148 Journal of Indian Society of Periodontology - Vol 14, Issue 3, Jul-Sep 2010

Review Article

Address for correspondence:

Dr. Prasad Dhadse, 404, Kaushalya Homes,

South Civil Lines, Madhya Pradesh – 482

005, India. E-mail: drprasaddhadse@

gmail.com

Submission: 13-05-2010 Accepted: 5-10-2010

DOI: 10.4103/0972- 124X.75908

Department of Periodontics, Hitkarini

Dental College and Hospital, Dumna Road,

Jabalpur - 482002, India

The link between periodontal disease and cardiovascular disease: How far we have come in last two decades ? Prasad Dhadse, Deepti Gattani, Rohit Mishra

Abstract: Many epidemiological studies have investigated the relationship between periodontal disease (PD) and cardiovascular disease (CVD), but their results are heterogeneous. This review article is designed to update the potential association, that forms the basis of understanding for a (causal) role for PD to cardiovascular events; as reported by various observational (case-control, cohort, cross-sectional) studies, epidemiological and interventional studies, not considering the other number of systemic health outcomes like cerebrovascular disease, pregnancy complications, chronic obstructive pulmonary disease, diabetes mellitus complications, osteoporosis, etc. A brief overview has been included for atherosclerosis (ATH), its pathophysiology and the association of periodontal infections as a risk factor for causing ATH, which seems to be a rational one; as development of ATH involves a chronic low-grade inflammation and moreover, it has long been set up prior to development of ischemic heart disease and thus provides potential contributing mechanisms that ATH may contribute singly or in concert with other risk factors to develop ischemic heart disease. This article goes on to discuss the correlation of evidence that is gathered from many scientific studies showing either strong, modest, weak or even no links along with their critical analyses. Finally, this article summarizes the present status of the links that possibly exist between PD and its role as a risk factor in triggering cardiovascular events, in the fairly long journey for the last two decades. Key words: Atherosclerosis, coronary artery disease, periodontitis, risk factor, systematic review

INTRODUCTION

Cardiovascular diseases (CVD), including acute myocardial infarction and angina pectoris are major health problems in developing countries, and are considered amongst most common medical problems in the general population.[1,2] Annual mortality from CVD is about 12 million cases per year and are responsible for 30% of all deaths in the United States.[3] Cardiovascular diseases are estimated to have led to 1.59 million deaths in India in year 2000 and this figure is projected to increase to 2.03 million for the year 2010.[4] The Framingham Heart Study revealed that for people who reach the age of 40, 49% of men and 32% for women show clinical manifestations of ischemic heart disease during their lifetime.[1]

Gingivitis associated with extensive plaque and calculus deposits are most prevalent, extensive and severe in developing countries and in population with limited access to health education and dental care.[5,6] Mild forms of periodontal disease (PD) affect 75% of adults in the United States, and more severe forms affect 20 to 30% of adults. Since PD is common in population, it may account for significant portion of proposed infection-associated risk for CVD.[7] This can be reasonably explained by concrete evidence for current research, which

states that ATH is the main underlying vascular disease responsible for cardiovascular and cerebrovascular morbidity and mortality.[8]

Cardiovascular disease affects 43 million individuals in the United States with a marked increase in geriatric population. Since this population group is increasing in number and since more elderly individuals are dentate than in the past, there is also an increased incidence of PD in this patient group.[9] This paradoxical finding is applicable to global population subsequently involving the proportionate risk for CVD.

This evidence coupled with recent evidence of linking PD to coronary heart disease suggest the need to evaluate the extent to which the strength of this association has been established through several scientific studies in the last two decades.

PATHOPHYSIOLOGY OF ATHEROSCLEROSIS

Atherosclerosis (ATH) is an insidious process that typically takes decades to worsen to the point of causing signs and symptoms. The term is derived from the Greek words for hardening (sclerosis) and gruel or the accumulation of lipid (athere). The process is localized to the inner wall of arteries with a predisposition to form

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at locations of “disturbed” blood flow, such as points where arteries branch.

Atherosclerosis lesions begin with deposition of lipoproteins in the intimal layer of the affected artery. The lipoprotein particles such as low-density lipoproteins (LDLs) then seem to permit the accumulation of monocytes and lymphocytes in the intimal layer.[10] Early in the formation of atherosclerotic plaques, circulating monocytes adhere to vascular endothelium. This adherence is mediated through several adhesion molecules on the endothelial cell surface, including intercellular adhesion molecule 1(ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1) and vascular cell adhesion molecule 1 (VCAM-1).[11,12] Activation of monocytes (macrophage) in the blood vessels leads to release of hydrolytic enzymes, cytokines, chemokines and growth factors, which induce further damage leading to focal necrosis. The monocytes recruitment from the blood stream occurs which pass through the endothelium into the blood vessels and differentiate into macrophages, which slowly become lipid-laden “foam cells” characteristic of atheromatous plaques.[10,13] Macrophages also accumulate lipids especially LDLs in both oxidized and modified form. Modified LDL can be a major cause of injury to both endothelium and underlying smooth muscles.[9] These lipid-laden cells eventually die and leave a necrotic lipid-rich element behind, in the arterial wall. These lipid containing area calcify to varying degrees. At the same time, smooth muscle cells in the arterial wall are stimulated to migrate in the intimal layer, where they can proliferate.[10]

Meanwhile microvessels invade the affected area, which can cause intraplaque hemorrhages. A fibrous cap that faces the interior of the artery eventually covers the atherosclerotic lesion.[10] A fatty streak can become a fibrous plaque, which becomes complex with lipid core, calcification and deposition of extracellular matrix proteins. Activated T-cells may stimulate metalloproteinase production by macrophages; which remodel the fibrotic plaque. Through remodeling of the extracellular matrix, the fibrous cap may become thin and rupture leading to activation of clotting system with thrombosis and subsequent occlusion of the artery that may be responsible for as many as one half of the cases of myocardial infarction.[14]

The role of infections has been discussed for many years. Recently, evidence has shown that certain common oral infections play a significant role in ATH[9] Atherosclerosis can occur in large and medium size elastic and muscular arteries. They can lead to ischemic lesions of brain, heart or extremities and can result in thrombosis and infarction of affected vessels, leading to death.[15]

Atherosclerosis is an insidious process, supported by considerable body of evidence that it is an inflammatory disease.[8] This hypothesis is also termed as the Ross’, “Response to Injury Hypothesis” of ATH, popularized by the pathologist Dr. Ross who proposed that the initial lesions result from injury to the endothelium and lead to chronic inflammatory process in the artery.[16] However, this hypothesis was first postulated in mid-1800 by European pathologists.

Role of infections in endothelial injury There is accumulating evidence of an association between

some common infections of man and ATH. One possible mechanism is through endothelial injury by infectious agents, triggering in part; an inflammatory response seen in ATH. The role of infections has been recently reviewed by Danesh and colleagues; there is mounting evidence that infection by Chlamydia pneumoniae, Helicobactor pylori, Periodontal bacteria, and Cytomegalovirus are associated with heart disease.[13,17]

There is increasing amount of evidence that periodontal infections may directly contribute to the pathogenesis of ATH and thromboembolic events by providing repeated systemic challenges with liposaccharides and inflammatory cytokines.[5]

Herzberg and co-workers have reported that the Streptococcus sanguis and Porphyromona gingivalis have been shown to induce platelet aggregation and activation through the expression of collagen-like platelet aggregation-associated proteins. The aggregated proteins may play a role in atheroma formation and thromboembolic events.[18]

A recent study by Haraszthy et al. identified periodontal pathogens in human carotid atheromas (direct evidence). Fifty carotid atheromas obtained at endarterectomy were analyzed for the presence of bacterial 16S rDNA by P C R ( p o l y m e r a s e c h a i n r e a c t i o n ) u s i n g s y n t h e t i c oligonucleotide probes specific for periodontal pathogens Aggregatibacter actinomyecetemcomitans, Bacteriodes forsythus, P. gingivalis and P. intermedia. Thirty percent of specimens were positive for B. forsythus; 26% for P. gingivalis, 18% for Aggregatibacter actinomyecetemcomitans, and 14% for P. intermedia.[19] Additional direct evidence comes from infections with P. gingivalis that contribute to systemic inflammation comes from animal studies (mice) shows calcification of aortic atherosclerotic plaque with exposure to P. gingivalis infection.[20] Increasing the length of exposure to the pathogens increases the amount of calcification. Moreover 44% of atheromas have one or more periopathogens.[19]

These and other studies suggest that periodontal pathogens may be present in atherosclerotic plaques, where like other infectious organisms periodontal pathogens too play a role in atherogenesis.

