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Invasive dental treatment and acute vascular events: A systematic review and meta‐analysis

Abstract Background Acute infection/inflammation increases the risk of acute vascular events (AVEs). Invasive dental treatments (IDTs) trigger short‐term acute inflammation. Purpose The aim of this work is to critically appraise the evidence linking IDTs and AVEs. Data Sources Six bibliographical databases were searched up to 31 August 2021. A systematic review following PRISMA guidelines was performed. Study Selection Intervention and observational studies reporting any AVEs following IDT were included. Data Extraction Two reviewers independently extracted data and rated the quality of studies. Data were pooled using fixed‐effect, inverse variance weights analysis. Risk of Bias Risk of bias was assessed by the Newcastle–Ottawa Quality Assessment Scale for observational studies and the Cochrane Handbook–Rob 2.0 for randomized controlled trials. Data Synthesis In 3 out of 16 clinical studies, a total of 533,175 participants, 124,344 myocardial infarctions, and 327,804 ischaemic strokes were reported. Meta‐analysis confirmed that IDT did not increase incidence ratios (IR) for combined vascular events either at 1‐4 weeks (IR of 1.02, 95% CIs: 0.92 to 1.13) and at 5‐8 weeks (IR of 1.04, 95% CIs: 0.97 to1.10) after treatment. Limitations A high level of heterogeneity (study designs and time point assessments) was found. Conclusion Patients who received IDT exhibited no substantial increase in vascular risk over 8 weeks post treatment.


| INTRODUCTION
Cardiovascular diseases (CVDs) are the leading cause of death worldwide (World Health Organization, 2014). Endothelial dysfunction is the earliest step in the development of atherosclerosis (Ross, 1993), and it precedes the intra-vascular inflammatory and prothrombotic changes linked to atheroma formation and evolution (Davignon & Ganz, 2004). Acute and chronic inflammation (Smeeth et al., 2004) are the major drivers of endothelial dysfunction and plaque evolution (Libby, 2013) leading to acute cardiovascular events such as myocardial infarction (MI), ischaemic stroke (IS), and peripheral arterial disease (PAD) (Hansson, 2005;Herrington et al., 2016;Yang et al., 2018). The risk of an acute cardiovascular event increases considerably during periods of acute infection (Smeeth et al., 2004) or influenza seasons (Nguyen et al., 2016).
Invasive dental procedures have also been linked to infective endocarditis. This association, however, remains controversial (Chen et al., 2018). Current evidence confirms that IDTs result in a weeklong acute inflammatory response (D'Aiuto, Nibali, et al., 2004;Luthra et al., 2019) with transient impairment of vascular function  and the creation of a pro-thrombotic state . While it is now accepted that the risk of distant vascular infections (i.e., endocarditis) is negligible except in some limited circumstances (Cahill et al., 2017), some evidence indicates that IDTs could result in an increased risk of acute vascular events (AVEs) in the first 4 weeks post treatment (Minassian et al., 2010). The strength of the evidence, however, is questionable (Nordendahl et al., 2018;Chen et al., 2019). Our aim was therefore to perform a critical appraisal of all the available evidence on the link between IDT and incidence of AVEs over the first 2 months after treatment.

| Protocol and registration
A systematic review protocol was registered with PROSPERO (CD42019131124, Appendix 1) and followed the PRISMA 2020 guidelines (Appendix 2).
The focused research question posed was as follows: "What is the effect of IDTs on the risk of AVEs compared to non-treatment or controlled intervention in adults?"

| Eligibility: Inclusion and exclusion criteria
The following PICO outline was used:

| Comparison
No treatment or intervention was provided; only oral hygiene instruction was provided, only supragingival cleaning was performed, or only community (non-specialist) dental care was provided.

| Outcome
Any measure of the prevalence of AVEs including MI, stroke, or death within 8 weeks from the intervention.

| Study design and duration
Both experimental and observational studies were included if they reported any AVEs following IDTs and reported in English language.
Non-human studies, reviews, letters to the editors, and studies with non-invasive dental procedures were excluded.

| Study selection and data extraction
Titles and abstracts of all search results were independently screened by two reviewers (Shailly Luthra and Roberto Rotundo) to select relevant studies. Disagreements were resolved by discussion, and if necessary, involving a third reviewer (Yago Leira). Full-text articles of the selected studies were appraised. When manuscripts lacked information/data, the authors were contacted to provide missing information.
Detailed reasons for exclusion/inclusion of manuscript were recorded (Appendix 3: T2 and T3). Kappa score was used to assess the agreement between the reviewers based on full-text screening. The selected studies were combined for qualitative and quantitative analysis.

