Table 2.
Inclusion Criteria in Selected Previous and Ongoing Clinical Trials and Registries of Patients With HFpEF
| Trial | Clinical Dx HF | Prior HF Admission |
EF % |
Atrial Fibrillation/ Atrial Flutter |
BNP * pg/ml |
NT- proBNP *pg/ml |
Event Rate† (1-yr) |
Primary Endpoint | Clinical Findings |
|---|---|---|---|---|---|---|---|---|---|
| CHARM- PRESERVED (11) |
NYHA II-IV >4 weeks, hospitalized for cardiac reason, history of hospital admission for cardiac reason |
68.8 | >40 | 29.3% | -- | -- | 9.1% | CV death or HF hospitalization |
No reduction in CV death; fewer patients in treatment group had HF hospitalization |
| PEP-CHF (18) | Age ≥70, on diuretics, Echo with DD, 3/9 clinical, 2/4 echo criteria, CV hospitalization within 6 months |
100 | >40 | 22% | -- | 453 | 11.96% | Composite of all- cause mortality and unplanned HF hospitalization |
No reduction in all-cause mortality or HF hospitalization |
| DIG-PEF (87) | NSR, HF symptoms |
-- | >45 | 0 | -- | -- | 7.8% | Combined HF hospitalization or HF mortality |
Digoxin had no effect on mortality or all-cause CV hospitalization |
| SENIORS (28) | Age ≥70, HF history + ≥1 HF hospitalization or EF ≤35% within past 6 months |
-- | >35 | 37.1% | -- | -- | 19.2% | All-cause mortality or CV hospitalizations |
No difference of nebivolol effect on elderly patients with HFpEF vs. HFrEF |
| I-PRESERVE (19) |
NYHA II-IV | 44% | ≥45 | 17% | -- | 320 | 10.54% | All-cause mortality or CV hospitalization |
No improvement from irbesartan in primary endpoints |
| ELANDD (88) | NYHA II-III, Echo DD |
-- | >45 | -- | -- | 147 | -- | Change in 6MWD after 6 months |
No change in 6MWD or peak VO2 |
| J-DHF (89) | Modified Framingham criteria for HF within 12 months |
60% | >40 | 45.6% | 235 – mean |
-- | 8.5 | Composite of CV death and unplanned HF hospitalization |
No improvement from carvedilol |
| ALDO-DHF (52) | Ambulatory NYHA Class II-III HF, Echo DD |
4% | ≥50 | 9% | -- | 148 | -- | Coprimary: change in diastolic function (E/e’) and peak VO2 at 12 months |
Improved DD but no change in peak VO2 |
| Ex-DHF (90) | Symptomatic NYHA II-III outpatients, age ≥45 yrs, DD grade ≥1, NSR, 1 CV risk factor |
-- | ≥50 | -- | -- | -- | -- | Change in peak VO2 after 3 months |
Peak VO2 increased 3.3 ml/min/kg, E/e’ and LAVI decreased |
| PARAMOUNT (21) |
NYHA II-IV | 45% | ≥45 | 43% | -- | >400 | n/a | Change in NT- proBNP from BL to 12 weeks |
LCZ696 reduced NT- proBNP more than valsartan at 12 weeks |
| RELAX (51) | Stable outpatients with HF, elevated NT-proBNP or elevated filling pressures, reduced exercise capacity |
39% | ≥50 | 50 | -- | 648 | 12.6 | Change in peak VO2 after 24 weeks of therapy |
No improvement in peak VO2 |
| RELAX-AHF (91) |
Admitted for AHF (dyspnea at rest or minimum exertion, pulmonary congestion on chest radiograph & BNP ≥350 pg/ml or NT- proBNP ≥1,400 pg/ml and eGFR 30-75 ml/min per 1.73 m2 |
29.5% | ≥50 | 61.2% | -- | 3992 | 12.75%‡ | Change from BL in VAS AUC to day 5 and proportion of patients with improved dyspnea by Likert scale during first 24 h |
Improved dyspnea relief by the VAS- AUC and Likert scale |
| RAAM-PEF (92) | NYHA II-III, clinical HF and BNP ≥100 pg/ml within 2 months |
60.9% | ≥50 | 13% | 284 | -- | -- | Change in 6MWD | No change in 6MWD |
| SHIFT- PRESERVED (68) |
Signs or symptoms of HF, Echo with DD, Exercise capacity <80% age/sex predicted, E/e’ >13 after exercise |
-- | ≥50 | -- | 62 | -- | -- | Exercise capacity, E/e’ |
Improved peak VO2 and improved E/e’ after exercise |
| TOPCAT (48) | History of hospitalization within previous 12 months with HF component or elevated BNP within 60 days |
71.5% | ≥45 | >100 235 |
>360 1017 |
20.4% | Composite of CV mortality, aborted cardiac arrest, or hospitalization for HF |
No improvement in composite endpoint |
|
| Enrollment on the basis of HF hospitalization past 1 yr |
-- | -- | -- | -- | -- | 19.1% | -- | -- | |
| Enrollment on the basis of BNP/NT- proBNP criteria |
-- | -- | -- | -- | -- | 23.6% | -- | -- | |
| Enrollment in the Americas |
-- | -- | -- | -- | -- | 12.6% | -- | -- | |
| Enrollment in Eastern Europe |
