High Incidence of Pneumonia in Heart Failure With Preserved Ejection Fraction

Colored chest X-ray (front view) of a patient aged 47, showing an enlarged heart (cardiomegaly, pink, center left and center right). This disease has caused heart failure (cardiac insufficiency) in which the heart cannot supply enough blood to the body.
Researchers aimed to determine the rate and impact of pneumonia in the PARADIGM-HF and PARAGON-HF trials.

Pneumonia incidence is high in patients with heart failure (HF), particularly in those with HF with preserved ejection fraction (HFpEF), with the first episode of pneumonia associated with a 4-fold higher mortality risk, according to research results published in the Journal of the American College of Cardiology.

Using patient data from the Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) and Prospective Comparison of ARNI with ARB Global Outcomes in Heart Failure with Preserved Ejection Fraction (PARAGON-HF) trials (ClinicalTrials.gov Identifiers: NCT01035255 and NCT01920711, respectively), researchers conducted a post-hoc analysis to investigate the rate and impact of pneumonia. They also evaluated pneumonia outcomes for longer-term sequelae.

The total study population included 8399 patients with HF with reduced ejection fraction (HFrEF) from the PARADIGM-HF cohort and 4796 patients with HFpEF from the PARAGON-HF cohort. The studies were randomized, double-blind, controlled trials comparing sacubitril/valsartan with a renin-angiotensin system blocker used alone.

Pneumonia cases during follow-up were identified through investigator-reported adverse events. The primary endpoint of the PARADIGM-HF study was time to first occurrence of HF hospitalization or cardiovascular death; the primary outcome of PARAGON-HF was all HF hospitalizations or cardiovascular death.

Of patients in the PARADIGM-HF trial, 528 (6.3%) developed pneumonia with an incidence rate of 29 per 1000 patient-years (95% CI, 27-32 per 1000 patient-years). In the PARAGON-HF trial, 510 patients (10.6%) of patients developed pneumonia, representing an incidence rate of 39 per 1000 patient-years (95% CI, 36-42 per 1000 patient-years).

Patients in the PARADIGM-HF trial with vs without pneumonia were generally older and more likely to be men (66.9 vs 63.6 years, respectively; 83.9% vs 77.8% men, respectively; P <.001). Patients in this trial also had a longer duration of HF but did not have a different frequency of previous HF hospitalizations. Kansas City Cardiomyopathy Questionnaire clinical summary scores (KCCQ-CSS) were generally worse in patients who developed pneumonia compared with those who did not (76 vs 80, respectively), although no differences were noted in New York Heart Association (NYHA) functional class. Patients who developed pneumonia also had more HF signs and symptoms compared with those who did not.

In the PARAGON-HF trial, the baseline characteristic differences between those who did and did not develop pneumonia were “broadly similar” to those seen in the PARADIGM-HF trial. Patients with vs without pneumonia were older and more likely to be men, but the sex difference was not significant (75.6 vs 72.4 years, respectively; 51.2% vs 48% men, respectively). Patients in this trial with pneumonia had a higher frequency of previous HF hospitalization but no difference in disease duration. Lower KCCQ-CSS scores and worse NYHA functional class was also noted.

Overall, patients with pneumonia had more comorbidities, including chronic obstructive pulmonary disease, diabetes, and atrial fibrillation, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels and lower estimated glomerular filtration rate (eGFR) than those who did not develop pneumonia.

The first pneumonia occurrence was associated with a 3- to 5-fold risk elevation for subsequent outcomes, which remained significant even after adjusting for other variables. Rate for death from any cause was 7.4 per 100 patient-years before pneumonia, and 39.5 per 100 patient years after pneumonia — a 4-fold elevation risk for death from any cause (adjusted hazard ratio [aHR], 4.34; 95% CI, 3.73-5.05).

In the PARAGON-HF trial, risks for all outcomes were elevated 2- to 5-fold after pneumonia, similar to the risks for the PARADIGM-HF trial. The AHR for risk for death from any cause was 3.76 (95% CI, 3.09-4.58).

Excess risk was significantly elevated even in sensitivity analyses. There was limited attenuation of the excess risk for sensitivity analyses that excluded episodes of pneumonia coinciding with HF hospitalization (19% and 15% of cases in PARADIGM-HF and PARAGON-HF, respectively).

In both trials, the elevated risk for all events examined was “extremely high” in the first month after a pneumonia episode, remained elevated by 2- to 4-fold during months 1 to 3, and stabilized thereafter. The elevation risk remained 1.5- to 2-fold higher than prior to the pneumonia episode.

In a comparator group of patients with urinary tract infection, 4.7% and 12.1% of patients in the PARADIGM-HF and PARAGON-HF trials were reported, which corresponded to rates of 22 and 45 per 1000 person-years, respectively.

Investigators found that sacubitril/valsartan did not reduce pneumonia risk for either trial. The hazard ratio (HR) for sacubitril/valsartan vs enalapril in the PARADIGM-HF trial was 0.99 (95% CI, 0.83-1.17); in PARAGON-HF, the HR for sacubitril/valsartan vs valsartan was 0.97 (95% CI, 0.81-1.15).

Study limitations included those inherent to retrospective research, the inclusion of patients who were less likely to have comorbidities compared with those in the real world, investigator reporting of pneumonia as serious adverse events with the possibility of different diagnosis criteria being used, and a lack of information on the specific causes of pneumonia cases.

“We found that incidence of investigator-reported pneumonia was high in patients with HF, especially HFpEF,” the researchers concluded. “An episode of pneumonia was of considerable prognostic importance, as it was associated with an approximately 4-fold elevation in risk [for] death.”

Disclosure: These clinical trials were supported by Novartis. Please see the original reference for a full list of authors’ disclosures.


Shen L, Jhund PS, Anand IS, et al. Incidence and outcomes of pneumonia in patients with heart failure. J Am Coll Cardiol. 2021;77(16):1961-1973. doi:10.1016/j.jacc.2021.03.001