Ensayos clínicos en IC preservada: resultados del PARAGON-HF

Ensayos clínicos en IC preservada:
resultados del PARAGON-HF Dr. Josep Comín Colet
Ensayos Clínicos en IC Preservada:
resultados del PARAGON-HF
Dr. Josep Comín Colet.
Jefe del Servicio de Cardiologia del Hospital Universitario de
Bellvitge, L’ Hospitalet de Llobregat, Barcelona.

Up to 2 weeks Valsartan 160 mg b.i.d.
Sacubitril/valsartan 200 mg b.i.d.
Sac/val
100 mg b.i.d.
On top of optimal background medications for
comorbidities (excluding ACEIs and ARBs)
Valsartan
80 mg b.i.d.
Screening
Single-blind run-in period
Double-blind, long-term follow-up period¥Randomization
N=4822
1─4 weeks* 2─4 weeks^
Safety and
tolerability check
Safety and
tolerability check
Diseño del Estudio
Solomon, SD et al. JACC Heart Fail. 2017;5:471–482

Criterios Inclusión & Exclusión
Key inclusion criteria:
• Age 50 years; LVEF 45%
• Symptoms of HF requiring treatment with
diuretic(s) for 30 days prior to screening
• Current symptomatic HF
(NYHA class II−IV)
• Structural heart disease within the 6 months
prior to screening (LAE and/or LVH)
• Patients with at least 1 of the following:
– HF hospitalization within 9 months prior to
screening and NT-proBNP >200 pg/mL for
patients without AF or >600 pg/mL for
patients with AF*
OR
– NT-proBNP >300 pg/mL for patients without
AF or >900 pg/mL for patients with AF*
Key exclusion criteria:
• History of LVEF <40%
• MI, CABG or any event within the 6 months prior to
screening that could have reduced the LVEF (unless
LVEF confirmed as 45%)
• Current acute decompensated HF requiring therapy
• Requirement for treatment with two or more of the
following: ACEI, ARB or renin inhibitor
• SBP <110 mmHg OR SBP 180 mmHg at
screening^
• Serum potassium >5.2 mmol/L at screening, or
>5.4 mmol/L at the end of each run-in period
• eGFR <30 mL/min/1.73m2 at screening, OR at the
end of each run-in period eGFR <25
mL/min/1.73m2 or eGFR reduction of >35%
compared to that at screening

Primary objective
• To evaluate the efficacy of sacubitril/valsartan compared with valsartan in reducing the rate of the composite
endpoint of CV death and total (first and recurrent) HF hospitalizations
Secondary objectives
• To compare the effects of sacubitril/valsartan vs. valsartan on:
➢ improvement in the KCCQ clinical summary score for HF symptoms and physical limitations at 8 months
➢ improvement in NYHA functional classification at 8 months
➢ delay in the time to the first occurrence of a composite renal endpoint*
➢ delay in the time to all-cause mortality

Disposición de los Pacientes
11302 patients screened at 788 centers in
43 countries
5754 entered valsartan run-in phase
4822 patients randomized to receive
sacubitril/valsartan or valsartan
Common reasons for screen failure were:
• Insufficient NT-proBNP: 61%
• Elevated potassium: 10%
• eGFR below inclusion cut-off: 6%
• Diagnoses other than HFpEF: 6%
• Elevated LFTs: 4%
Common reasons for run-in failures were:
• Predefined safety AEs*: 65%
• Subject decision: 15%
• Protocol deviation: 12%
• Non-compliance: 5%
• Death: 2%
5210 entered sacubitril/valsartan run-in phase
Solomon, SD et al., Circ Heart Fail. 2018;11:e004962. DOI:
10.1161/CIRCHEARTFAILURE.118.004962

Solomon et al. New England Journal of Medicine, September 1, 2019 DOI: 10.1056/NEJMoa1908655

Characteristic Sacubitril/valsartan
(n = 2407)
Valsartan
(n = 2389)
Age—yr 72.7 ± 8.3 72.8 ± 8.5
Female sex — no. (%) 1241 (51.6%) 1238 (51.8%)
Region — no. (%)
North America 288 (12.0%) 271 (11.3%)
Latin America 191 (7.9 %) 179 (7.5 %)
Western Europe‡ 699 (29.0%) 691 (28.9%)
Central Europe 856 (35.6%) 859 (36.0%)
Asia–Pacificand Other 373 (15.5%) 389 (16.3%)
Systolic blood pressure — mm Hg §. † 130.5 ± 15.6 130.6 ± 15.3
Estimated glomerular filtration rate (eGFR) – ml/min/1.73 m2
63  19 62  19
Ischemic etiology — no. (%) 899 (37.4%) 824 (34.5%)*
Left ventricular ejection fraction — % 57.6 ± 7.8 57.5 ± 8.0
Median N-terminal pro–B-type natriuretic peptide (IQR) — pg/ml 904 [475 , 1596] 915 [453 , 1625]
NYHA functional class at randomization — no. (%)†
I 73 (3.0%) 64 (2.7%)
II 1866 (77.5%) 1840 (77.0%)
III 458 (19.0%) 474 (19.8%)
IV 8 (0.3 %) 11 (0.5 %)

Characteristic Sacubitril/valsartan
(n = 2407)
Valsartan
(n = 2389)
Medical history — no. (%)
Hypertension 2304 (95.7%) 2280 (95.4%)
Diabetes 1046 (43.5%) 1016 (42.5%)
Atrial fibrillation 775 (32.2%) 777 (32.5%)
Stroke 266 (11.1%) 242 (10.1%)
Hospitalization for heart failure 1135 (47.2%) 1171 (49.0%)
Myocardial infarction 561 (23.3%) 522 (21.9%)
Treatments at Randomization – no.(%)
Diuretics† 2268 (94.2%) 2266 (94.9%)
ACE inhibitors or Angiotensin Receptor Blockers (at
screening)
2074 (86.2%) 2065 (86.4%)
Mineralocorticoid Receptor Antagonists† 581 (24.1%) 638 (26.7%)
Beta-Blockers† 1897 (78.8%) 1883 (78.8%)

Ensayos clínicos en IC preservada: resultados del PARAGON-HF

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Ensayos clínicos en IC preservada: resultados del PARAGON-HF