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Burden of HFpEF Symptoms and Response to Therapy
Quick Takes
- Post hoc analyses of randomized trials comparing sacubitril-valsartan to valsartan in HFpEF showed that sacubitril-valsartan did not change global burden of HF symptoms but only improved dyspnea on exertion.
- Increased global burden of HF symptoms was associated with increased risk for HF hospitalizations and cardiovascular death in HFpEF patients.
- Orthopnea and rales were individually associated with HF hospitalization and cardiovascular death in HFpEF patients, independent of BNP levels.
Study Questions:
In patients with heart failure with preserved ejection fraction (HFpEF), what is the prognostic importance of HF signs and symptoms? And what is the effect of sacubitril-valsartan on HF signs and symptoms, stratified by burden of symptoms?
Methods:
PARAGON-HF was a randomized, multicenter, double-blinded trial comparing the efficacy of sacubitril-valsartan to valsartan in patients aged ≥50 years with New York Heart Association class II-IV symptoms on diuretics and left ventricular EF (LVEF) ≥45%. Serial physical exams and symptom assessments were performed during the trial and a global score of HF signs and symptoms was devised. Patients were categorized as having low (≤2 signs and symptoms) or high (≥3 signs and symptoms) HF burden. This cut off was used based on an increase in the incidence of the primary endpoint. The primary endpoint consisted of a composite of all HF hospitalizations and cardiovascular death.
Results:
A total of 4,725 patients with complete exam and symptom assessment were enrolled. This included 2,953 (62%) who had a low burden of HF signs and symptoms at randomization. Patients in the high burden group were more likely to be women with a slightly lower EF, higher body mass index, higher comorbidity burden, and were more likely to be on diuretics and renin-angiotensin antagonists prior to randomization. Incidence of the primary endpoint was higher in patients with high HF burden (17.4 per 100 patient-years) compared to the low burden group (11.4 per 100 patient-years). High burden of signs and symptoms was also associated with an increased risk for all-cause death, but this was attenuated after multivariable adjustment.
Among HF signs and symptoms, orthopnea was associated with the primary endpoint (rate ratio [RR], 1.29; 95% confidence interval [CI], 1.04-1.61) with presence of rales (RR, 1.52; 95% CI, 1.10-2.10). Only orthopnea was independently associated with cardiovascular death. Global HF burden score increased immediately prior to first HF hospitalization or cardiovascular death. For patients who did not have any cardiovascular events, HF burden score improved over time. The effect of sacubitril-valsartan on the primary endpoint did not differ by HF burden. Sacubitril-valsartan did not improve global HF signs and symptoms over the course of the study compared to valsartan. However, sacubitril-valsartan did improve dyspnea on exertion (odds ratio, 0.76; 95% CI, 0.63-0.93), but other signs and symptoms did not change.
Conclusions:
In a post hoc analysis of the PARAGON-HF trial, a greater burden of HF signs and symptoms at randomization was associated with an increased risk for total HF hospitalizations and cardiovascular death in HFpEF patients. Presence of orthopnea or rales was associated with total HF hospitalizations and cardiovascular death. Global HF score increased prior to first HF hospitalization or cardiovascular death. Sacubitril-valsartan use in HFpEF patients only decreased dyspnea on exertion, but did not have an impact on other symptoms.
Perspective:
Physical exam correlates poorly with hemodynamics in HF patients, in part due to development of compensatory mechanisms. Nonetheless, HF signs and symptoms in HF with reduced EF correlate with adverse outcomes. However, significance of HF signs and symptoms for HFpEF patients is not as well studied. Results of this study highlight the relevance of a careful assessment of HF signs and symptoms among HFpEF patients: a higher burden of HF signs and symptoms predicted an increased risk for HF hospitalization and cardiovascular death. Notably, presence of orthopnea and rales individually correlated with a higher risk of hospitalization and cardiovascular death, independent of B-type natriuretic peptide (BNP) levels. Treatment with sacubitril-valsartan did not lead to improvement in HF symptoms in HFpEF patients, but did lead to improvement in dyspnea on exertion.
Clinical Topics: Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Novel Agents, Acute Heart Failure, Heart Failure and Cardiac Biomarkers
Keywords: Angiotensins, Comorbidity, Diuretics, Dyspnea, Heart Failure, Natriuretic Peptide, Brain, Physical Exertion, Renin, Risk, Stroke Volume, Symptom Assessment
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