Is the largest randomised controlled trial for Infective Endocarditis “POET” a practice changer? A review of IE treatment.

Infective endocarditis (IE) accounts for an estimated annual incidence of 3 to 10 cases per 100,000 in most surveys⁽¹⁾ and worldwide poses significant risk of morbidity/mortality. In 2010, it was observed that IE caused 1.58 million disability - adjusted life-years attributed to illness / impairment and death.⁽²⁾ On average, it accounts for around 7.5 admissions per 10,000 patients in a district general hospital.⁽³⁾ These admissions usually last weeks to months and in contrast to other infectious diseases, switching from parenteral to oral treatment has not been an option so far in IE.

The characteristic lesion of IE is the endocardial vegetation which is composed of inflammatory cells, platelets, fibrin and a plethora of bacteria. Over time, if untreated, endocardial tissue invasion ensues, followed by haematogenous spread peripherally as septic emboli.^(4-5) As we all know, the bacteria are deeply embedded in the vegetations, therefore an effective and adequate therapeutic concentration of antibiotics is required for sustained period of time to penetrate into these vegetations and achieve a cure. For these reasons, the gold standard treatment, backed by existing evidence, remains a prolonged course of intravenous antibiotics.^(4-7)

As per current European Society of Cardiology (ESC) and American Heart Association (AHA) guidelines^(8-9), the recommended treatment duration of intravenous (IV) antibiotics can vary from 2 to 6 weeks depending upon many factors including infecting organism, endocarditis of native valve or prosthetic valve and associated complications. It has been seen that the majority of complications including death occurs during the initial phase of treatment, usually within the 1st week.^(10-12)

Receiving antibiotics for 6 long weeks, often through central access (which itself also carries risk) can be daunting and associated with increased risk of complications. It is therefore interesting and appropriate to look for approaches that allow early discharge of clinically stable patients if they could safely complete the course of IV antibiotics as an outpatient.

What if certain groups of IE patients could safely receive domiciliary antibiotics orally, after the initial phase of IV treatment, and successfully cure the disease? It would just be “wow’ both for the patients and cardiologists. The POET trial (Partial Oral Treatment of left sided Endocarditis) tested this hypothesis.

Evidence from the past

Unfortunately, due to a relatively low incidence of IE, clinical variability and complexity derived from at-risk populations, multiple causative organisms and underlying risk-factors, there has been paucity of studies evaluating the efficacy and safety of oral antibiotics for treating IE. Many observational studies have been done in the past but only few randomised controlled trials were done to study this question.

Heldman et al ⁽¹³⁾ focused on the treatment of S. aureus infective endocarditis affecting the right sided valves in intravenous drug users with oral antibiotics. It was a randomised, prospective, non-blinded trial in 85 patients, comparing the safety and efficacy of oral rifampicin and ciprofloxacin versus IV antibiotics therapy, both administered as inpatient. The cure rate was reported to be 89% and 90%, respectively (P=0.9). Drug related adverse effect was more common in IV group, 61.5% versus 2.8% (P<0.0001).

Stamboulian et al ⁽¹⁴⁾ treated 30 patients with left sided endocarditis caused by penicillinsusceptible streptococci (S. Bovis and S.Viridians). This was an open-label, prospective, randomised, non-blinded trial performed in Argentina which compared the efficacy of 2 weeks course of IV Ceftriaxone followed by 2 weeks of oral amoxicillin versus standard 4 weeks of IV Ceftriaxone. They reported the cure rate to be 100% in both group of patients and drew the inference that the combination of IV and oral antibiotics can be as effective as IV antibiotics. It also concluded that approximately 380 days of hospital stay were saved by treating with oral antibiotics as an outpatient (estimating an average of 20 days hospital stay per patient).

Interestingly, analysis of these trials showed the trend that treatment with an oral antibiotic regimen is an acceptable alternative to intravenous treatment for certain groups of patients. However, small sample sizes, the lack of allocation concealment, unblinded design and lack of blinded assessment of outcomes were the major limitations of these trials. In the face of such limitations, it is not surprising that they had no significant impact in changing the approach to the management of infective endocarditis. Furthermore, none of these trials included prosthetic valve endocarditis and covered only few organisms but fortunately the Danish trial – POET was planning big.

Then comes the POET

The POET trial was the largest study performed so far to cast new light on the management of IE with oral antibiotics. It was a randomised trial, which recruited patients in all Danish heart centres. The goal was to determine whether the treatment with oral antibiotics following an initial 10 days of IV antibiotics is non-inferior to the established paradigm of 6 continuous weeks of IV antibiotics.

Figure 1: The POET trial design¹⁵

Of 1954 screened patients, a total of 400 patients, who had confirmed left-sided endocarditis secondary to Staphylococcus aureus, Streptococci, Enterococcus faecalis or Coagulase negative staphylococci and had adequate response to at least 10 days of initial IV antibiotics, were randomised to receive oral antibiotics (n= 201) versus IV antibiotics (n=199). In the oral therapy arm, two different class of antibiotics combination were used with good bioavailability including moxifloxacin, clindamycin, amoxicillin, rifampicin, dicloxacillin, linezolid and fusidic acid.

Mean age group was 67 years, 23% were females, 73% had native valve endocarditis, the rest had an infected prosthetic valve and 38% had valve surgery during the disease course. After randomisation, the duration of antibiotic therapy was not different between the oral and IV groups at 17 and 19 days respectively (p=0.48).⁽¹⁵⁾

The patients were followed-up for 6 months and the primary endpoint was a composite of death, cardiac surgery, embolic events and bacteraemia relapse with the original pathogen. The study showed that the oral therapy arm was noninferior to the IV arm with an incidence of 9% and 12% respectively for the primary endpoint.

The incredibly strict inclusion/exclusion criteria and stringent monitoring of participants was commendable. POET enrolled only those patients who had normal gastrointestinal uptake and every patient underwent transoesophageal echocardiogram at least twice during the trial to ensure these patients were safe for randomisation and having adequate response to the therapy (especially for the oral arm). The demographics of the patients enrolled, which included very low rates of chronic liver disease and IV drug users, are critical in evaluating the generalisability of these findings to real world care settings. Furthermore, the trial was not powered for outcome analysis of subgroups, in particular the various empirically defined oral antibiotic regimens.

Conclusion

Now, after this trial, shall I send my patient home who has staphylococcal aureus endocarditis of the native mitral valve and doing well after 10 days of IV antibiotics in hospital or wait for the next ESC congress for the outcome of another trial?

I suspect POET is a landmark trial which has the potential to impact on management of endocarditis. Applying this to current practice warrants significant experience and careful selection of patients and education, adherence with the antibiotic therapy and adequate monitoring. I anticipate findings of POET and further trials with favourable outcomes would likely generate major cost savings for the NHS in the near future.

References

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