Pneumonia in HF Patients Is Common, Lethal, and Preventable

Analysis of PARADIGM-HF/PARAGON-HF shows a fourfold higher mortality, underscoring the importance of vaccinations.

Pneumonia in HF Patients Is Common, Lethal, and Preventable

For patients with heart failure, the risk of dying after an episode of pneumonia is up to fourfold higher than if they had not contracted the disease, with the risk for vascular events and death remaining high for months after recovery, according to a post hoc analysis of the PARADIGM-HF and PARAGON-HF trials.

While pneumonia is typically considered an acute illness, prior research has documented a link to subsequent ACS; whether it can also exert long-term risks for heart failure was unclear, the authors say. And while pneumonia vaccines against the two most-common strains are widely available and vaccination is recommended in HF guidelines, uptake has been poor.

“The main reason for doing this study was the fact that many heart failure patients are not vaccinated (as they should be) against pneumonia—both pneumococcus and influenza vaccination—and we wanted to document the frequency and consequences of pneumonia in patients with heart failure to help highlight this deficiency in care,” senior author John J.V. McMurray, MD (University of Glasgow, Scotland), said in an email.

PARADIGM-HF and PARAGON-HF were both randomized, double-blind, controlled trials comparing sacubitril/valsartan (Entresto; Novartis) against a renin-angiotensin-aldosterone-system alone—the former in heart failure patients with reduced ejection fraction (HFrEF), the later in those with preserved ejection fraction (HFpEF). Characteristics of patients in both trials who developed pneumonia were similar and included older age; lower Kansas City Cardiomyopathy Questionnaire clinical summary score; and higher prevalence of comorbidities, including chronic obstructive pulmonary disease, diabetes, and atrial fibrillation. Pneumonia patients in both trials also had higher baseline NTproBNP levels and lower estimated glomerular filtration rate than patients who did not develop pneumonia.

Even after recovering, patients who had pneumonia retained an elevated risk of all-cause death, CV death, and HF hospitalization that was 1.5- to twofold higher than their pre-pneumonia risk for those events. That finding, McMurray said, aligns with a prior study of patients with CAD and acute MI that found that the risk of vascular events and death associated with an episode of pneumonia persists long after the acute event resolves.

In an editorial accompanying the new analysis published today in the Journal of the American College of Cardiology, Donna Mancini, MD and Gregory T. Gibson, MD (both Icahn School of Medicine at Mount Sinai, New York, NY), offer suggestions as to why HF patients may be particularly vulnerable to developing pneumonia and having poor outcomes from it.

“Acutely, increased alveolar fluid in heart failure could impair bacterial clearance and affect local defense mechanisms, resulting in pneumonia, but previous research also implicated dysregulation of inflammatory pathways and decreased nitric oxide production with resulting endothelial dysfunction,” they write. “This persistence of an elevated inflammatory state might contribute to the development or worsening of heart failure symptoms and might explain why persistently worse outcomes were seen in this study even after patients had recovered from the acute pneumonia event.”

To TCTMD, McMurray said while the inflammatory hypothesis is a possibility, “it is also possible that it is myocardial, kidney and/or vascular damage occurring at the time of acute infection that leaves such patients at increased subsequent risk of poor outcome.”

Quadrupling of Risk

McMurray and colleagues, led by Li Shen, MBCHB, PhD (Hangzhou Normal University, China), examined the rate and impact of pneumonia in the PARADIGM-HF and PARAGON-HF trials.

Approximately 6% of PARADIGM-HF patients developed pneumonia, for an incidence rate of 29 per 1,000 patient-years. The numbers were even higher in PARAGON-HF, where 10.6% of patients developed pneumonia, for an incidence rate of 39 per 1,000 patient-years.

When pneumonia did occur, it was associated with a significant increase in components of the primary endpoint and death from any cause compared with not having pneumonia.

Risk of Outcome Events After Pneumonia


HR (95% CI)

All-Cause Death

4.34 (3.73-5.05)

CV Death

3.62 (3.02-4.34)

HF Hospitalization

2.39 (1.86-3.07)

CV Death or Hospitalization

2.72 (2.27-3.26)



HR (95% CI)

All-Cause Death

3.76 (3.09-4.58)

CV Death

3.03 (2.31-3.98)

HF Hospitalization

1.98 (1.52-2.58)

A look at all outcome events by time from pneumonia episode found that the risks were highest in the first month, but remained elevated two- to fourfold from months 1 to 3. By treatment group, those who received sacubitril/valsartan were no less likely to develop pneumonia than those receiving only valsartan.

Mancini and Gibson note that pneumonia was not a prespecified endpoint in either trial, and point out that “there were no clinical criteria by which patients were diagnosed, no adjudication of these events, and no available data regarding the methods of diagnosis, severity, culture or serology results, and treatment.” Another unknown is the proportion of pneumonia events that were related to community exposure versus those acquired in the hospital.

Future Vaccination Goals

To TCTMD, McMurray said the take-home message is to focus on preventing pneumonia by ensuring that HF patients get vaccinated against it. If recent evidence is any indication, that message is needed now more than ever. Data from the Get With The Guidelines–Heart Failure registry shows that the rate of pneumococcal vaccination declined from 71% of HF patients in 2013 to 60% in 2016.

Mancini and Gibson also point out that data on the efficacy of pneumococcal vaccination in HF patients is limited and contradictory. It remains to be seen whether getting more patients vaccinated and/or using a higher dose of trivalent vaccine will make a difference in this population. So, while vaccination alone is unlikely to be a panacea, they say, “it is a readily accessible tool for mitigating disease severity and improving outcomes.”

Both McMurray and the editorialists acknowledge that the current COVID-19 pandemic is yet another reminder of the dangers of respiratory infections for patients with HF.

“In this sense, I suppose the current COVID-19 situation provides a good educational opportunity for patients and doctors regarding the importance of our other vaccines (ie, those to protect against pneumococcus and influenza),” McMurray said.

  • PARADIGM-HF and PARAGON-HF were funded by Novartis.
  • Shen reports no relevant conflicts of interest.
  • McMurray reports support from a British Heart Foundation Centre of Research Excellence Grant.
  • Mancini and Gibson report no relevant conflicts of interest.