STUDIES ESTABLISHING THE LINK BETWEEN PERIODONTAL DISEASE AND

CARDIOVASCULAR DISEASE

Case control studies In 1989, Kimmo Mattila and his co-workers in Finland conducted two separate case control studies totaling 100 patients with acute myocardial infarction and they compared these patients with 102 control subjects selected from the community. A dental examination was performed on all the patients and a dental index was computed. In this original report, subjects with evidence of oral infection were 30% more likely to present with myocardial infarction as against subjects without oral infections.[21]

In a second case control report, Mattila and co-workers noted association between dental infections and degree of ATH. This study examined the same subjects as the first report with diagnostic coronary angiography. Accordingly the

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left main coronary artery, the circumflex artery, and the left anterior descending artery were assessed diagnostically and graded for the degree of occlusion on a 5-point scale. Again the total dental index score was used as a general score for dental caries, periapical lesions, and periodontal infections. In a multivariate analysis, significant associations were found between dental infections, age and triglycerides and severe coronary atheromatosis. These links remain significant even after adjusting for other known risk factors like total cholesterol, HDL, smoking, hypertension, socioeconomic status, and body mass index.[21] Mattila’s provocative findings generated a great deal of interest in the scientific community.

The authors postulated that bacterial infections have profound effect on endothelial cells, monocytes–macrophages, thrombocytes and blood coagulation and lipid metabolism; and concluded that dental infections are the only risk factor outside the scope of classic coronary risk factors, which have shown independent association with the severity of adult coronary ATH in their multivariate assessment. Continuing to monitor for myocardial infarction among the cases in these first case control reports, Mattila et al. presented Cox proportional hazard models further implicating dental infections as a significant risk factor for new cardiovascular events.[22]

COHORT STUDIES

De Stefano and co-workers assessed the association between PD and CVD with National Health and Nutrition Examination survey (NHANES) I, which followed subjects for 14 years. This cohort study examined several potentially confounding variables including age, gender, race, education, marital status, systemic blood pressure, total cholesterol levels, body mass index, diabetes, physical activity, alcohol consumption, poverty and cigarette smoking. These investigators reported that among the 9760 subjects examined longitudinally, those with periodontitis has 25% increased risk of coronary heart disease related to those with minimal PD adjusted for the co-variables mentioned above. Interestingly, males younger than 50 years of age with periodontitis were 72% more likely to develop coronary heart disease compared to their periodontally healthy counterparts.[23]

Using data in the normative aging studies, Beck and co-workers evaluated 921 men aged between 21 and 80 years who were free of coronary heart disease at baseline. Over 18 years follow-up period, 207 men developed coronary heart disease, 59 died of coronary heart disease, and 40 had strokes. Odds ratio adjusted for age and established cardiovascular risks factors were 1.5, 1.9, and 2.8 for periodontal bone loss and total coronary heart disease, fatal coronary heart diseases and stroke, respectively. These data indicated that persons with radiographic evidence of periodontitis were 0.5–2.8 times more likely to develop coronary heart disease or suffer from a vascular event.[24]

In a larger six-year cohort study, Joshipura and co-workers studied 44, 119 men in the health professionals via mailed questionnaire with a self-reported history of PD and missing teeth. This study found no significant relation between self- reported history of PD and incidence of heart disease after adjusting for traditional risk factors (RR - 1.04). The study did however demonstrate that men with tooth loss and PD were 70% more likely to exhibit coronary heart disease.[25]

Genco and co-workers investigated the association between periodontal infections and risk of CVD in 1372 in Native Americans of Gila River Indian community, a group with high prevalence of diabetes mellitus. At baseline, alveolar bone level was measured and cardiovascular status was monitored for up to 10 years for electrocardiographic evidence of CVD using a pooling criteria. Among all age groups alveolar bone level was predictive for coronary heart disease, but did not remain significant in a multivariate analysis.[RR - 2.68 (95% CI 1.30–5.50)]. In contrast, for persons younger than 60 years of age, alveolar bone level was predictive of coronary heart disease (odds ratio of 2.68).[26]

CROSS-SECTIONAL STUDIES

Arbes and colleagues[27] evaluated the link between PD and CHD in the NHANES III, and found that the odds of having history of heart attack increased with the severity of PD. The highest severity of PD in the population was associated with the odds ratio (OR) for 3.8 [95% CI (1.5–9.7)] compared with no PD; after adjusting for age, sex, race, poverty, smoking, diabetes, hypertension, BMI, and serum cholesterol level. Thus this cross-sectional study confirmed the association and also showed a direct relationship between heart disease and increasing levels of PD.

Genco and colleagues[28] assessed the association between specific subgingival periodontal organisms and MI. They compared 97 subjects with non-fatal MI with 233 control subjects. A panel of nine subgingival bacteria was evaluated, and subjects infected with one or more of these bacteria were compared with non-infected subjects. For MI the adjusted OR (95% C.I) was 2.99 (1.40–2.65) for the presence of B. forsythus, and 2.52 (1.35–4.70) for P. gingivalis; two periodontopathic bacteria. These findings support the notion that specific pathogenic bacteria found in cases of PD also may be associated with myocardial infarction.

META-ANALYSIS OF OBSERVATIONAL STUDIES

Janket et al. performed a meta-analysis of nine cohort studies of PD as a risk factor for future cardiovascular and cerebrovascular events RR 1.19; (95% CI [1.08–1.32]) and found an overall 19% increased risk of such events in individuals with periodontitis.[33] The increase in risk was greater (44%) in people under age 65.

Scannapieco et al,[34] concluded in an extensive systematic review that a moderate degree of evidence exists to support an association between PD and ATH, MI and CVD, but that causality is unclear.

Results of another metal-analysis by Khader et al[35] combining six cohort and two cross-sectional studies are lower RR 1.15; (95% CI [1.06–1.25]).

In 2009, a more promising and extensive metal-analysis of observational studies was conducted by Alessandra Blaizot et al.[2] in Toulouse, France, to examine the association between exposure to periodontitis and CVDs. Studies published between 1989 and 2007 (nearing two decades)

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were retrieved by electronic and manual search from seven databases. The included articles reported the results from observational studies and assessed the link between periodontal exposure and CVDs as confirmed by one of the following criteria: diagnosed coronary artery disease, angina pectoris, myocardial infarction, mortality due to cardiac pathology. The study characteristics were abstracted by independent researchers following a standardized protocol. The MOOSE guidelines for meta-analysis for observational studies were followed.[36] From 215 epidemiological studies, 47 were observational; of which 29 articles could be combined by meta-analysis methodology. The pooled odds ratio calculated from 22 case control and cross-sectional studies was 2.35 (95% CI [1.87–2.96)]; P<0.0001). The risk of developing CVD was found to be significantly (34%) higher in subjects with PD compared to those without PD (pooled relative risk from seven cohort studies was 1.34 (95% CI [1.27–1.4], P<0.0001). This result shows that subjects with PD have higher odds and higher risk of developing CVD.[2]

INTERVENTIONAL STUDIES

Noack and colleagues[37] demonstrated that C-reactive protein levels were highest in patients who were infected with periodontal pathogens where as CRP is an independent risk factor for CVD; however, detailed information is lacking about the mechanisms by which CRP participates in the pathogenesis of atheroma formation. C-reactive protein localizes the complement in human hearts during myocardial infarction, suggesting that CRP binds diseased muscle tissue, fixes complement and hence, triggers complement mediated inflammation that contributes to atheroma formation.[38]

Recently (i.e. 2010), Cesar de Oliveira and colleagues conducted Scottish Health Survey[39] to examine if self-reported tooth brushing behavior is associated with CVD and markers of inflammation (C-reactive protein) and coagulation (fibrinogen). The database of the study drew 11,869 men and women from the population living in households in Scotland into the study. The results showed that there were a total of 555 CVD events over an average of 8.1 (SD 3.4) years of follow-up, of which 170 were fatal. In about 74% (411) of CVD events, the principal diagnosis was coronary heart disease. Participants who reported poor oral hygiene (never/rarely brushed their teeth) had an increased risk of CVD events (HR 1.7; 95% CI 1.3–2.3; P<0.001) in a fully adjusted model. They also had increased concentration of both C-reactive protein (β 0.04, 0.01–0.08) and fibrinogen (0.08,-0.01–0.18).

