Antibiotic prophylaxis prescribing for infective endocarditis in the United Kingdom stayed relatively constant until the introduction of the NICE guideline in March 2008; most (91.9%) prescribing was by dental practitioners. After the introduction of the guideline a large (78.6%) and rapid decrease occurred in prescribing of antibiotic prophylaxis. However, we did not detect a significant increase in the number of infective endocarditis cases above the long term baseline trend over this period. Neither was there a significant increase in the rate of infective endocarditis related deaths in hospital nor a significant increase in the number of cases due to streptococci of possible oral origin.
Limitations of the study
The study has several limitations. Firstly, it was retrospective and limited to England and therefore may not be generalisable to other populations. Secondly, the data rely on hospital coding. In the United Kingdom, data are collected on every patient admitted to hospital, and the coding is done by trained and accredited staff. Although these data can be subject to coding errors, the coding has been shown to be more reliable and complete in capturing data on, for example, all cases of vascular surgery than a national research database specifically designed for that purpose.18
Furthermore, as the coding was done independently of the study it was not subject to study bias or influenced in any way by the introduction of the NICE guideline. As the study sample was based on national data, the size of the dataset and the consistency of the process are likely to average out any error.
Although patients with infective endocarditis may present to different hospital specialties and the disease may be difficult to diagnose initially, data from hospital episode statistics records only the discharge diagnosis and should therefore reflect as accurately as possible the actual number of cases treated. None the less, because the diagnosis of endocarditis is sometimes uncertain, some cases will undoubtedly have been missed and others will have been erroneously labelled as endocarditis. The number of deaths from infective endocarditis in hospital were obtained from hospital episode statistics data, defining the status at discharge from hospital (dead or alive). Thus the data reflect deaths that are the immediate result of a hospital admission for infective endocarditis and will not have captured deaths before admission or deaths at home as a result of the late complications of the disease. The mortality data are therefore not directly comparable to long term follow-up studies of patients with infective endocarditis.
Thirdly, there is no requirement to record anything other than a primary diagnosis for each patient; a causal organism was recorded in only around 70% of cases towards the end of the study. In addition there is no specific ICD-10 code for viridians group streptococci. We therefore had to use codes for “unspecified” or “other” streptococci to identify cases of infective endocarditis with a possible viridians group streptococcal cause. Nevertheless, these codes exclude group A, B, and D streptococci and S pneumoniae
and, given the microbiology of the oral cavity and infective endocarditis, it is possible that oral viridians group streptococci account for a high proportion of the organisms in this group.19 20
Fourthly, although 35-45% of cases of infective endocarditis are caused by oral viridians group streptococci,5 6 7 8 9
good data are lacking on the proportion resulting from an invasive dental procedure. However, the strategy of giving antibiotic prophylaxis to prevent infective endocarditis is based on the premise that a high proportion of these cases result from oral bacteria entering the circulation during dental procedures. An alternative view, however, is growing that oral bacteria continuously enter the circulation21 22
as a result of daily activities such as chewing food and tooth brushing, and these may be far more important causes of oral viridians group streptococci associated cases of infective endocarditis. If true, the proportion of cases caused by invasive dental procedures could be low. The reality could, however, lie anywhere between these two extremes.
Without accurate data on the proportion of cases caused by dental procedures it is difficult for statistical analysis purposes to predefine a clinically relevant level of change after the cessation of antibiotic prophylaxis, or to determine the sample size needed to detect the change. Using the premise that a high proportion of cases are caused by dental procedures, a large increase in the number of cases would be expected if antibiotic prophylaxis was stopped and was effective, and a comparatively small population would be needed to detect a statistically significant change. On the other hand, if the number of cases caused by dental procedures was small, it would require an infinitely large population to detect any increase in the number. Indeed, to exclude a 1% increase in the incidence of infective endocarditis above the baseline trend, assuming a similar incidence of infective endocarditis and variability in the numbers of cases on a month by month basis, would require a study population of 478.5 million people. For this reason, even with a study covering the entire population of England, the possibility of a small increase in cases after cessation of antibiotic prophylaxis cannot be excluded. However, that we identified no significant increase in cases in a population of this size, despite a large decrease in prescribing of antibiotic prophylaxis, suggests that invasive dental procedures are unlikely to account for a high proportion of the cases.
Because of this, and because of the nature of the statistical test we applied, we used the quality of the available data to determine the limits of detection rather than estimate a clinically relevant level of change. The 15% margin of error set for the statistical analysis was determined a priori based on the variability in monthly incidence figures for cases of and deaths from infective endocarditis in the period before March 2008. After the analysis was done, however, we were able to exclude a 9.3% increase in the number of cases and a 12.3% increase in deaths in the setting of a 78.6% decrease in prescribing of antibiotic prophylaxis. Although oral viridians group streptococci are likely to account for only 35-45% of cases, if antibiotic prophylaxis was effective we would expect the number of cases and deaths to increase significantly more than 9.3% and 12.3%, respectively, and the number of cases with a probable oral streptococcal origin to rise much higher.