| Risk of bias in individual studies
Quality assessment of included studies was undertaken independently and in duplicate by two reviewers (Shailly Luthra and Yago Leira) as a part of the data extraction process. The Newcastle-Ottawa Quality Assessment Scale (NOS) was used to assess observational studies (Stang, 2010). Scores ranging from 4/9 to 9/9 were used, and studies were categorized as high, medium, or low risk of bias within the respective study design. The NOS scores were converted into Agency for Health Research and Quality standards as good, fair, and poor quality of evidence based on the number of starts achieved in three different domains (selection, comparability, and outcome/exposure). The Cochrane Handbook-Rob 2.0 (Cumpston et al., 2019) tool was used to assess randomized controlled trials (RCTs).

| Summary measures
The main outcome variables were reports of the odds ratio (OR), incidence ratio (IR), hazard ratio (HR), or risk ratio.

| Data analysis and synthesis of results
Descriptive statistics were performed to comment on the evidence retrieved to define the quantity of data, examining further for study variations in terms of study characteristics and results. This assisted in corroborating the appropriateness of further synthesis methods. Statistical analyses to generate forest plots were performed using the statistical software R.
AVEs reported over common time periods (1-4 and 5-8 weeks) were combined when possible. Analyses with ORs and IRs were computed separately using a fixed-effect analysis. When a limited number of studies were identified, random effect models were also used. If the study outcome was reported over days, inverse weighted variance assessment was done to combine the data from the time points and convert days to weeks.

| Risk of bias across studies: Publication bias
Owing to the limited number of studies, a formal publication bias assessment could not be performed.
The selected studies were conducted across three continents and included several ethnicities. Data drawn from healthcare and insurance databases (4 out of 5 case-control studies and 10 out of 11 observational studies) or hospital outpatients (1 case-control and 1 observational study) were retrieved. Reviewers achieved good agreement when selecting/extracting data (Cohen's κ = 0.86).
Bias assessment confirmed that four case-control studies were scored as of high quality, while one was scored as of fair quality. For the observational studies, nine studies were of high quality, whereas two studies were considered of fair quality (Appendix 3: T4). The only RCT identified was based on a pilot trial, reporting three serious cardiovascular adverse events, but there was no information about the group in which these events occurred. The timeline of these events could not be established even after contacting the authors. There was low risk of bias for randomization and selection reporting; however, assignment, adherence, and missing data and outcome contributed to an overall high risk of bias (Appendix 3: T5).

| Qualitative analysis
Sixteen studies, including 15 observational studies and 1 randomized control trial, were assessed. Both studies confirmed that maintaining good periodontal health (HR = 0.95; 95% CI: 0.91-0.99) and providing periodontal treatment (HR = 0.79; 95% CI: 0.69-0.92) were associated with a long-term decrease in the risk of IS. Nordendahl et al. (2021) completed a 3-year Swedish registrybased case-control study and reported no association between MI and periodontitis as assessed by one or more sessions of dental cleaning or gum surgery (OR = 1.02; 95% CI: 1.00-1.05). In a separate report by the same group, it was concluded that IDTs were not associated with an increased risk of MI (OR = 0.98; 95% CI: 0.91-1.06) (Nordendahl et al., 2018). Haheim et al. (2011) used a nested casecontrol study with 1173 participants but reported a positive association between IDTs and AVEs (OR = 1.64; 95% CI: 1.24-2.16). Data from a large insurance dataset including 720,343 participants monitored over 10 years suggested that diagnosis of periodontitis was associated with future raised long-term risk of MI (Lee et al., 2015).

Aarabi et al. (2020) conducted a retrospective analysis using
German health insurance data claims including patients who were hospitalized for symptomatic PAD. They concluded that patients who did not receive treatment for the gum problems had 1.97-times greater odds of presenting with PAD (p < .0001; 95% CI: 1.83-2.13) when compared to those who had received treatment of periodontitis and after adjustments for age, diabetes, and gender differences.  Lastly, the Periodontitis and Vascular Events pilot study (PAVE-2008) was designed as a feasibility trial of secondary prevention of major cardiovascular events in the US population (Beck et al., 2008).
The authors reported a total of 15 serious adverse events occurring in the community care group versus the treatment group (6.6% vs. 3.3%; p = .19) but provided limited information on the type of procedures performed and the exact timings of the occurrence of these severe events.

| Quantitative analyses
Of the 16 studies identified, only 3 reported data (as case-control or self-controlled case series) according to the pre-specified timeline after IDTs which could then be combined for meta-analyses (Table 1).
Demographic and study designs differences, however, were observed ( CI: 0.94-1.00) but pooled analysis could not be carried out, as data at this time point were reported in only one study .
No differences were observed even when analysing odds for combined events (MI and IS) (Appendix 4: F3).

| AVEs over 1-4 weeks post treatment (IRs)
No substantial changes in the incidence of MI or IS (as well as combined) in the first 4 weeks following IDTs were observed (Figure 1).

| AVEs over 5-8 weeks post treatment (IRs)
A minor but statistically not significant increase in overall IR for all vascular events was reported at 5-8 weeks after invasive dental treatments. This was attributable to a statistically increased IR for IS over the same period (1.05; 95% CI: 1.01-1.09; p = .014) (Figure 2).