Interventional studies conducted by Ebersole and colleagues[40] have shown that treating patients who have PD with scaling, root planing and flurbiprofen is associated with a trend towards reduced CRP levels one year after therapy.

There are also studies being designed to look at the effect of intervention on CVDs. David Paquette et al., along with colleagues at Boston University; SUNY – Buffalo, University of Maryland and Oregon Health Science University (OHSU), have initiated plans for the “Periodontal Intervention and Vascular Events” (PAVE) pilot trial. This proposed multicentre study hopes to ultimately design and conduct a large clinical trial on periodontal therapy in patients at risk of cardiovascular events.

SUMMARY

Epidemiologic studies show conflicting relations between PD and CVDs. Some studies have reported that PD is significantly associated with CVD as a risk factor,[24] while others have failed to show such correlation.[41] Interventional studies trying to explain this relationship generally use C-reactive protein as a major cardiac outcome with statistical methods unsuitable for its skewed distribution.[42] For this reason the interpretation and use of these results are questionable.[2]

For a causal role, however, the size of how the risk increases is one of the most important criteria by which epidemiologists judge causality, and the reported PD–CHD associations fall well below the limits of what is considered to be convincing. If the nine cohort studies had identified association that fell above some generally accepted limit (for example >200%), the need for methodological rigor would have been less pressing. Under those circumstances, a more detailed adjustment of smoking or health awareness would have been unlikely to lead to different conclusion. However, since nine cohort studies considered for this review consistently identified small or no risk increase, methodological rigor is essential. Even small errors in the control of smoking history, health awareness or other lifestyle factors can induce biases that are substantially larger than the observed PD–CHD association.[43]

The potential role of PD for causal role to CVD can be explained in a way that, since oral and CVDs have many factors in common, it is important to rule out these as alternative explanations before interpreting the link as causal. The evidence support a moderate link but not a causal relationship between PD and coronary heart diseases.[7,31]

From these studies, by assessing the total coronary heart disease and fatal heart disease, it appears that the analyses were adjusted for many of the important risk factors, which are relevant to both PD and heart disease. It is of considerable interest that Beck and colleagues also found that the cumulative incidence of coronary heart disease increase with greater levels of age-adjusted alveolar bone loss at baseline, suggesting a dose response that is, the more PD at baseline, the greater is the cumulative incidence of coronary heart disease over time.[12]

DeStefano and colleagues[23] found that PD and poor oral hygiene may be an indicator or surrogate for lifestyle affecting personal hygiene and health care, and thus explains the relationship of PD and heart disease. Thus cumulative index for coronary heart disease argues against lifestyle as a simple explanation for this association.

Meta-analysis of longitudinal studies have shown that pre-existent PD; as determined by direct oral examination, independently conferred excess risk for increased morbidity and mortality due to CVD. The increase risk ranges from a modest 20% (OR of 1.2) to 180% (OR of 2.8).

A study by Genco and colleagues[28] demonstrated positive correlation between PD and coronary heart disease in a population that is largely nonsmoking.

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Some studies include more than 1000 subjects and other more than 10000 subjects. Some extend over decades. Most of these studies began as CVD studies and have controlled for traditional risk factors; such as gender, smoking, body mass, lipid profile, exercise, familial history, socio-economic status, education, and other cardiovascular risk factors. Thus several criteria appear to be satisfied for establishing an association; multiple studies, large number of subjects, prospective cohort design, valid cardiovascular and oral examination data, and

specificity by controlling for confounders and co-variables [Tables 1 and 2].

However, the magnitude of risk is variable and appears modest in many studies. Modest degree of excess risk, such as odds ratios less than 2, may potentially be due to what epidemiologists refer to as residual confounding or that the potential existence of underlying risk factors were not fully considered, adjusted for or even measured. This issue, however

Dhadse, et al.: The link between periodontal and cardiovascular disease…

Table 1: Summary of association between oral conditions and CVD in six longitudinal studies with positive findings Source, year, total no. of subjects

Country (follow-up period)

Exposure Outcome Measure of association

Adjusted for potential confounders

DeStefano and colleagues,[23] 1993, 9,760 (men and women)

United States (15 years)

Russel’s periodontal index

Admitted to hospital/death from CHD* (men < age 50 years)

RR#=1.2$ RR=1.7$

Smoking, hypertension, age, sex, triglycerides, SES, diabetes, serum lipids, BMI, Previous myocardial infarction

Mattila and colleagues,[22] 1995 214 (182 males, 32 females)

Finland (7 years)

Total dental index New myocardial infarction or death from CHD

HR+=1.2$ Age, sex, race, education, poverty, marital status, SBP**, BMI, Cholesterol level, diabetes, physical activity, alcohol use, smoking

Joshipura and colleagues[25] 1996 44,119 (male health professionals)

United States (6 years)

Reported tooth loss due to periodontitis in men

Fatal and non- fatal myocardial infarction and sudden death

RR=1.7$ Age, BMI, exercise, smoking, alcohol use, vitamin E, family history of myocardial infarction before age 60 years

Beck and colleagues,[24] 1996 921 (men)

United States (18 years)

Whole-mouth bone level

New CHD Fatal CHD Stroke

OR++=1.5$ OR=1.9$ OR=2.8$

Age, sex, cholesterol level, smoking, diabetes, blood pressure, family history, education.

Morrison and colleagues[29] 1999

Canada (23 years)

Mild, severe gingivitis periodontitis

Fatal CHD and stroke

RR at age 35–69 years; mild gingivitis=3.6$; severe=6.9$; periodontitis=3.4$

Age, sex, cholesterol level, smoking, diabetes, hypertension, province of residence

Wu and colleagues, 2000[30] 9962 adults

United States (NHANES-I: 21 years)

Gingivitis and periodontitis (>4 mm pockets); edentulous by Russell’s periodontal index

Incident non- hemorrhagic stroke

RR: Gingivitis=1.2$; periodontitis=2.1$

Sex, age, race, education, poverty index, diabetes, HT, smoking status, alcohol use, BMI, cholesterol level, sample design

CHD* = Coronary heart disease; RR# = Relative risk; HR = Hazard Ratio; OR++ = Odds ratio; SBP** = Systolic blood pressure; $ = Statistically significant adjusted measure of association; 16S,JADA,Vol133,June2002.

Table 2: Summary of association between oral conditions and CVD in three longitudinal studies with negative findings Source, year, total no. of subjects

Country (Follow-up period)

Exposure Outcome Measure of association

Adjusted for potential confounders

Joshipura and colleagues,[25] 1996 44,119 (male health professionals)

United States (6 years)

Reported history of PD in men

Fatal and non- fatal myocardial infarction and sudden death

RR*=1.04 Age, BMI**, exercise, smoking, alcohol consumption, vitamin E use, family history of MI before age 60 years

Hujoel and colleagues,[31] 2000 8032 dentate adults

United States (National Health and Nutrition Examination Survey I: 21 years)

Gingivitis and periodontitis (>1-mm pockets) by Russel’s periodontal index

Death or hospitalization due to CHD$ or revascularization

Gingivitis HR%=NS#; periodontitis HR=1.14

Age, age squared, sex, race, poverty index, marital status, education, marital status/sex+, log++ smoking duration, log height and weight log alcohol use per day, physical activity, nervous breakdown, sample design

Howell and colleagues,[32] 2001 22,0711 (U.S. male physicians)

United States (12.3 years)

Reported history of PD

Death due to CHD, non-fatal myocardial infarction or stroke

RR=1.13 (confidence limits: 0.99-1.28) adjusted for age and treatment; RR=1.01 (confidence limits: 0.88–1.15) fully adjusted

Age, aspirin and beta carotene treatment assignment, smoking, alcohol use, history of hypertension, BMI, history of diabetes, physical activity, parental history of MI, history of angina

RR* = Relative risk; BMI** = Body mass index; CHD $ = Coronary heart disease; HR% = Hazard Ratio; NS# = Not significant; + Marital Status / Sex = Interaction between marital status and sex; ++ Log = Logarithm; 17S, JADA,Vol133,June2002

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is, a potential problem as there is always one more parameter that could be considered in any study design.