There is the concern that the period of follow-up was not long enough. However, in over 90% of cases the incubation period for infective endocarditis is less than six weeks, and other studies have used three months as the cut off for capturing all cases of infective endocarditis that will develop after exposure to the risk of infection.8 9
We therefore believe that if antibiotic prophylaxis was effective in preventing infective endocarditis the large decrease in prescribing of antibiotic prophylaxis that occurred after the introduction of the NICE guideline would have resulted in a detectable increase in cases during the 25 months of the study. Any such change should have been particularly noticeable among those cases where the causal organism was of possible oral streptococcal origin. Regardless, we intend to periodically monitor the rate of endocarditis in the English population over time.
The 78.6% decrease in prescribing of antibiotic prophylaxis in the months after the introduction of the guideline was large and suggests much better compliance than is often seen after policy changes in medicine. Compliance was particularly good among dentists who, as well as being strongly urged to adopt the new guidelines by the chief dental officer, NICE, and the dental press, were advised by the malpractice insurance organisations that it would be difficult to defend cases where the new guidelines had not been followed. A residual level of prescribing does, however, seem to persist at around 20% of the level before the guideline. There are several possible explanations for this. Firstly, the guideline allows antibiotic prophylaxis to be prescribed to patients who have previously received it and insist on continuing to have it, even after the rationale for the change in policy has been fully explained. Secondly, anecdotal evidence suggests that some cardiologists are pressurising dentists or, where dentists refuse to prescribe, the patient’s general medical practitioner to provide antibiotic prophylaxis for patients they regard at particularly high risk of infective endocarditis, such as patients with significant congenital heart lesions, prosthetic heart valves, or a history of infective endocarditis. In other words, some clinicians in the United Kingdom may be implementing the European Society for Cardiology or American Heart Association guidelines rather than the NICE guideline.23
Finally, anecdotal evidence also suggests that a small proportion of dentists in the United Kingdom prescribe a 3 g dose of amoxicillin (or 600 mg dose of clindamycin) to treat acute dental infections. The precise contribution of each of these explanations to the residual 20% prescribing figure is hard to quantify.
Over the past 10 years a general move has been to reduce antibiotic prescribing to save cost and to prevent the development of antibiotic resistant bacteria. Although this could have played a part in the reduction in prescribing of antibiotic prophylaxis, it seems unlikely given the size and suddenness of the reduction, its coincidence with the introduction of the NICE guideline, the low cost of a single dose of amoxicillin or clindamycin, and national prescribing data that show a slight increase in the general prescribing of penicillins and macrolide antibiotics over the same period.
The results of this analysis cover a large group of patients for whom antibiotic prophylaxis was prescribed before the introduction of the NICE guideline. Our results suggest that for most of these patients, including those with a history of rheumatic fever or a heart murmur, there may be little or no benefit in giving antibiotic prophylaxis to prevent infective endocarditis. However, because we cannot exclude the possibility that residual antibiotic prophylaxis prescribing targets those perceived to be at highest risk of infective endocarditis, it does not completely tackle the problem of whether a subset of patients, particularly those with prosthetic heart valves or a history of infective endocarditis, might still benefit from antibiotic prophylaxis. To more directly answer this question a carefully designed, randomised, placebo controlled trial of antibiotic prophylaxis in these patients would be required.
Our data suggest that despite a substantial decrease in prescribing of antibiotic prophylaxis in England since the introduction of NICE guideline No 64 in March 2008 there has been no significant increase in the number of cases of infective endocarditis, as measured using data from hospital episode statistics.
Some clinicians remain concerned that the NICE recommendation to stop antibiotic prophylaxis in the United Kingdom, and the reduced number of patients receiving antibiotic prophylaxis in the United States and Europe as a result of the restriction of antibiotic prophylaxis to patients thought to be at high risk in the latest American Heart Association2
and European Society of Cardiology3
guidelines, will result in an increased incidence of infective endocarditis. Although one small study found no cause for concern after the change in the American Heart Association guidelines24
the present trial is the first large scale study to evaluate the effect of the NICE guideline recommendation to stop antibiotic prophylaxis to prevent infective endocarditis.
Although these findings lend support to the NICE guideline recommendations and suggest that antibiotic prophylaxis before invasive dental procedures is unlikely to be of value in preventing infective endocarditis in patients with a history of rheumatic fever or a heart murmur, our findings do not exclude the possibility that a small number of patients at highest risk, such as those with prosthetic valves, might benefit. Ongoing monitoring of the data is required for confirmation, and further studies are needed to determine if antibiotic prophylaxis has a role in protecting a small group of patients at highest risk from infective endocarditis.
What is already known on this topic
- Previous policy in the United Kingdom was to provide antibiotic prophylaxis to patients at risk of infective endocarditis before invasive dental procedures
- Antibiotic prophylaxis for patients thought to be at high risk of infective endocarditis is still the policy in most other parts of the world
- In March 2008 NICE recommended the complete cessation of antibiotic prophylaxis before dental and other invasive procedures
What this study adds
- After the introduction of NICE clinical guideline No 64 a large (78.6%) and rapid decrease occurred in prescribing of antibiotic prophylaxis
- Despite this reduction, no large increase occurred in the incidence of infective endocarditis cases or deaths in the two years after the guideline was introduced
- The findings support the cessation of prescribing of antibiotic prophylaxis recommended by the guideline