-- | -- | -- | -- | -- | 2.3% | -- | -- | |
| PARAGON-HF (93) |
NYHA II-IV requiring treatment with diuretics for ≥30 days, LAE or LVH by echo, and HF hospitalization within 9 months or elevated NT- proBNP |
≥45 | Elevate d |
Composite endpoint of CV death and total HF hospitalizations (first and recurrent) |
-- | ||||
| SOCRATES- PRESERVED (94) |
Worsening HF requiring hospitalization or IV diuretic as outpatient |
-- | ≥45 | -- | -- | -- | -- | NT-proBNP from BL to 12 weeks, change of LAVI, safety |
-- |
| EDIFY(95) | Stable symptomatic NYHA II-II ≥3 months, HR >70, E/e’ >13 or e’ lateral <10 cm/s and e’ septal <8 cm/s or LAVI >34 ml/m2 |
-- | -- | -- | >80 | >220 | -- | Diastolic function (E/e’), NT-proBNP and 6MWD |
-- |
| Ontario, Canada (30) |
1st time admission for HF (only) on the basis of Framingham HF criteria |
-- | ≥50% | 31.8 | -- | -- | 31.1% | HF survival rate similar between HFrEF and HFpEF |
22.2% 1-yr mortality, 13.5% 1-yr Readmission for HF, 9.4% 30-day mortality or readmission for HF |
| Olmsted County (4) |
All consecutive patients hospitalized at Mayo Clinic Hospitals from 1987-2001 (ICD code 428 and DRG code 127) |
-- | ≥50 | 41.3 | -- | -- | 29% | Prevalence and survival of patients with HFpEF over a 15-yr period |
Increased prevalence of HFpEF with similar rate of death over a 15-yr period |
| ADHERE (96) | AHF as new-onset HF or decompensated chronic HF with symptoms requiring hospitalization; ICD-9 discharge diagnosis of HF |
63% | ≥40 | 21% (1st ECG) |
-- | -- | 2.8%§ | Prevalence and outcomes of patients with HFpEF |
In-hospital mortality was lower in patients with HFpEF vs. HFrEF. |
| OPTIMIZE-HF (23) |
Hospitalized new- onset or worsening HF as primary cause of admission or significant HF symptoms that developed during hospitalization with HF as primary discharge diagnosis |
-- | ≥40 | 33% | 602 | -- | 35.3%║ | Prevalence and outcomes of patients with HFpEF (in- hospital mortality, rehospitalization rate) |
HFpEF and HFrEF had similar lengths of hospital stay, in- hospital mortality was lower in HFpEF |
| ≥50 | 32% | 537 | -- | 36.8%║ | |||||
| MAGGIC (25) | Meta-analysis of observational studies and RCTS through 2006, with eligible studies including patients with HF and death from any cause where EF criterion was not used for study entry |
-- | ≥50 | 27% | -- | -- | 12.1%¶ | Survival of HFpEF vs HFrEF patients |
HFpEF patients have a lower risk of death than patients with HFrEF but absolute mortality in HFpEF is still high |
| GWTG-HF (5) | Hospitalization for acute, decompensated HF on the basis of clinical diagnosis. |
54% 56% |
≥50 40-50 |
34% 34% |
551 761 |
3401 5495 |
2.5%# 2.3%# |
Trend in therapies and outcomes |
Hospitalizatio n for HFpEF is increasing relative to HFrEF, with in-hospital mortality for HFpEF declining over study period |
AHF = acute heart failure; BL = baseline; BNP = B-type natriuretic peptide; CV = cardiovascular; DD = diastolic dysfunction; DRG = diagnosis related group; Dx = diagnosis; E/e’ = peak early transmitral ventricular filling velocity/early diastolic tissue Doppler velocity; EF = ejection fraction; eGFR = estimated glomerular filtration rate; ICD = International Classification of Diseases; IV = intravenous; LAE = left atrial enlargement; LAVI = left atrial volume index; LVH = left ventricular hypertrophy; NSR = normal sinus rhythm; NT-proBNP = N-terminal pro-B-type natriuretic peptide; NYHA = New York Heart Association; VAS-AUC = visual analog scale-area under curve; VO2 = peak oxygen consumption; 6MWD = 6 min walk distance. Other abbreviations as in Table 1.
*
NP levels are median levels unless otherwise specified and if used as inclusion criteria are listed with > or < symbols
†
Data are from placebo groups in clinical trials unless otherwise noted
‡
RELAX-AHF event rate is cardiovascular death or HF/renal failure hospitalization through Day 60
§
ADHERE event rate is in-hospital mortality
║
OPTIMIZE-HF event rate is post-discharge mortality/rehospitalization at 60-90 days
¶
MAGGIC meta-analysis event rate was number of deaths/100 patient-years
#
GWTG-HF event rate is in-hospital mortality.