The report by Arbes[27] et al. analyzing the NHANES III data shows a strong association between history of myocardial infarction (a very robust and valid measure for CVD) and increasing PD severity in a dose response manner. The greater the PD, the greater the risk with odds ratio greater than 5 for the most of severe PD groups. This was present after adjustment of traditional risk factors for CVD. With odds ratio of this magnitude, the likelihood is lower than residual confounding is responsible for a spurious finding. Thus the epidemiologic link data are fairly strong.

CONCLUSION

It is now clear from the epidemiologic studies that a potential link does exist between PD and CVD. Oral healthcare professionals can identify patients who are unaware of their risk of developing serious complications as a result of CVD and who are in need of medical intervention.

Prospective interventional studies are required to determine the exact link between PD and CVD as well as to evaluate whether periodontal treatment may reduce the risk of developing CVD. Some studies which are in progress to evaluate the moderation of vascular disease (ATH) owing to interventional periodontal therapy and the extent to which it (ATH) is responsible for triggering cardiovascular events. However, the challenge remains whether PD can be considered one amongst the traditional risk factors for CVD as the link established from different studies is not limited to a recent CVD. Overall, PD seems to be associated with no more than a modest increase (~20%) in cardiovascular risk in the general population.

As the ongoing studies report and confirm the strength of the association between PD and CVD, in the next two decades, the oral healthcare professionals and the medical professionals have to prepare for better planning of prevention programs. It seems from the scientific evidence gathered so far that interventional periodontal care remains invaluable not only for oral health but for general health as well.

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27. Arbes SJ Jr, Slade GD, Beck JD. Association between extent of periodontal attachment loss and self reported history of heart attack: An analysis of NHANES III data. J Dent Res 1999;78:1777- 82.

28. Genco RG, Wu TJ, Grossi S, Genco RJ, Wu TJ, Grossi S, et al. Periodontal microflora related to the risk for myocardial infarction; a case control study. J Dent Res 1999;78:457.

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30. Wu T, Trevisan M, Genco RJ, Dorn JP, Falkner KL, Sempos CT. Periodontal disease and risk of cerebrovascular disease: The first national health and nutrition examination survey and its follow-

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33. Janket SJ, Baird AE, Chuang SK, Jones JA. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:559-69.

34. Scannapieco FA, Bush RB, Paju S. Associations between periodontal disease and risk for atherosclerosis, cardiovascular disease and stroke: A systematic review. Ann Periodontol 2003;8:38-53.

35. Khader YS, Albashaireh ZS, Alonari MA. Periodontal diseases and the risk of coronary heart and cerebrovascular diseases: A meta-analysis. J Periodontol 2004;75:1046-53.

36. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: A proposal for reporting Meta- analysis of observational studies in epidemiology (MOOSE) group. JAMA 2000;283:2008-12.

37. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ, De Nardin E. Relation between periodontal infection and C- reactive protein. J Periodontol 2001;72:1221-7.

Source of Support: Nil, Conflict of Interest: None declared.

38. Lagrand WK, Visser CA, Hermens WT, Niessen HW, Verheugt FW, Wolbink GJ, et al. C- reactive protein localizes with complement in human heart during acute myocardial infarction. Circulation 1997;95:97-103.

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42. Ford ES, Giles WH, Myers GL, Mannino DM. Population distribution of high sensitivity C- Reactive protein among U.S Men: Finding from National Health and nutrition Examination survey 1999 – 2000. Clin Chem 2003;49:686-90.

43. Spiekerman C, Hujoel PP, Drangsholt MT, Spiekerman C, Hujoel PP, Drangsholt MT, et al. Inadequate adjustment for smoking in periodontitis: Systemic disease associations. Ann Periodontol 2001;6:222.

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Avinash K
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268  |  wileyonlinelibrary.com/journal/jcpe J Clin Periodontol. 2020;47:268–288.

Received: 6 June 2019  |  Revised: 13 August 2019  |  Accepted: 22 August 2019 DOI: 10.1111/jcpe.13189

O R I G I N A L A R T I C L E

Periodontitis and cardiovascular diseases: Consensus report

Mariano Sanz1  | Alvaro Marco del Castillo2 | Søren Jepsen3  | Jose R. Gonzalez‐ Juanatey4 | Francesco D’Aiuto5 | Philippe Bouchard6 | Iain Chapple7 | Thomas Dietrich7 | Israel Gotsman8  | Filippo Graziani9  | David Herrera1  | Bruno Loos10  | Phoebus Madianos11  | Jean‐Baptiste Michel12 | Pablo Perel13,14 | Burkert Pieske15,16 | Lior Shapira17  | Michael Shechter18 | Maurizio Tonetti19  | Charalambos Vlachopoulos20 | Gernot Wimmer21

1Department of Dental Clinical Specialties, ETEP Research Group, Faculty of Odontology, University Complutense of Madrid, Madrid, Spain 2Cardiology Department, Hospital Universitario Ramon y Cajal, Madrid, Spain 3Department of Periodontology, Operative and Preventive Dentistry, University of Bonn, Bonn, Germany 4Cardiology Department, University Hospital, IDIS, CIBERCV, Univerity of Santiago de Compostela, Santiago de Compostela, Spain 5Department of Periodontology, Eastman Dental Institute and Hospital, University College London, London, UK 6U.F.R. d'odontologie, Université Paris Diderot, Hôpital Rothschild AP‐HP, Paris, France 7School of Dentistry, Institute of Clinical Sciences, College of Medical & Dental Sciences, The University of Birmingham, Birmingham, UK 8Heart Institute, Hadassah University Hospital, Jerusalem, Israel 9Department of Surgical, Medical and Molecular Pathology and Critical Care Medicine, University of Pisa, Pisa, Italy 10ACTA University, Amsterdam, The Netherlands 11Department of Periodontology, School of Dentistry, National and Kapodistrian University of Athens, Athens, Greece 12Inserm Unit 1148, Laboratory for Translational CV Science, X. Bichat Hospital, Paris, France 13World Heart Federation, Geneva, Switzerland 14Centre for Global Chronic Conditions, London School of Hygiene & Tropical Medicine, London, UK 15Department of Internal Medicin & Cardiology, Charité Universitätsmedizin Berlin, Berlin, Germany 16DZHK (German Center for Cardiovascular Research) Partnersite Berlin, German Heart Institut Berlin, Berlin, Germany 17Department of Periodontology, Hebrew University – Hadassah Faculty of Dental Medicine, Jerusalem, Israel 18Leviev Heart Center, Chaim Sheba Medical Center, tel Hashomer and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv‐Yafo, Israel 19Department of Periodontology, Prince Philip Dental Hospital, The University of Hong Kong, Hong Kong, Hong Kong 201st Department of Cardiology, National and Kapodistrian University of Athens, Athens, Greece 21Department of Prosthetic Dentistry, School of Dental Medicine, Karl‐Franzens University Graz, Graz, Austria

Abstract Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non‐communicable disease (NCD) with a high prevalence, being severe peri‐ odontitis, affecting 11.2% of the world's population, the sixth most common human disease.

Correspondence Mariano Sanz, Department of Dental Clinical Specialties and ETEP Research Group, Faculty of Odontology, University Complutense of Madrid, Plaza Ramon y Cajal, E‐28040 Madrid, Spain. Email: [email protected]

Funding information DENTAID Oral Health Experts

This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made. © 2019 The Authors. Journal of Clinical Periodontology published by John Wiley & Sons Ltd

     |  269SANZ et Al.

