Around 100 years ago, the first link between infective endocarditis (IE) and dental procedures was hypothesised; shortly after, physicians began to use antibiotics in an effort to reduce the risk of developing IE. Whether invasive dental procedures are linked to the development of IE, and antibiotic prophylaxis (AP) is effective, have since remained topics of controversy. This controversy, in large part, has been due to the lack of prospective randomised clinical trial data. From this suboptimal position, guideline committees representing different societies and countries have struggled to reach an optimal position on whether AP use is needed for invasive dental procedures (or other procedures) and in whom. We present the findings from an investigation involving a large US patient database, published earlier this year, by Thornhill and colleagues. The work featured the use of both a cohort and case-crossover design and demonstrated there was a significant temporal association between invasive dental procedures and development of IE in high-IE-risk patients. Furthermore, the study showed that AP use was associated with a reduced risk of IE. Additional data, also published this year, from a separate study using nationwide hospital admissions data from England by Thornhill’s group, showed that certain dental and non-dental procedures were significantly associated with the subsequent development of IE. Two other investigations have reported similar concerns for non-dental invasive procedures and risk of IE. Collectively, the results of this work support a re-evaluation of the current position taken by the National Institute for Health and Care Excellence (NICE) and other organisations that are responsible for publishing practice guidelines.
Introduction
Infective endocarditis (IE) is a devastating syndrome with a high in-hospital and one-year mortality.1,2 Frequently, valve replacement is required, and inpatient stays are prolonged. Moreover, the incidence of IE is increasing in the UK and across Europe.3,4 There is likely no one cause for this increase, and it probably represents the convergence of multiple factors. These include an ageing population, increasing rates of diabetes mellitus, rising rates of medical intervention, and, possibly, a reduction in the provision of antibiotic prophylaxis in the setting of invasive procedures.
Links between dentistry and the development of IE stretch back almost 100 years. Lewis and Grant were the first to suggest that bacteria released into the bloodstream during dental procedures might cause IE in 1923.5 Okell and Elliott,6 in 1935, noted that most patients had oral viridans group streptococci detectable in their bloodstream following dental extraction, and directly linked this to the aetiology of IE. In 1941, the first recommendations for antibiotic prophylaxis (AP) were produced, using sulfanilamide, by Thomas et al.7 In 1955, the first national guidelines with recommended protocols for AP and invasive procedures to prevent IE were published in America, and included in a revised statement on the prevention of rheumatic fever, originally published in 1953 by the American Heart Association (AHA).8
Ten years later, the AHA published its first document solely focused on the prevention of IE, and also recognised the importance of both dental and non-dental procedures.9 There were further iterations, with refinements and expansion in those recommended to receive prophylaxis and which ‘at-risk’ procedures should be considered, culminating in the AHA 1997 guidelines.10-13 These guidelines recommended prophylaxis for specific dental, respiratory, gastrointestinal and genitourinary tract procedures in those at moderate risk (e.g. native valve disease) and high risk (e.g. a prosthetic heart valve).
Guideline evolution
In the UK and Europe, similar guidelines were developed over time. The British Society of Antimicrobial Chemotherapy (BSAC) produced its first recommendation in 1982.14 The European Society of Cardiology (ESC) produced its first consensus document in 1995.15 These paralleled the recommendations of the AHA guidelines. In 2004, the ESC, British Cardiac Society (BCS) and Royal College of Physicians (RCP) of London came together to produce a comprehensive set of guidelines. This too recommended prophylaxis to patients with a wide variety of cardiac conditions for a wide variety of procedures,16 similar to the AHA 1997 guidelines.
But the tide was turning; David Durack published an editorial in 1998 which had a considerable impact.17 There was concern about the development of antimicrobial resistance and the recognition that only a small proportion of cases were likely to be prevented by AP. Between 2007 and 2009, guidelines from the AHA, ESC and National Institute for Health and Care Excellence (NICE) drastically scaled back recommendations for AP.