| Risk of bias within studies
The bias assessment across case-control and cohort studies was low.
Publication bias could not be carried out.
F I G U R E 1 Acute vascular event over 1-4 weeks post treatment-incidence ratio (IR). Summary forest plot for incidence ratio of acute vascular events. vs. 1.7%) and with a tripled risk when compared to healthy controls (0.2%) (Dalager-Pedersen et al., 2014). Daily activities such as toothbrushing or chewing (Kinane et al., 2005;Forner et al., 2006;Crasta et al., 2009) can also be associated with bacteraemia similar to that seen after an IDT (Yoshimura, 1983;Heimdahl et al., 1990;Lockhart et al., 2008). This would suggest that IDT could trigger a short-term acute increased vascular risk.
Periodontitis is a very common inflammatory disease initiated by a dysbiotic dental biofilm, but it is also a common trigger of systemic inflammation (D' Aiuto, Nibali, et al., 2004). Effective treatment of periodontitis does improve oral health and resolve systemic inflammation (D'Aiuto et al., 2006). This treatment could involve tooth extractions and/or intensive sessions of dental cleaning. A transient impairment of endothelial function , acute inflammation Habbab et al., 2019), increased leukocyte counts (Luthra et al., 2019), and short-lived bacteraemia (Kinane et al., 2005) are commonly observed within 24 h of intensive treatment of periodontitis (D'Aiuto, Nibali, et al., 2004;Luthra et al., 2019). Similar acute changes plus a rise in serum levels of high-sensitivity cardiac troponin T, fibrinogen, and endotoxin activity have been reported in patients with established cardiac problems undergoing dental extractions (Habbab et al., 2019). Other common dental procedures such as root canal treatment (Debelian et al., 1995) or dental implant F I G U R E 2 Acute vascular event over 5-8 weeks post treatment-incidence ratio (IR). Summary forest plot for incidence ratio of acute vascular events. (a) Ischaemic stroke (IS), (b) myocardial infarction (MI), and (c) all combined vascular events over 5-8 weeks post treatment in self-controlled case series studies. The fixed-effect, inverse variance weighed pooled analysis was used and the data markers indicates the time length and events in each study. CI, confidence interval placement (Piñeiro et al., 2010) have been associated with short-term bacterial dissemination (Schenkein et al., 2020). An increased inflammatory burden or bacterial dissemination could represent plausible mechanisms linking common dental treatments, endothelial dysfunction, and altered vascular risk (Figure 3). The idea that acute infection/ inflammation is linked to vascular events was first reported by Valtonen et al. (1993) (4% increased risk of MI and 10% of IS). Even a brief exposure to bacterial endotoxins or transient acute inflammation impairs endothelium-dependent relaxation for several days (Bhagat et al., 1996). There is evidence to suggest that increased thrombotic activity and endothelial dysfunction can result from an acute inflammatory response following IDTs (D'Aiuto et al., 2005;Joshipura et al., 2004). Further evidence that infectious agents trigger systemic inflammation and increase the risk of vascular events comes from recent reports confirming raised levels of myocardial injury biomarkers Tn1 (Shi et al., 2020) and TnT (Guo et al., 2020) in patients affected by the coronavirus disease .
A separate unanswered question is whether individuals who already suffer from a medical condition might be at a greater risk of AVEs when facing an acute inflammatory status or infection. A large retrospective cohort study (Wilcox et al., 2021) (n = 3,848,501) confirmed that the 30-day event rate of perioperative MI increased in a step-wise manner with the presence of additional CVD risk factors (0.41% for one, 0.81% for two, and 1.07% for three; p < .001) (Wilcox et al., 2021). Similar evidence was reported on the effect of periodontitis and its treatment on the risk of PAD (Yang et al., 2018;Aarabi et al., 2020

| Limitations and strengths
There are some limitations in this review that should be highlighted. A significant variation in the study designs including several dental treatments and inconsistent time points used to record events inevitably increased the heterogeneity of the evidence retrieved. Only a limited number of studies could be included in the quantitative analysis. One study in particular  had the largest weight in the analysis and hence it influenced the overall results and interpretation.
We urge, therefore caution in interpreting the data and hope that more studies will be performed and published in the future. This review, however, included data on more than 5 million participants across three continents using a robust methodology to screen and extract the available evidence, with particular emphasis in performing quantitative analyses.

| CONCLUSIONS
This review does not support an association between IDTs and AVEs.
As a large number of dental procedures are performed worldwide, healthcare systems should enable better integration and facilitate communication between dental care professionals and medical teams when essential or advanced dental treatments are planned, especially in patients with multiple co-morbidities.  Figure 3 (Plausible mechanistic links between invasive dental treatments and acute vascular events) image was created using the BioRender Software.

CONFLICT OF INTEREST
The authors declare that there is no conflict of interest.

DATA AVAILABILITY STATEMENT
All data relevant to the study are included in the article or uploaded as supplementary information.