1   |   I N T R O D U C T I O N

Non‐communicable diseases (NCDs) are rising in prevalence glob‐ ally in line with an increasingly ageing population, refined diets and sedentary lifestyles and account for 41 million deaths each year, or 71% of all global deaths (G. B. D. Risk Factors Collaborators, 2016). Approximately 80% of people over 65‐years of age in the United States are affected by one or more NCDs and 77% exhibit at least two NCDs, creating a significant burden of disease to individuals and to the healthcare economy (Centres for Disease Control & Prevention, 2011). The comorbid presence of two or more NCDs presents a major challenge to the economy, equating to two‐thirds of all health costs in the United States (Centres for Disease Control & Prevention, 2013); however, <1% USA health expenditure is focussed on prevention to improve overall health (U.S. Senate Committee on Health, 2011).

The greatest global NCD burden arises due to cardiovascular disease (CVD), responsible for 17.9 million deaths (a third of total mortality), and 45% of NCD‐induced mortality (Roth et al., 2017). In Europe, CVD is responsible for 3.9 million deaths (45% of deaths), and whilst CVD mortality rates are reducing, the absolute numbers have increased in the last 25 years, due to an increasingly ageing population (Wilkins et al., 2017). Ischaemic heart disease, stroke, hypertension (leading to heart failure), rheumatic heart disease, car‐ diomyopathy and atrial fibrillation cause over 95% of CVD‐related deaths (Roth et al., 2015).

In this consensus report, the term CVD is used as a general term for atherosclerotic diseases, principally coronary heart disease, cerebrovascular disease and peripheral vascular disease. A number of chronic infectious, inflammatory and immune diseases are associ‐ ated with significantly higher risks of adverse cardiovascular events,

including rheumatoid arthritis, psoriasis, systemic lupus erythema‐ tosus and periodontitis (Roth et al., 2015), consistent with the the‐ sis that chronic elevations in the systemic inflammatory burden are causally related to CVD development and its sequelae. Whilst there is evidence for over 50 gene polymorphisms playing a role in the modulation of atherogenesis (Holdt & Teupser, 2015), effect sizes are small and the major traditional risk factors for CVD remain the lifestyle factors, principally tobacco smoking, dyslipidaemia, hyper‐ tension and altered glucose metabolism. The latter correlate strongly with diets high in saturated fats, salt and refined sugars and contrib‐ ute to obesity and type 2 diabetes mellitus, major attributable risk factors for myocardial infarction (Joseph et al., 2017). The same risk factors account for over 90% of the stroke burden (O'Donnell et al., 2016), yet all are modifiable through improved lifestyles including reducing salt, saturated fat and refined carbohydrate intake, exer‐ cising, increasing intake of antioxidant micronutrients and regular moderate alcohol consumption (Joseph et al., 2017).

Periodontitis is also a NCD with a high prevalence of 45%– 50% overall, with the most severe form affecting 11.2% of the world's population, being the sixth most common human disease (Kassebaum et al., 2014). The Global Burden of Diseases, Injuries, and Risk Factors Study (2017) of years lost to disability (YLD) re‐ ported that from 1990 to 2017 oral diseases (mainly periodontitis and caries) contributed the most YLD in age‐standardized preva‐ lence rates from 354 diseases and injuries across 195 countries (G. B. D. Disease Injury & Incidence & Prevalence Collaborators, 2018). There is now a significant body of evidence to support indepen‐ dent associations between severe periodontitis and several NCDs including diabetes (Chapple, Genco, & Working group 2013 of the joint EFP/AAP Workshop, 2013), cardiovascular disease (Tonetti et

Material and Methods: There is now a significant body of evidence to support in‐ dependent associations between severe periodontitis and several NCDs, in particu‐ lar CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerg‐ ing evidence to support these associations Results and Conclusions: The present review reports the proceedings of the work‐ shop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the po‐ tential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients vis‐ iting both the dental and medical practices.

K E Y W O R D S

anti thrombotic therapy, atherosclerosis, bateremia, cardiovascular disease, chronic inflammation, periodontal therapy, periodontitis

270  |     SANZ et Al.

al., 2013), chronic obstructive pulmonary disease (Linden, Lyons, & Scannapieco, 2013) and chronic kidney disease (CKD) (Sharma, Dietrich, Ferro, Cockwell, & Chapple, 2016). Indeed, severe peri‐ odontitis is independently and significantly associated with all‐ cause and cardiovascular mortality in several different populations (Linden et al., 2012; Sharma et al., 2016). Proposed mechanisms include bacteraemia and the associated systemic inflammatory sequelae, including elevations in C‐reactive protein and oxidative stress (Schenkein & Loos, 2013). In populations with multimorbid‐ ity, for example chronic kidney disease with comorbid diabetes and periodontitis, periodontitis is associated with significantly reduced survival from all‐cause and cardiovascular mortality (Sharma et al., 2016). It appears therefore that periodontitis may be a modifiable non‐traditional risk factor for CVD.

In 2012, a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. The consensus report was based upon four technical papers that systematically reviewed the evi‐ dence for epidemiological associations between periodontitis and incident CVD (Dietrich, Sharma, Walter, Weston, & Beck, 2013), mechanisms of biological plausibility relating to periodontal bac‐ teria and systemic inflammation (Reyes, Herrera, Kozarov, Roldan, & Progulske‐Fox, 2013; Schenkein & Loos, 2013) and periodontal intervention studies (D'Aiuto, Orlandi, & Gunsolley, 2013). The workshop concluded that there was consistent and strong epide‐ miological evidence that periodontitis imparts increased risk for future atherosclerotic cardiovascular disease. It also concluded that the impact of periodontitis on CVD was biologically plausible, via translocated circulating oral microbiota, which may directly or indirectly induce systemic inflammation that impacts upon the de‐ velopment of atherothrombogenesis, and whilst in vitro, pre‐clin‐ ical and clinical studies supported the interaction and associated biological mechanisms, intervention trials were not sufficiently adequate to draw further conclusions at that time.

The present workshop was jointly organized by the EFP and the World Heart Federation (WHF) to include global experts in both periodontal and cardiovascular disciplines and was held in Madrid on 18th and 19th February 2019. Four technical reviews updating the evidence base from the 2012 workshop were prepared and supplemented by additional studies discussed at the workshop. The reviews focussed on epidemiological associations (Herrera, Molina, Buhlin, & Klinge, 2019), mechanistic links (Schenkein, Papapanou, Genco, & Sanz, 2019), results from intervention studies (Orlandi, Graziani, & D’Aiuto, 2019) and the potential risk and complications of periodontal therapy in patients undertaking antithrombotic (anti‐ platelet and anticoagulant) therapy.

Whilst this consensus report focuses predominantly on relevant evidence published since the 2012 workshop, there are biological areas that have subsequently come to prominence, where the un‐ derpinning body of evidence was not covered in the 2013 consensus report, and hence, certain pre‐2012 manuscripts are referenced to ensure the context of these recent studies is clear.

Furthermore, section 4.3 “What is the effect of statin intake on clinical periodontal outcomes?” and section 5 “Cardiovascular risks and complications of periodontal therapeutic interventions” were not dealt in the previous workshop, and hence, a full appraisal of the scientific evidence was carried out in this consensus meeting.

Finally, following the review of the presented evidence, recom‐ mendations for both medical and dental teams, as well as patients and the public, were elaborated.

2   |   E P I D E M I O L O G I C E V I D E N C E O N T H E A S S O C I AT I O N B E T W E E N P E R I O D O N T I T I S A N D C V D

2.1 | Do people with periodontitis have a higher prevalence of subclinical cardiovascular disease?

There is evidence from epidemiological studies that periodontitis patients exhibit significant endothelial dysfunction, measured by flow‐mediated dilation (FMD), arterial stiffness (e.g. pulse wave ve‐ locity—PWV) and a significantly greater thickness of the carotid in‐ tima‐media (cIMT) and elevated arterial calcification scores. There is one imaging study (ATHEROREMO‐IVUS study) associating high levels of antibodies against periodontal pathogens and a lower ex‐ tent of positive atheromatous plaque remodelling (de Boer et al., 2014).