The AHA was first in 2007.18 They restricted recommendations for AP to those undergoing dental procedures only, and only in those patients deemed to be at high risk of an adverse outcome related to IE. The ESC produced very similar guidance in 2009.19 NICE went further, however, in 2008, effectively banning AP in the UK.20
We documented this impact, and found a drastic fall in prescribing of AP and a concomitant acceleration in the rate of increase of IE cases.21 Although there was a temporal association between the changes, it did not confirm causation, and in 2015 NICE reiterated its guidance that “antibiotic prophylaxis against infective endocarditis is not recommended for people undergoing dental procedures”. Nonetheless, that study and other pressures led NICE to change their wording in 2016. They added the word ‘routinely’, so the guidance became “antibiotic prophylaxis against infective endocarditis is not routinely recommended for people undergoing dental procedures”.20
Table 1. Patients at high risk who should be considered for antibiotic prophylaxis (from Scottish Dental Clinical Effectiveness Programme – SDCEP)*
| Patients with any prosthetic valve, including a transcatheter valve, or those in whom any prosthetic material was used for cardiac valve repair |
| Patients with a previous episode of infective endocarditis |
Patients with congenital heart disease (CHD):
|
| *The American Heart Association (AHA) includes “Cardiac transplant recipients who develop cardiac valvulopathy” as a fourth category. |
This, however, caused further confusion for dentists and cardiologists. To try and address this confusion the Scottish Dental Clinical Effectiveness Programme (SDCEP) produced advice (endorsed by NICE) on how to implement the NICE guidelines, stating that “The vast majority of patients at increased risk of IE will not be prescribed antibiotic prophylaxis. However, for a very small number of patients (table 1), it may be prudent to consider antibiotic prophylaxis (non-routine management) in consultation with the patient and their cardiologist or cardiac surgeon”.22 Dentists were advised to consult with the patient’s cardiologist or cardiac surgeon to determine if they should be considered for AP before invasive dental procedures. In patients for whom cardiologists recommend consideration of AP, SDCEP advises dentists they must “discuss the potential benefits and risks of prophylaxis for invasive dental procedures with the patient to allow them to make an informed decision about whether prophylaxis is right for them.” Unfortunately, the data to inform such discussions has been lacking. The NICE/SDCEP advice, therefore, still lacks the preciseness and clarity of the ESC and AHA guidance.
Medico-legal consequences
From a medico-legal perspective, when the NICE guidelines were introduced in March 2008, the position in relation to AP to prevent IE was clear in the UK. AP was no longer recommended. This meant that practitioners could, in theory, be at risk if they prescribed AP and an adverse drug event occurred. Indeed, dental defence unions withdrew cover for such an event very rapidly after the introduction of the guidance.
In light of the Montgomery versus Lanarkshire Health Board ruling,23 and the SDCEP implementation advice, as well as current AHA and ESC recommendations, it is now essential that patients at high risk are told about the potential risks and benefits of AP prior to embarking on an invasive dental procedure, and not to do so potentially opens the practitioner up to legal challenge if they develop an adverse drug reaction or they develop IE.
The long-term limitation that guideline writers have had to accept is the lack of evidence. There has never been a randomised placebo-controlled clinical trial defining the efficacy and safety of AP. Due to the large number of patients that would have to be enrolled, because of the rarity of IE, coupled with the enormous financial cost and ethical concerns about withholding or prescribing placebo AP to patients at high IE risk, it is unlikely that there will ever be such a trial. Therefore, the guideline writers have had to balance estimates of the risks to patients and society of giving AP against the risks of developing IE and its complications.
