PARAGON-HF Trial: Purpose and Treatment Approach
Trial Design and Primary Objective
PARAGON-HF was a randomized, double-blind trial comparing sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor) to valsartan alone in 4,796 patients with heart failure and preserved ejection fraction (HFpEF, LVEF ≥45%). 1, 2
The trial enrolled patients with:
- LVEF ≥45% (mean 57.5%) 2
- NYHA class II-IV symptoms 1, 2
- Elevated natriuretic peptides (median NT-proBNP 911 pg/mL) 2
- Evidence of structural heart disease 1, 2
Primary Results and Overall Findings
The trial showed a 13% reduction in the primary composite endpoint (cardiovascular death and total HF hospitalizations) with sacubitril/valsartan versus valsartan, which was of borderline statistical significance (rate ratio 0.87; 95% CI 0.75-1.01; p=0.06). 3, 4, 5
Sacubitril/valsartan did not reduce overall mortality, cardiovascular death, or sudden death compared with valsartan in the overall trial population. 6
Key Subgroup Findings That Matter Clinically
Women Benefit More Than Men
In prespecified subgroup analysis, women experienced significant benefit with sacubitril/valsartan (rate ratio 0.73; 95% CI 0.59-0.90) while men showed no benefit (rate ratio 1.03; P interaction = 0.017). 3, 4 This benefit in women was primarily driven by reduction in HF hospitalizations. 3
Lower Ejection Fraction Within HFpEF Range
Patients with LVEF in the lower range of preservation (45-57%, below the median) showed greater benefit (rate ratio 0.78; 95% CI 0.64-0.95) compared to those with higher LVEF. 3, 4, 5
Reduced Kidney Function
The treatment effect was most pronounced in patients with baseline eGFR ≤45 mL/min/1.73 m² (rate ratio 0.69; 95% CI 0.51-0.94), with the greatest benefit observed in those with both LVEF ≤57% and eGFR ≤45 mL/min/1.73 m² (HR 0.66; 95% CI 0.45-0.97). 7
Current Guideline Recommendations Based on PARAGON-HF
The 2022 AHA/ACC/HFSA guidelines give sacubitril/valsartan a Class 2b recommendation (may be considered) for HFpEF, specifically noting potential benefit in patients with LVEF on the lower end of the spectrum (41-57%) and in women. 3
SGLT2 inhibitors receive a stronger Class 2a recommendation (can be beneficial) for HFpEF and should be prioritized over sacubitril/valsartan in most patients. 3, 4
Clinical Algorithm for Sacubitril/Valsartan Use in HFpEF
Consider sacubitril/valsartan in HFpEF patients who meet ALL of the following:
- LVEF 45-57% (lower range of HFpEF spectrum) 3, 4
- Female sex OR eGFR ≤45 mL/min/1.73 m² 3, 7
- Elevated natriuretic peptides 1, 2
- Symptomatic despite SGLT2 inhibitor therapy 4
- Structural heart disease on echocardiography 1
Do not use sacubitril/valsartan as first-line therapy in HFpEF; prioritize SGLT2 inhibitors, blood pressure control, and management of comorbidities (diabetes, obesity, atrial fibrillation) first. 4
Important Caveats and Pitfalls
The trial enrolled a highly selected population after sequential run-in periods with both valsartan and sacubitril/valsartan to ensure tolerability, meaning real-world patients may have higher discontinuation rates. 1
Women are at higher risk of angioedema with sacubitril/valsartan due to higher bradykinin production after neprilysin inhibition, though this was not systematically analyzed by sex in the trial. 3
The high prevalence of diabetes (43%) and chronic kidney disease (47%) in PARAGON-HF makes these results more applicable to contemporary HFpEF populations than earlier trials. 2