2.2 | Do people with periodontitis have a higher prevalence of coronary artery disease and risk of myocardial infarction and other coronary events?

There is robust evidence from epidemiological studies for a positive association between periodontitis and coronary heart disease. A systematic review (Dietrich et al., 2013), which was updated in prep‐ aration for this workshop, identified a total of 6 case–control and co‐ hort studies epidemiological studies, published in the last five years, which demonstrated an increased risk of a first coronary event in patients with clinically diagnosed periodontitis or more severe peri‐ odontitis compared to patients without periodontitis or less severe periodontitis. Relative risk estimates vary between studies, depend‐ ing on population characteristics and periodontitis case definitions. There are two cohort studies reporting an association between peri‐ odontitis and higher cardiovascular mortality (due to coronary heart disease and cerebrovascular disease).

2.3 | Do people with periodontitis have a higher prevalence of cerebrovascular disease and risk of stroke?

There is evidence from epidemiologic studies for a positive associa‐ tion between periodontitis and cerebrovascular disease. A system‐ atic review (Dietrich et al., 2013), which was updated in preparation for this workshop, identified a total of three case–control and cohort studies, which demonstrate an increased risk of a first cerebrovascu‐ lar event in patients with clinically diagnosed periodontitis or more

     |  271SANZ et Al.

severe periodontitis compared to patients without periodontitis or less severe periodontitis. Relative risk estimates vary between stud‐ ies, depending on population characteristics and periodontitis case definitions. Furthermore, a recent analysis of data from the ARIC study demonstrated an association between periodontal profile class and incident ischaemic stroke. In this cohort, patients with periodontitis had more than double the risk of cardioembolic and thrombotic stroke compared with periodontally healthy individuals (Sen et al., 2018). In addition, as previously documented, there are two cohort studies reporting an association between periodontitis and higher cardiovascular mortality (due to coronary heart disease and cerebrovascular disease) (Dietrich et al., 2013).

2.4 | Do people with periodontitis have a higher prevalence and incidence of Peripheral Artery Disease (PAD)?

There is limited but consistent evidence that individuals with periodontitis have a higher prevalence and incidence of PAD com‐ pared to individuals without periodontitis (Yang et al., 2018). For cross‐sectional data, the most significant evidence comes from two large, population‐based studies in the United States (NHANES 1999–2002) and South Korea (KoGES‐CAVAS). Both studies found a positive association between the extent of clinical attachment loss (NHANES 1999‐2002) and severity of radiographic bone loss (KoGES‐CAVAS) with PAD, defined using the Ankle Brachial Index (ABI), with adjusted odds ratios (OR) of 2.2 (95% confidence inter‐ val [1.2; 2.4]) and 2.0 (95% CI [1.1; 3.9]), respectively (Ahn et al., 2016; Lu, Parker, & Eaton, 2008). One prospective cohort study conducted in male veterans in the United States reported a posi‐ tive association between periodontitis (measured by severity of radiographic bone loss) and the incidence of PAD over a 25‐ to 30‐year follow‐up period, with an adjusted OR of 2.3 (95% CI [1.3; 3.9]) (Mendez et al., 1998). There are no studies that have evaluated the association between periodontitis and the incidence of Major Adverse Limb Events (MALE).

2.5 | Do people with periodontitis have a higher risk of other CVDs or conditions (heart failure, atrial fibrillation)?

Several studies report positive associations between periodontitis and heart failure. There is evidence from a large Asian study using the Taiwanese National Health Insurance Research Database reporting a sig‐ nificantly higher incidence of atrial fibrillation in individuals with periodon‐ tal diseases compared to individuals without periodontal diseases (hazard ratio—HR = 1.31, 95% CI [1.25, 1.36]) (Chen, Lin, Chen, & Chen, 2016).

2.6 | Do people with a history of cardiovascular disease have a different incidence or progression of periodontitis?

There is currently limited scientific evidence that CVD is a risk factor for the onset or progression of periodontitis.

2.7 | Do people with periodontitis with history of cardiovascular disease have a higher chance of experiencing a subsequent event?

From three studies investigating the association between peri‐ odontitis and secondary cardiovascular events, two large studies did not find a significant association (Dorn et al., 2010; Reichert et al., 2016); however, a small study (100 subjects) reported a sig‐ nificant association (HR = 2.8, 95% CI [1.2; 6.5]) with recurrent cerebrovascular events (Sen et al., 2013).

3   |   M E C H A N I S M S T H AT M AY E X P L A I N T H E E P I D E M I O L O G I C A L A S S O C I AT I O N S B E T W E E N P E R I O D O N T I T I S A N D C V D

3.1 | Is there evidence of a higher incidence of bacteremia following oral function/intervention in periodontitis patients compared to periodontally healthy subjects?

There is evidence that oral bacterial species can enter the circula‐ tion and cause bacteremia, which has been demonstrated follow‐ ing daily life activities (toothbrushing, flossing, chewing or biting an apple), although it has been studied more frequently following professional interventions (tooth polishing, scaling, tooth extrac‐ tion, surgical extraction of third molars and periodontal probing).

The risk of bacteremia has been associated with periodontal health status in a systematic review, suggesting a higher risk of bacteremia associated with gingival inflammation (Tomas, Diz, Tobias, Scully, & Donos, 2012). A recent randomized clinical trial (RCT) concluded that periodontal therapy (by means of scaling and root planing, SRP) induced bacteremia in both gingivitis and periodontitis patients, but the magnitude and frequency were greater among periodontitis patients (Balejo et al., 2017).

Whilst there are methodological limitations in some of the re‐ ported studies, the overall picture supports the contention that bacteremia results from daily life activities and oral interventions, and it is more frequent of longer duration and involves more virulent bacteria in periodontitis patients.

3.2 | Is there evidence for the presence of oral bacteria in atheroma lesions?

There is evidence through traces of DNA, RNA or antigens derived from oral bacterial species, mainly periodontal pathogens, that have been identified in atherothrombotic tissues. Studies have attempted to correlate the presence of these bacteria in atherothrombotic tis‐ sues, with other sample sources (subgingival plaque, serum, etc.), in the same patients, and these suggest that in periodontitis patients there is a higher probability of a positive correlation (Armingohar, Jørgensen, Kristoffersen, Abesha‐Belay, & Olsen, 2014; Mahendra, Mahendra, Felix, & Romanos, 2013). At least two studies have demonstrated viable P. gingivalis and A. actinomycetemcomitans in atherothrombotic tissue

272  |     SANZ et Al.

when culturing the atheroma samples (Kozarov, Dorn, Shelburne, Dunn, & Progulske‐Fox, 2005; Rafferty et al., 2011).

3.3 | Do we have evidence that periodontal bacteria and/or bacterial products and virulence factors influence the pathophysiology of atherosclerosis?

Different animal models have been employed to provide evidence that periodontal pathogens can promote atheroma formation. P. gin‐ givalis has been shown to accelerate atherosclerosis in murine mod‐ els, to induce fatty streaks in the aorta of rabbits and to induce aortic and coronary lesions after bacteremia in normocholesterolaemic pigs (Schenkein & Loos, 2013).

Recently, further evidence has emerged using hyperlipidemic ApoEnull mice after infection with P. gingivalis and also with a poly‐ microbial experimental infection (P. gingivalis, Treponema denticola, Tannerella forsythia and Fusobacterium nucleatum). A polymicrobial infection was shown to induce aortic toll‐like receptor (TLR) and inflammasome signalling, with an enhanced oxidative stress reac‐ tion generated within the aortic endothelial cells (Chukkapalli et al., 2015; Velsko et al., 2014, 2015).

