sec 11.0 m/sec 0.03 • No improvements in outcomes in past Urinary 209 pmol/mmol Cr 144 pmol/mmol Cr 0.02 F2-Isoprostanes twenty years in contrast to systolic HF Urinary 7 ng/24 hr 12 ng/24 hr 0.01 Aldosterone • All cause mortality is high and comparable to systolic HF Hummel SL, et al. Hypertension. 2012;60:1200-1206 Owan, NEJM 2006; Borlaug, JACC 2009; Lee, Circulation 2009 11

9/30/16 EF Changes Over Time MESA cohort Lam CSP . JACC-HF 2014;2(5):541-543 Cheng S, et al. Circ CV Imaging 2009;2:191-198 12