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NEW ORLEANS — Longer-term follow-up of stabilized patients with infective endocarditis in the left side of the heart shows no delayed treatment failure with a change from intravenous to early oral antibiotic treatment, sparing them weeks of in-hospital treatment.

The results, a post hoc exploratory analysis of the POET trial, were presented here at the ACC 2019 Scientific Session (ACC.19), and published online March 17 as Correspondence in the New England Journal of Medicine.

Primary findings of the POET trial were presented at the European Society of Cardiology Congress 2018, and published online August 28, 2018, also in the New England Journal of Medicine.

They showed that initial intravenous (IV) therapy followed by a switch to two-drug oral antibiotic therapy was noninferior to IV-only treatment for the primary composite end point of all-cause death, unplanned cardiac surgery, embolic events, or relapse of bacteremia at 6 months. The findings were consistent across subgroups, including type of bacteria, native vs prosthetic heart valves, and surgically vs conservatively treated patients.

“Based on these results, more than 50% of all patients with endocarditis may be candidates for partial oral antibiotic treatment,” lead author Henning Bundgaard, MD, Copenhagen University Hospital, Denmark, concluded at that time.

At the meeting here, Bundgaard presented an extended analysis looking at outcomes out to a median of 3.5 years.

Infective endocarditis is treated using IV antibiotics given over about 6 weeks in the hospital and is associated with high in-hospital mortality and complication rates, he said. “Mortality generally is said to be about 20%, but these complications are mainly seen during the early phase of the disease.”

After the patients are stabilized, then the main reason for staying in hospital is to receive IV antibiotics, “and we all know that hospital stays, per se, can cause complications, he explained.

To see if a switch to oral antibiotics would be possible, POET enrolled 400 patients with left-sided infective endocarditis, stabilized after at least 10 days of IV antibiotic treatment, and assigned them randomly to receive continued intravenous therapy (199 patients) or to switch to oral antibiotic treatment (201 patients). Those who received oral antibiotics were eligible for outpatient rather than in-hospital treatment, and 80% of the patients were treated at least partly in the outpatient setting.

For the extended follow-up, the researchers examined the same primary outcome end points: a composite of all-cause mortality, cardiac surgery that was unplanned at randomization, embolic events, or relapse of bacteremia with the primary pathogen. Patients in this study had endocarditis stemming from streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci.

A clinical event committee, blinded to treatment assignment, adjudicated the clinical events. None of the patients were lost to follow-up, Bundgaard noted.

After a median follow-up of 3.5 years, a composite outcome event occurred in 76 (38.2%) patients in the IV group and 53 (26.4%) in the oral switch group (hazard ratio [HR], 0.64; 95% CI, 0.45 – 0.91).

No significant differences were seen in other outcomes, including unplanned cardiac surgery, embolic events, “or — of particular interest — relapse of infection,” the researchers note in their publication.

Of the 87 (21.8%) patients who died, 54 (27.1%) were in the IV-only group and 33 (16.4%) were in the oral-treatment group (HR, 0.57, 95% CI, 0.37 – 0.87), which is a significant difference in the rate of survival, Bundgaard noted.

The main causes of death were cardiovascular disease, infections, and cancer, he said, “and for all three entities, the values were numerically higher in the intravenously treated group, compared with the orally treated group.”

Both groups were in the hospital for 17 days from the time of diagnosis to the time of randomization, and those receiving IV and oral treatment assignments were treated for an average of 19 and 17 days, respectively, after randomization. However, although IV patients spent all 19 of those days in the hospital, the orally treated group stayed in the hospital for a median of only about 3 days after randomization (< .001).

“On this basis, we conclude that efficacy and safety of changing to oral antibiotic treatment is noninferior to continued intravenous antibiotic treatment short-term, and with reassuring — I would say very reassuring — long-term outcomes in stabilized patients with left-sided endocarditis caused by one of these four bacteria,” Bundgaard said.

Changing Practice?

During discussion of the study after the presentation, David Mushatt, MD, MPH, chief of infectious diseases, Tulane University, New Orleans, called these results “very timely, in light of the opioid epidemic, and hopes that these data may actually help us shorten length of stay and reduce picc-line complications in this very challenging population.”

He put forward a couple of caveats in terms of extrapolating these data from this Danish cohort to the American population. “Most of the patients actually had strep, not staph — about 22% had Staph aureus — and there were no individuals with MRSA (methicillin-resistant Staphylococcus aureas), unlike in this country,” Mushatt noted. “Only five subjects were injection-drug users, less than 6% had large vegetations, and patients in the oral arm were seen two to three times a week, which would be difficult to pull off in our academic health centers.”

He asked Bundgaard why he thought the mortality trended significantly lower in the oral group in the long-term follow-up. “I don’t quite understand that, especially in terms of the decrease in cardiovascular death,” Mushatt said.

“First of all, I think that the positive outcome in the oral group was not related to the administration of antibiotics,” Bundgaard responded. “I think the major difference between the two groups was that the intravenously treated patients stayed in hospital more than 2 weeks longer than the orally treated patients, and we all know that staying in hospital may cause physical as well as mental losses.

“The patients’ capacities are reduced and these patients are quite often elderly and have significant comorbidities,” he added. “So maybe they don’t ever recover from a functional loss after their prolonged hospital stays,” making them more vulnerable when struck by a subsequent heart failure, pneumonia, or cancer.

Gurusher Panjrath, MD, chair of the ACC Heart Failure and Transplant Council, assistant professor of Medicine, George Washington University School of Medicine, Washington, DC, who discussed the study during a press conference here, was also cautious on the generalizability of the findings.

Panjrath called the data strong, pointing out that the primary outcome was met, and commending researchers on 100% follow-up. However, he also raised the question of how data from this trial can be extrapolated to the United States in terms of the lack of MRSA patients and the lower number of intravenous drug users, compared with the population presenting with infective endocarditis in the United States.

“So this is a great first step, but we need maybe a little more information before we just jump right in applying these findings,” he said, perhaps with “better collaborative efforts across the ocean on future trials.”

Supported by grants from the Danish Heart Foundation, the Svend Andersens Foundation, the Capital Regions Research Council the Hartmann’s Foundation, and the Novo Nordisk Foundation.

N Engl J Med. Published online March 17, 2019. Correspondence

American College of Cardiology (ACC) 2019 Scientific Session. Presented March 17, 2019.

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