IJCS | Volume 33, Nº3, May / June 2020

279 Saraiva & Oliveira PARAGON-HF: lessons learned and perspectives Int J Cardiovasc Sci. 2020; 33(3):278-281 Viewpoint monophosphate (cGMP) content, and protein activity associated with cardiomyocyte hypertrophy, as well as decreased titin protein phosphorylation, which increases passive stiffness. 7 With respect to treatment, there is no specific treatment to reduce mortality associated with HFpEF. Despite the availability of multiple therapies tomodify the prognosis in patients with reduced LVEF, to this day, no therapy has proven to reducemorbidity andmortality for patients with LVEF (≥ 40%). HFpEF has been defined as a heterogeneous disease. For the past 20 years, no clinical trials involving therapeutic strategies focused on neurohormonal modulation (which have been proven successful in HFrEF patients) have been able to show clinical benefit for HFpEF patients. Drugs like irbesartan, perindopril, spironolactone and candesartan have failed to show statistically significant benefit comparedwith placebo. 9-13 Possible explanations for the inaccurate diagnosis of HFpEF include the fact that the pathophysiology is not completely understood (with wrong mechanisms of action), non-optimal inclusion criteria or outcomes in the studies, geographical variations in the diagnosis and treatment of HFpEF, and type and frequency of comorbidities. The most probable hypothesis is that we have been treating a syndrome and not a disease anymore, and in fact, this syndrome is made up of a heterogeneous group of related diseases that may not respond to a single treatment approach. Symptomatic treatment of HFpEF is empirical and consists mainly of diuretics used to reduce congestion, although there isn’t enough data to support their use. Similarly, data about heart rate control in patients with atrial fibrillation, which is highly prevalent in HFpEF, are also limited. It is not yet clear whether rhythm control would be beneficial in patients with HFpEF and atrial fibrillation. 14 Yet these trials have not evaluated the effect of neprilysin inhibition, and the beneficial cardiovascular effects of natriuretic peptides in this population. The angiotensin receptor–neprilysin inhibitor sacubitril/ valsartan resulted in a lower rate of hospitalization for HF or death from cardiovascular causes compared with enalapril among patients with HF and reduced LVEF (≤ 40%) in the PARADIGM-HF trial. 15 As for patients withHFpEF, sacubitril/valsartan resulted in a lower level of N-terminal pro–B-type natriuretic peptide, a larger reduction in left atrial size, and greater improvement in the NYHA functional class than valsartan in a phase II, randomized, placebo controlled clinical trial. 16 The results of these two previous clinical trials provided the rational for the PARAGON-HF trial design. This was a phase III randomized, placebo controlled, event-driven trial designed to evaluate the safety and efficacy of sacubitril/valsartan compared to valsartan alone in patients with HF and preserved LVEF (≥ 45%). 17 The primary composite outcome of total hospitalizations for HF and death from cardiovascular causes did not differ significantly between the two groups. There were 894 primary events (690 hospitalizations for HF and 204 deaths from cardiovascular causes) in 526 patients in the sacubitril–valsartan group and 1,009 primary events (797 hospitalizations for HF and 212 deaths from cardiovascular causes) in 557 patients in the valsartan group (rate ratio, 0.87; 1 95% confidence interval [CI], 0.75 to 1.01; p = 0.06). 18 Despite the results for the primary endpoint, the PARAGON-HF was a step closer to understandingHFpEF. Of the 12 prespecified subgroups, two showed possible heterogeneity of treatment effect. The findings suggested beneficial effects in patients with an EF lower than the median (57%), and in women, who represented 52%of patients included in the final analysis. It is worth pointing out that the size of both subgroups was large enough for analysis (half the population in each subgroup). 18 A secondary analysis of the PARAGON-HF has been recently published, 19 revealing that, compared with valsartan, sacubitril/valsartan reduced the risk of HF hospitalization more in women than in men. On the primary outcome (total HF hospitalizations and cardiovascular death), there was a more favorable treatment effect in women than in men (rate ratio 0.73 [0.59-0.90] inwomen; 1.03 [0.84-1.25] inmen; p interaction = 0.017). Further analysis presented in this publication showed that this difference in effect was not explained by differences in the KCCQ questionnaire, NYHA class or renal outcomes. 19 Another recent publicationwas a pre-specified pooled analysis of 13,195 patients from PARADIGM-HF (LVEF ≤ 40%; n = 8,399) and PARAGON-HF (LVEF ≥ 45%; n = 4,796), two similarly designed pivotal clinical trials. Pooled data enabled an analysis of treatment effect across the continuum of LVEF. Among the findings, rates of primary composite events decreased with increasing LVEF, with lower rates of cardiovascular death, mainly in patients with the highest LVEF compared with patients with the lower