Recent publications
Our group, led by Professor Thornhill, recently published several studies that may shed light on this ongoing conundrum. The first paper was published in the Journal of the American College of Cardiology in September 2022.24 We combined US data on patients with employer-provided medical, dental and prescription benefits cover to examine admissions with IE, invasive dental procedures, and the administration of AP in almost 8 million people. It is important to highlight that we did not have access to medical records to manually confirm the accuracy of each record or the underlying microbiology. It was also retrospective and non-randomised. We undertook both cohort and case-crossover studies. As expected, the risk of developing IE in those at high risk was significantly greater than in those at low/unknown risk (467.6 per million procedures vs. 3.8 per million procedures). We demonstrated an association between invasive dental procedures and the development of IE; it was strongest for dental extractions and oral surgical procedures. We also found an association between AP and a reduced risk of IE (figure 1). We noted that, despite AHA guideline recommendations that patients at high risk should receive AP before invasive dental procedures, we could only find evidence of AP preceding an invasive dental procedure in 33% of cases. Similarly, low compliance has also been reported in other countries where AP is recommended, for example, in France.25 We tried to repeat the analysis with UK data but could not because of limitations in collecting dental records nationally.26
This study supports current ESC and AHA guidance, and contradicts the current NICE guideline recommendations, by providing evidence to support the recommendation that those at high IE risk should receive AP before invasive dental procedures. It also provides data on the risk of IE associated with invasive dental procedures and the potential benefit provided by AP for those at high IE risk that, along with earlier data on the risks of AP,27 can be used to inform the type of discussions with patients advised by SDCEP. It also highlights the need for improved education of dentists, and communication between patients, dentists, cardiologists, and cardiothoracic surgeons.
The second study looked at invasive procedures more broadly; recall that AP was recommended for several invasive medical, as well as dental procedures, before 2007. Studies by Janszky et al.28 and Mohee et al.29 have previously identified several invasive medical procedures as being associated with the development of IE. We used English hospital admissions data to identify patients admitted with IE and found an association between specific procedures and the subsequent development of IE.30 As expected, dental extractions and cardiac implantable electronic device implantation were associated with the development of IE. However, there were also associations with other procedures, particularly upper and lower gastrointestinal endoscopy and bronchoscopy. Findings from the study suggest that the restriction and focus of AP only on dental procedures may have been premature. Again, this study suffers from the same limitations associated with using administrative data as did our previous study.
Future developments
So what further evidence might become available? Professor Bruno Hoen is leading a study in France – PROPHETS (Effectiveness of antibiotic PROPHylaxis of infective Endocarditis before invasive dental procedures in high-risk patienTS) – a randomised registry-based trial (like TASTE31).32 However, numerous methodological assumptions will have to be met, particularly the effectiveness of a dental education package, if this study is to achieve its aims and produce a definitive result. This study builds on work by Tubiana et al.,25 which highlighted that only around one-half of patients eligible for AP in France received it. They leveraged that difference and showed a statistically significant association between invasive dental procedures and oral streptococcal IE in patients with prosthetic heart valves, but the authors noted that their study lacked sufficient statistical power to demonstrate if AP was effective in reducing this risk.25
Although some guideline committees may be reluctant to change their guidance, these studies provide previously missing evidence of the link between invasive dental procedures and the development of IE, and the effect of AP in reducing the risk of IE following invasive dental procedures in those at the highest risk. In the final analysis, all agree, however, that maintaining excellent oral hygiene and reducing the risk of infection at the time of procedures by careful preparation and procedural techniques that may involve AP (for example, recommended for device implantation procedures in the UK)33 is critical in preventing IE.
The recent data demonstrating a significant association between invasive dental procedures (particularly dental extractions and oral surgery procedures) and IE, and the data showing that AP significantly reduced the incidence of IE for patients at high IE risk undergoing these procedures, suggest it is time NICE consider revising its guidelines, in light of the new evidence, to better align with ESC and AHA guidelines recommending AP for those at highest IE-risk. Whether NICE will consider new guidance remains to be seen.
Key messages
- New data support the hypothesis that there is a link between certain invasive procedures and the development of infective endocarditis (IE) in those at high risk of IE
- New data have also linked the use of antibiotic prophylaxis and a reduced risk of developing IE following invasive dental procedures in those at high risk of IE
- Prospectively gathered randomised trial data to confirm these observations remains elusive
Conflicts of interest
MJD reports payment for expert testimony from Bevan Brittan, honoraria for presentations and support for attending meetings from Biotronik. MT reports other grant support from the National Institutes for Health (USA) and Delta Dental of Michigan Research and Data Institute’s Research Committee and Renaissance Health Service Corporation (USA). LMB reports consulting for Boston Scientific and Roivant Sciences, and royalty payments from UpToDate, Inc.
Funding
None.
References
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