Title: The Invasive Dentistry – Endocarditis Association Study: The IDEA Study
Funder: Department of Health and Social Care

Abstract: Background: Infective endocarditis (IE), an infection of the lining of the heart – particularly the heart valves, is a serious disease with high morbidity and mortality. Viridans group streptococci (VGS) from the oral cavity are implicated as the cause in 35-45% of cases. It is not clear if, and to what extent, VGS enter the circulation during daily activities such as chewing food and cleaning teeth or as a result of invasive dental procedures (IDP) such as extractions, endodontic treatment and dental scaling. Because of the hypothesised link to IDP, antibiotic prophylaxis (AP) prior to IDP has been the focus of IE prevention for over 60 years and remains the standard of care for individuals at high-risk of IE in most of the world. However, there has never been a randomised clinical trial (RCT) of AP. Because of this, NICE produced a guideline recommending cessation of AP in 2008. However, the UK is the only country in the world where AP is not currently recommended for patients at high-risk of IE. Furthermore, recent research has shown a significant increase in the incidence of IE following introduction of the 2008 NICE guideline. This has raised concerns about the advice not to give AP prior to IDP in the UK. Ethical concerns along with the size, cost and complexity explain why an RCT has not taken place to date and is unlikely to in the near future. Before an RCT would be worthwhile, we need to be certain that there is a link between IDP and episodes of IE and that is the purpose of the IDEA-study. Indeed, such a study could render an RCT unnecessary. Methods: The IDEA-Study will link national data on courses of dental treatment and on hospital admissions for IE to investigate if there is a link between IDP and the development of IE. Incubation period data indicates that nearly all IE cases present within 3 months of a causal bacteraemic event such as an IDP. So we will address the following questions: 1. Is the incidence of IDP higher in the 3 months immediately preceding an IE diagnosis than in earlier 3 month matched control periods (case-crossover design study)? 2. Do courses of dental treatment (CoT) involving an IDP occur more frequently than CoT that do not contain an IDP in the 3 months immediately preceeding an IE diagnosis? 3. If there is an association between IDP and IE, how soon after the IDP is the peak incidence of IE? We will plot Kaplan-Meier survival analysis curves comparing IE free survival following CoT with and without an IDP. 4. We will also investigate if IE occurs more frequently after specific types of IDP (extraction, scaling etc) or in individuals at high-risk of developing IE. Importance: This study is important because there are ~2,000 cases of IE in England annually with ~600 deaths. All require hospitalization and intensive long-term treatment with antibiotics. A high proportion require surgery to replace damaged heart valves and long-term morbidity and mortality is high. The resulting cost to individuals, families, society and the NHS is extremely high. So if there is a link between IDP and IE, there may be substantial financial, personal and societal savings in giving AP. Alternatively, if no link exists, the costs and risks (antimicrobial resistance and adverse drug reactions) of AP can be avoided and prevention re-focussed on improving oral hygiene in those at high-risk of IE. This study will provide important data upon which NICE and other guideline committees around the world can base their guidelines.

Lay abstract: Infective endocarditis (IE) is a serious infection of the heart. Around 30% of those who get IE die in the first year and many survivors develop serious on going complications. Bacteria from the mouth are the cause in 35-45% of cases but it is not clear to what extent these enter the blood during daily activities such as chewing food and tooth brushing, particularly in those with poor oral hygiene, or during invasive dental procedures (IDP) e.g. extractions, dental scaling or root canal treatment. Because of the possible link to IDP, the focus of IE prevention has been to give antibiotics to those at risk of IE before any IDP. This is called antibiotic prophylaxis (AP) and is the standard of care for individuals at high-risk of IE in most of the world. However, there has never been a clinical trial to test if AP works. Because of this, NICE (National Institute for Health & Care Excellence) recommended that AP stop in 2008 and the UK is now the only country where AP is not recommended for patients at high-risk of IE. A recent study, however, found a significant increase in IE following introduction of the 2008 NICE guideline. This has raised serious concerns about the advice not to give AP in the UK. However, for AP to be effective there must be a causal link between IDP and IE, and the purpose of this study is to determine if there is a link or not. Using personal details to link 2 national databases we will identify every patient who has an IDP performed and track them see if they develop IE or not over the following year. If IDP are linked to IE we would expect IE cases to peak in the 3 months after an IDP (since we know that IE develops within 3 months of infection with a causal bacteria). If instead, activities such as tooth brushing enable oral bacteria to cause IE, we would expect IE cases to be unrelated to IDP. As a further check, we can compare the occurrence of IE following a visit to the dentist that includes an IDP with the occurrence following a visit that does not include an IDP. We can identify all dental visits because dentists complete a form for each patient they treat and send it to the NHS Business Service Authority in order to be paid. This records patient details and the types of dental procedure performed, including IDP, during each visit. IE patients are all admitted to hospital and we can identify them using the Hospital Episode Statistics database. This records the diagnosis and personal details of every hospital admission. NOTE: The NHS Health & Social Care Information Centre (guardian of these 2 databases) will link patient data across the 2 databases and anonymise it before making it available to us. The research team will therefore have no identifying information about patients in the study. The study is important because there are ~2,000 IE cases a year requiring intensive treatment often involving open-heart surgery and long hospital stays, Unfortunately, ~600 will die in the first year and survivors are at high-risk of further problems and require intensive long-term care. The cost to individuals, families, society and the NHS is very high. So if there is a link between IDP and IE, the financial, personal and societal savings resulting from AP could be very large. Alternatively, if no link exists, the costs and risks (antibiotic resistance and adverse drug reactions) of AP can be avoided and prevention re-focussed on improving oral hygiene in those at risk of IE.

Research activity codes: 2.2 FACTORS RELATING TO PHYSICAL ENVIRONMENT
Health categories: CARDIOVASCULAR;INFECTION