There is also in vitro evidence of intracellular entry by periodon‐ tal pathogens (P. gingivalis, A. actinomycetemcomitans, etc.) (Reyes et al., 2013). In vivo and in vitro studies demonstrate the importance of the fimbriae of P. gingivalis to host cell entry and to promote athero‐ thrombotic lesions in experimental models (Yang et al., 2014). In vitro experiments have shown that certain bacterial strains expressing P. gingivalis hemagglutinin A (HagA) have an increased capability to adhere and enter human coronary artery endothelial cells (HCAEC) (Belanger, Kozarov, Song, Whitlock, & Progulske‐Fox, 2012).

3.4 | Do we have evidence that periodontitis patients exhibit increased production and/or levels of inflammatory mediators that also associated with the pathophysiology of atherosclerosis?

There is evidence of significantly higher levels of C‐reactive pro‐ tein (CRP) in periodontitis patients versus healthy controls and in CVD and periodontitis patients compared with either condition alone. The effect of periodontal therapy has been shown to as‐ sociate with a significant decrease in CRP levels, along with im‐ provements in surrogate measurements of cardiovascular health (Demmer et al., 2013; Koppolu et al., 2013; Patil & Desai, 2013).

There is evidence of elevated levels of serum interleukin (IL)‐6 in periodontitis patients and lower levels of IL‐4 and IL‐18. The effect of periodontal therapy has shown a significant decrease in the serum levels of IL‐6, serum amyloid A and alpha 1 anti‐chymo‐ trypsin. Peripheral neutrophils from periodontitis patients release excess IL‐1β, IL‐8, IL‐6 and tumour necrosis factor (TNF)‐α when stimulated by periodontal pathogens. Periodontal therapy only par‐ tially reduces the cytokine hyper‐reactivity with some evidence of a constitutively elevated response (Ling, Chapple, & Matthews, 2016).

3.5 | Do we have evidence that periodontitis patients develop elevations in thrombotic factors that are also associated with the pathophysiology of atherothrombosis?

There is evidence of significantly higher levels of fibrinogen in peri‐ odontitis patients versus healthy controls, and in CVD and periodonti‐ tis patients compared with either condition alone (Chandy et al., 2017). Periodontal therapy appears to result in a significant decrease in fibrino‐ gen levels (Lopez et al., 2012; Vidal, Cordovil, Figueredo, & Fischer, 2013).

There is evidence from different studies of significantly higher levels of platelet activation markers in periodontitis patients and that these higher levels may be reversed by periodontal ther‐ apy (Arvanitidis, Bizzarro, Alvarez Rodriguez, Loos, & Nicu, 2017). However, there is conflicting evidence that significantly higher levels of plasminogen activator inhibitor (PAI) are found in periodontitis pa‐ tients (Schenkein & Loos., 2003).

3.6 | Do we have evidence that periodontitis patients demonstrate elevated serum antibody levels that cross‐react with antigens in cardiovascular tissues?

There is evidence that HSPs from periodontal pathogens (Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actin‐ omycetemcomitans and Fusobacterium nucleatum) generate antibod‐ ies that can cross‐react with human HSPs. These antibodies have been shown to activate cytokine production, as well as monocyte and endothelial cell activation.

The presence of anti‐cardiolipin antibodies has been significantly as‐ sociated with periodontitis patients, which reversed following periodon‐ tal therapy. There is some evidence that periodontal pathogens can elicit antibodies that cross‐react with cardiolipin (Schenkein & Loos., 2003).

In three out of four population‐based studies (Parogene study, NHANES III, DANHES), higher levels of serum immunoglobulin (Ig)G against P. gingivalis were associated with periodontitis patients and car‐ diovascular disease (acute coronary syndrome, death from cardiovas‐ cular disease and cardiovascular disease). The ATHEROREMO‐IVUS study failed to demonstrate an association between serum levels of IgG and IgA against P. gingivalis, A. actinomycetemcomitans, T. forsythia and P. intermedia and major adverse cardiac events (MACE) (de Boer et al., 2014). This is consistent with data from Boillot et al. (2016).

3.7 | Do we have evidence that periodontitis patients exhibit dyslipidaemia?

There is evidence from systematic reviews that serum total choles‐ terol levels, low‐density lipoproteins (LDL), triglycerides, very‐low‐ density lipoproteins (VLDL), oxidized LDL and phospholipase A2 are elevated in periodontitis. High‐density lipoprotein (HDL) levels are reduced in periodontitis patients compared with controls (Schenkein & Loos., 2003). These levels are reversed after periodontal therapy (Teeuw et al., 2014).

     |  273SANZ et Al.

3.8 | Do we have evidence for peripheral blood neutrophil hyper‐responsiveness in reactive oxygen species and protease production in periodontitis patients?

There is strong mechanistic evidence that peripheral blood neutro‐ phils (PBNs) from periodontitis patients produce higher levels of total and extracellular reactive oxygen species (ROS) than healthy controls, under various conditions of priming and stimulation and from unstim‐ ulated cells (Ling et al., 2016; Matthews, Wright, Roberts, Cooper, & Chapple, 2007a). This hyper‐reactivity to stimulation by periodon‐ tal bacteria is reduced following successful periodontal therapy to control patient levels, but the unstimulated hyperactivity remains, suggesting that constitutive and reactive mechanisms underlie neu‐ trophil hyper‐responsiveness in periodontitis (Matthews, Wright, Roberts, Ling‐Mountford, et al., 2007b). Gene expression data in PBNs support the functional data (Wright, Matthews, Chapple, Ling‐ Mountford, & Cooper, 2008). Serum antioxidant levels and those in gingival crevicular fluid (GCF) are reduced in periodontitis patients, reflecting increased ROS activity (Chapple, Brock, Milward, Ling, & Matthews, 2007). These data are supported by a study of endarter‐ ectomy samples, which demonstrated evidence for activation of the ROS‐generating systems in neutrophils, specifically the presence of myeloperoxidase (MPO), cell‐free DNA and DNA‐MPO complexes (Range et al., 2014).

3.9 | Are there common genetic risk factors between periodontitis and CVDs?

There is scientific evidence of pleiotropy between periodontitis and cardiovascular diseases (Aarabi et al., 2017; Munz et al., 2018; Schaefer et al., 2015, 2011). The highly pleiotropic genetic locus CDKN2B‐AS1 (chromosome 9, p21.3) associated with coronary ar‐ tery disease, type 2 diabetes, ischaemic stroke and Alzheimer’s dis‐ ease is also consistently associated with periodontitis (Aarabi et al., 2017; Ernst et al., 2010; Loos, Papantonopoulos, Jepsen, & Laine, 2015; Munz et al., 2018). Its function appears to be related to the regulation of gene expression (Hubberten et al., 2019). Interestingly, a pilot study identified that a genetic variant in the CDKN2B‐AS1 locus was associated with the extent of elevated levels of C‐reactive protein in periodontitis (Teeuw, Laine, Bizzarro, & Loos, 2015).

A conserved non‐coding element within CAMTA1 upstream of VAMP3, also first identified as a genetic susceptibility locus for cor‐ onary artery disease, was found to be associated with periodontitis (Schaefer et al., 2015). A GWAS suggested that the VAMP3 locus was associated with a higher probability of subgingival overgrowth of periodontal pathogens (Divaris et al., 2012).

There is evidence for plasminogen (PLG) as a shared genetic risk factor for coronary artery disease and periodontitis (Schaefer et al., 2015).

The 4th pleiotropic locus between coronary artery disease and periodontitis is a haplotype block at the VAMP8 locus (Munz et al., 2018).

These shared genetic factors suggest a mechanistic link or im‐ munological commonalities between coronary artery disease and periodontitis. The impairment of the regulatory pathways by genetic factors may be a common pathogenic denominator of at least coro‐ nary artery disease and periodontitis. There are indications that ab‐ errant inflammatory reactivity, determined by genetic variants in the loci CDKN2B‐AS1 (ANRIL), PLG, CAMTA1/VAMP3 and VAMP8 could partially explain the epidemiological link between periodontitis and cardiovascular diseases.

4   |   E V I D E N C E F R O M I N T E R V E N T I O N S T U D I E S

4.1 | Is there an effect of periodontitis treatment in preventing or delaying ACVD events?

