Trial Design and Oversight

The Partial Oral Treatment of Endocarditis (POET) trial was a nationwide investigator-initiated, multicenter, randomized, unblinded, noninferiority trial performed at cardiac centers in Denmark. The trial design has been published previously.17 The trial was overseen by an independent data and safety monitoring board. The protocol is available with the full text of this article at NEJM.org. The trial was approved by the regional scientific ethics committee for the Capital Region of Denmark and by the Danish Data Protection Agency and was performed in accordance with the principles of the Declaration of Helsinki. All participants provided written informed consent. All the authors vouch for the completeness and accuracy of the data and analyses presented and for the fidelity of the trial to the protocol.

Patients

Eligible patients were adults, 18 years of age or older, in stable condition who were receiving intravenous antibiotic treatment for endocarditis on the left side of the heart (on native or prosthetic valves), who fulfilled the modified Duke criteria,19 and who had blood cultures that were positive for streptococcus, Enterococcus faecalis, Staphylococcus aureus, or coagulase-negative staphylococci. Decisions about whether to offer surgery or to remove a pacemaker or an implantable cardioverter–defibrillator were made at multidisciplinary team meetings according to established guidelines and were not a part of the trial. Only patients in stable condition were enrolled (i.e., patients who had had satisfactory clinical responses to initial treatment, including antibiotic treatment administered intravenously for at least 10 days and, among patients who had undergone valve surgery, for at least 7 days after the surgery). In addition, transesophageal echocardiography performed before randomization had to show no signs of abscess formation or valve abnormalities that would require surgery (a full list of inclusion and exclusion criteria is provided in Table S1 in the Supplementary Appendix, available at NEJM.org). At the time of randomization, at least 10 days of scheduled antibiotic treatment had to remain. Patients assigned to receive intravenous treatment remained in the hospital until antibiotic treatment was completed. If feasible, patients assigned to receive oral treatment were treated in the outpatient clinics and were seen two to three times per week. Within 1 to 3 days before the completion of the assigned antibiotic treatment, transesophageal echocardiography was performed to confirm that the patient had a sufficient response to treatment. All patients were discharged from the hospital on the day the antibiotic treatment was terminated (determined before randomization); all patients were seen in the outpatient clinic at 1 week and at 1, 3, and 6 months after completion of antibiotic treatment. Enrollment and the assignment of treatment were performed by local investigators with a Web-based case-report-form system.

Choice of Antibiotics

Intravenous antibiotic treatment was administered in accordance with guidelines of the European Society of Cardiology, with modifications endorsed by the Danish Society of Cardiology.2,20 The trial investigators developed oral antibiotic treatment regimens as part of the trial (Table S2 in the Supplementary Appendix). Antibiotics for which published data showed moderate to high bioavailability were chosen. The oral regimens were based on pharmacokinetic calculations and expected minimal inhibitory concentrations (MICs) for each bacterial species published by the European Committee on Antimicrobial Susceptibility Testing (EUCAST).21 In all cases, susceptibility testing by means of disk diffusion was performed in accordance with EUCAST guidelines. MICs were determined with the use of Etest or VITEK2 (bioMérieux), and the choice of antibiotics for each patient was adjusted accordingly. In all cases, the oral regimens consisted of two antibiotics from different drug classes with different antimicrobial mechanisms of action and different metabolization processes to reduce the risk of de facto monotherapy (e.g., in the case of reduced gastrointestinal uptake or fast metabolization of one drug).

Pharmacokinetics

To ensure that patients received sufficient doses of antibiotics, blood samples for the measurement of plasma levels of orally administered antibiotics were obtained on day 1 after the administration of a single dose (30 minutes and 1, 2, 4, and 6 hours after administration) and on day 5, after the administration of multiple doses (with the assumption that a steady state would have been achieved by this time). Samples were also obtained from patients in the intravenously treated group on day 1. Samples were analyzed with the use of high-pressure liquid chromatography. For safety considerations, the first dose and steady-state pharmacokinetics were evaluated (Table S3 in the Supplementary Appendix). Antibiotic doses were adjusted according to pharmacokinetic findings, if necessary.

Trial Procedures

Participants were randomly assigned in a 1:1 ratio to continued intravenously administered antibiotic treatment or to a shift to orally administered antibiotic treatment. Randomization was performed with the use of a Web-based system, in permuted blocks of 2 to 6, with stratification according to randomization site.

Outcomes

The primary outcome was a composite of all-cause mortality, unplanned cardiac surgery, clinically evident embolic events, or relapse of bacteremia with the primary pathogen (detected in blood cultures obtained during follow-up or for clinical reasons) from randomization through 6 months after antibiotic treatment was completed. A clinical-event adjudication committee, whose members were unaware of the treatment assignments, adjudicated the prespecified clinical outcomes. The committee consisted of experienced cardiologists and a specialist in infectious diseases.

Statistical Analysis

The trial was designed as a noninferiority trial; that is, it was designed to determine, with the use of a noninferiority margin, whether partial oral treatment was noninferior to conventional intravenous treatment. We estimated event rates for the four components of the primary composite outcome from the literature17; we estimated the risk of all-cause mortality to be 2 to 5%, the risk of unplanned surgery to be 1 to 3%, the risk of embolic events to be 1 to 2%, and the risk of relapse of bacteremia to be 1 to 3%. Thus, the overall risk of the primary outcome was 5 to 13%. A risk difference (i.e., a noninferiority margin) of 10 percentage points was chosen (see the Supplementary Appendix). Under the assumption of a 10% event rate and a 5% loss to follow-up, we determined that inclusion of 400 patients would be required to provide a power of 90% to confirm noninferiority, with a one-sided confidence interval of 97.5%. Continuous variables are presented as means and standard deviations or medians and interquartile ranges, as appropriate, and were compared with the use of Student’s t-test or the Mann–Whitney U test. Categorical variables are expressed as absolute numbers and frequencies and were compared with the chi-square test, including Yates’ correction for continuity. Logistic-regression analysis was used to calculate odds ratios for the primary outcome in prespecified subgroups. Cox regression analysis was used to assess the components of the primary composite outcome to address competing risks (e.g., death). The proportional-hazard assumption was assessed with Schoenfeld residuals. All analyses were performed according to the intention-to-treat principle. A per-protocol analysis is also presented for the primary outcome; in the per-protocol analysis, patients who crossed over from their assigned treatment to the other treatment were excluded. Cumulative incidences were calculated for events with competing risk (death) for the outcomes of unplanned cardiac surgery, embolic events, and relapse of bacteremia with the primary pathogen. Two-sided P values of less than 0.05 were considered to indicate statistical significance. Analyses were performed with the use of SPSS software, version 22.0 (IBM), and R software, version 3.3.3 (R Foundation for Statistical Computing).22-24