A “paragon” is a comparison, and in particular a comparison with a model that serves as an example. The name derives from the use of a stone that would be used as model (or paragon) for other stones to be prepared in the same way in ancient Rome. A “paradigm” is also a model but more as an example or a scheme to follow, rather than something to be compared with. It is therefore rather fitting that we would be analyzing the results of the PARAGON-HF trial (The Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin-receptor blocker] Global Outcomes in heart failure [HF] with Preserved Ejection Fraction)1,2 to compare how sacubitril–valsartan (Entresto) performed in HF with preserved ejection fraction (HFpEF) in reference to the more established model of HF with reduced ejection fraction (HFrEF) that was explored in the PARADIGM-HF trial (Prospective comparison of ARNI with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and morbidity in Heart Failure).3,4
Sacubitril–valsartan contains a combination of 2 drugs, sacubitril, a neprilysin inhibitor prodrug, and valsartan, an ARB, targeting both natriuretic peptides enhancement and renin–angiotensin–aldosterone system blockade. The combination was approved by the US Food and Drug Administration for patients with chronic HFrEF and New York Heart Association (NYHA) functional class II to IV symptoms5 following the results of the PARADIGM-HF trial, which showed that sacubitril–valsartan reduced cardiovascular mortality or hospitalization for HF by 20% (95% confidence interval [CI], 0.73–0.87; P < 0.001) compared with a proven dose of the ACEI, enalapril.4,6 The results of the recently published PARAGON-HF trial2 are certainly less impressive and, therefore, a thorough comparison is warranted. The primary composite end point of total (first and recurrent) HF hospitalizations and cardiovascular death was reduced by 13% but narrowly missed statistical significance (95% CI: 0.75–1.1; P = 0.06) compared with valsartan.2
It is noticeable that the 2 trials enrolled subjects with 2 different forms of HF. Although there has been a push to consider HFrEF and HFpEF as similar conditions in the HF spectrum, it has become clear that they have different clinical, epidemiological, and pathophysiological profiles. Furthermore, therapies with proven mortality benefit in HFrEF have failed to improve mortality in HFpEF.7,8 Historically, population studies based on insurance claims or large electronic health records database have suggested similar mortality rates for patients with HFrEF and HFpEF.9 This was not replicated in a patient-level meta-analysis,10 including 41,972 patients (of which 10,347 with HFpEF) from prospective HF clinical trials that showed that the adjusted mortality rate in HFpEF was approximately 32% lower than that in HFrEF, highlighting a potential issue with the identification of the HFpEF population and the possible challenges of including as “HFpEF” some forms of HF due to other reasons (ie, severe valvular disease, infiltrative myocardial disease, pericardial disease) that may present with a preserved ejection fraction (EF). These conditions have been referred to as “secondary HFpEF syndromes” that are characterized by a significantly worse prognosis and require independent investigation in dedicated clinical trials (ie, cardiac amyloidosis).8
The PARADIGM-HF and PARAGON-HF allow for a unique opportunity to compare HF phenotypes in the context of the modern era of HF treatment strategies (Fig. 1). What is readily apparent is that the rate of cardiovascular mortality is lower in patients in the control arms of the PARAGON-HF than in those in the control arms of the PARADIGM-HF, supporting the concept of a higher cardiovascular mortality in HFrEF versus HFpEF.2,4 It is important to note that the control arms were not randomized to placebo but rather to an active treatment, valsartan and enalapril respectively, and there is no reason to suggest that valsartan would have been superior to enalapril in reducing cardiovascular death in HFpEF population because both 2 classes of drugs have consistently failed to reduce mortality in this population.2,4,11 Of note, the lower cardiovascular mortality in HFpEF cohorts was present despite a clear enrichment of patients with a higher risk profile during the enrollment process, suggesting that unselected HFpEF patients would have had even lower cardiovascular mortality.1 This has important implications because it points to different mechanisms of cardiovascular death in HFrEF versus HFpEF, with a reduction in left ventricular ejection fraction (LVEF) being a marker of risk, if not also a mediator. Reduced LVEF is, indeed, an established prognostic marker, and all treatments that preserve or restore LVEF in patients with HFrEF have a favorable impact on cardiovascular mortality. The mechanism by which reduced LVEF contributes to cardiovascular death cannot be extrapolated from these studies, but it likely includes a combination of arrhythmic events and worsening pump failure. The risk of death in patients with HFpEF on the other hand seems to be more similar to patients with hypertension and other risk factors without HFpEF and thus may also be driven by risk factors other than HF itself, whereas the cardiovascular mortality rates in patients with HFrEF are substantially higher, pointing to an additional mechanism of risk.9 An analysis of the PARADIGM-HF study also highlighted that the lower the LVEF, the greater the risk, and thus, the greater the absolute gain with sacubitril–valsartan.12 Therefore, it is not surprising that, in the PARAGON-HF study, a more favorable effect on the primary end point was seen in the prespecified subgroup of patients with an EF in the lower part of the range (relative risk [RR] = 0.780; 95% CI: 0.641–0.949 in those with LVEF 45%–57% vs. RR = 1.00; 95% CI: 0.81–1.23 in those with an LVEF >57%), a segment of the HF population also referred to as mid-range EF.
The lower risk of cardiovascular death emerging from clinical trials should not detract from focusing on HFpEF as a HF syndrome. Although direct comparisons between the hospitalization rates remain difficult due to reporting differences (PARAGON-HF reported total hospitalization events, whereas PARADIGM-HF reported only first hospitalization), the overall hospitalization rate remains quite high in the PARAGON-HF cohort.2,4,8 This has an important implication because it suggests that the mechanisms leading to HF symptoms and hospitalization are not necessarily the same mechanisms leading to cardiovascular death and may be shared by both HFrEF and HFpEF. It is also important to note that in the exploratory analysis of the individual components of the primary composite end point, sacubitril–valsartan appeared to reduce total HF hospitalizations in both HFpEF (RR 0.85; 95% CI: 0.72–1.00) and HFrEF (RR 0.79; 95% CI: 0.71–0.89).2,4 Moreover, the impaired cardiorespiratory fitness and exercise tolerance that accompany HF hospitalizations and are central to the HF syndrome seem to affect patients with HFrEF and HFpEF similarly.13 Further studies are warranted to explore the potential beneficial effects of sacubitril–valsartan on cardiorespiratory fitness in HFrEF and HFpEF.14
In conclusion, in the paragon on the effects of sacubitril–valsartan in HFrEF versus HFpEF, there is a striking difference between the natural history of HFpEF versus HFrEF. Neurohormonal inhibition has shown to be an ineffective therapeutic strategy to reduce cardiovascular mortality in HFpEF patients, and due to the frequent coexistence of comorbid conditions and the relatively high incidence of noncardiac death in patients with HFpEF,15 it remains to be determined which intervention, if any, will reduce cardiovascular mortality in this cohort of patients. However, the overall HF burden is significant in both syndromes; HFpEF is associated with a significantly lower rate of cardiovascular death than HFrEF. Given these considerations, the focus of treatment for patients with HFrEF and HFpEF are clearly different. Evidence-based treatments to reduce cardiovascular mortality should be strongly implemented in patients with HFrEF, whereas therapies able to reduce HF hospitalizations and symptomatic burden should be applied to patients with both HFrEF and HFpEF, with a particular attention to comorbid conditions, especially in the group of patients with HFpEF.
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2. Solomon SD, McMurray JJV, Anand IS, et al; PARAGON-HF Investigators and Committees. Angiotensin-neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med. 2019;381:1609–1620.
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