4.1.1 | Primary prevention

There have been no prospective randomized controlled periodontal inter vention studies on primar y prevention of cardiovascular diseases (including first ischaemic events or car‐ diovascular death) since the last consensus repor t (Tonetti et al., 2013). The Group questioned the feasibility of per forming adequately powered RCTs in primar y prevention at a popula‐ tion level due to impor tant ethical, methodological and finan‐ cial considerations.

However, consistent observational evidence suggests that sev‐ eral oral health interventions including self‐performed oral hygiene habits (toothbrushing) (two studies (de Oliveira, Watt, & Hamer, 2010; Park et al., 2019)), dental prophylaxis (one study Lee, Hu, Chou, & Chu, 2015), increased self‐reported dental visits (one study (Sen et al., 2018)) and periodontal treatment (three studies (Holmlund, Lampa, & Lind, 2017; Lee et al., 2015; Park et al., 2019)) produced a reduction in the incidence of ACVD events.

Cross‐sectional data of The Scottish Health Surveys from 1995 to 2003 pertaining 11,869 men and women (mean age of 50 years) were linked to a database of hospital admissions and deaths with follow‐up until December 2007 (Information Services Division, Edinburgh) (de Oliveira et al., 2010). Participants who brushed less than once a day exhibited the highest incidence of ACVD events (HR = 1.7, 95% CI [1.3; 2.3]) compared with those who brushed twice a day, indicating that self‐performed oral hygiene routines may re‐ duce the incidence of ACVD.

A retrospective nationwide, population‐based study in Taiwan, in‐ cluding 511,630 participants with periodontitis and 208,713 controls, used the Longitudinal Health Insurance Database 2000 to estimate the incidence rate of ACVD events from 2000 to 2015 (Lee et al., 2015). The hazard ratio for acute myocardial infarction was reduced more in the group of periodontitis patients who received dental pro‐ phylaxis (HR = 0.90, 95% CI [0.86; 0.95]) than intensive treatment (including gingival curettage, scaling and root planing, and/or peri‐ odontal flap operation and/or tooth extraction) (HR = 1.09, 95% CI [1.03; 1.15]). Consistent reductions in the incidence rate of ischaemic

274  |     SANZ et Al.

stroke were observed in both the dental prophylaxis (HR = 0.78, 95% CI [0.75; 0.91]) and intensive treatment groups (HR = 0.95, 95% CI [0.91; 0.99]).

A cohort of 8,999 patients with periodontitis who received a complete (non‐surgical and if needed surgical) periodontal treat‐ ment protocol was followed between 1979 and 2012 (Holmlund et al., 2017). During the study follow‐up, poor responders to the peri‐ odontal treatment had an increased incidence of ACVD events (in‐ cidence rate –IR = 1.28, 95% CI [1.07; 1.53]) compared with good responders, suggesting that successful periodontal treatment could reduce the incidence of ACVD events.

In the Atherosclerosis Risk in Communities (ARIC) study includ‐ ing 6,736 participants followed during 15 years, self‐reported regular dental care users had a lower risk for ischaemic stroke (HR = 0.77, 95% CI [0.63; 0.94]) compared with episodic care users (Sen et al., 2018).

In a prospective population‐based study using data from the National Health Insurance System‐National Health Screening Cohort (NHISHEALS) including 247,696 participants free from any CVD his‐ tory recruited between 2002 and 2003, reported that an increased number of dental caries lesions, the presence of periodontitis and a greater loss of teeth were all associated with an increased risk of fu‐ ture major cardiovascular events (MACEs), including cardiovascular death, acute myocardial infarction, heart failure, and stroke (Park et al., 2019). One additional toothbrushing episode per day was asso‐ ciated with a reduced incidence of ACVD events (HR = 0.91, 95% CI [0.89, 0.93]) and regular professional cleaning reduced the risk even further (HR = 0.86, 95% CI [0.82; 0.90]).

In summary, progression of ACVD may be influenced by success‐ ful periodontal treatment independent of traditional CVD risk factor management.

4.1.2 | Secondary prevention

There is only one pilot multicentre study on secondary prevention of ACVD events (PAVE (Couper et al., 2008; Offenbacher et al., 2009)), which reported no statistically significant difference in the rate of CVD events between patients who underwent treatment of peri‐ odontitis versus community care (risk ratio –RR = 0.72, 95% CI [0.23; 2.22]). Several methodological limitations highlighted in the trial limit the applicability/usefulness of such evidence to inform the research and healthcare communities.

Thus, there is insufficient evidence to support or refute the po‐ tential benefit of the treatment of periodontitis in preventing or de‐ laying ACVD events (Li et al., 2017).

4.2 | What is the effect of the treatment of periodontitis in improving surrogate parameters of CVD?

Table 1 summarizes the evidence on the effect of periodontal therapy on surrogate markers of CVD. There is moderate evi‐ dence for reduction of low‐grade inflammation as assessed by

serum levels of CRP, IL‐6 and improvements in surrogate meas‐ ures of endothelial function (flow‐mediated dilatation of the bra‐ chial artery).

Moderate evidence suggests that periodontal treatment does not have an effect on lipid fractions whilst there is limited evidence, suggesting that periodontal treatment reduces arterial blood pres‐ sure and stiffness, subclinical ACVD (as assessed by mean carotid intima‐media thickness) and insufficient evidence of an effect on ACVD biomarkers of coagulation, endothelial cell activation and ox‐ idative stress.

4.3 | What is the effect of statin intake on clinical periodontal outcomes?

Statins are medications prescribed to decrease LDL cholesterol. Numerous trials have demonstrated their benefit for the prevention of cardiovascular diseases (Yebyo, Aschmann, Kaufmann, & Puhan, 2019).

Interestingly, statins possess various additional properties rele‐ vant to the pathogenesis and treatment of periodontitis (Estanislau et al., 2015). In particular, it has been reported that statins are anti‐ inflammatory (Koh et al., 2002; Paumelle et al., 2006; Quist‐Paulsen, 2010; Rosenson, Tangney, & Casey, 1999; Sakoda et al., 2006) can promote bone formation (Garrett, Gutierrez, & Mundy, 2001; Liu et al., 2012; Mundy et al., 1999; Viereck et al., 2005), can inhibit matrix metalloproteinases (MMPs) (Koh et al., 2002; Luan, Chase, & Newby, 2003; Poston et al., 2016) and possess anti‐microbial properties (Ting, Whitaker, & Albandar, 2016).

A systematic review with meta‐analysis of pre‐clinical in vivo trials reported a positive effect of local or systemic statin adminis‐ tration for the prevention of alveolar bone loss in experimental peri‐ odontitis models in rodents (Bertl et al., 2018).

Several observational clinical studies have evaluated the effect of systemic statin intake on periodontal conditions (Lindy, Suomalainen, Mäkelä, & Lindy, 2008; Meisel, Kroemer, Nauck, Holtfreter, & Kocher, 2014; Sangwan, Tewari, Singh, Sharma, & Narula, 2013; Saver, Hujoel, Cunha‐Cruz, & Maupome, 2007; Saxlin, Suominen‐Taipale, Knuuttila, Alha, & Ylostalo, 2009; Subramanian et al., 2013). Statin use was not found to be associated with decreased tooth loss in adults with chronic periodontitis when analysing administrative health plan data (Saver et al., 2007). However, a 5‐year population‐based follow‐up study com‐ paring participants treated with statins with those who did not medi‐ cate with statins concluded that long‐term treatment with statins was associated with reduced tooth loss (Meisel et al., 2014). Furthermore, patients on statin medication were reported to exhibit significantly fewer signs of periodontal inflammatory lesions than patients without a statin regimen (Lindy et al., 2008). A cross‐sectional study compared the periodontal status of patients with hyperlipidaemia (with or without statin intake) to normolipidaemic individuals and found higher gingival bleeding and probing depths in the hyperlipidaemic patients who were not statin users (Sangwan et al., 2013). In a RCT, periodontal patients with risk factors or with established atherosclerosis were assigned to either high‐ of low‐dose statin intake (Subramanian et al., 2013). After 3

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months, a significant reduction of periodontal inflammation was seen in the high‐dose compared to the low‐dose group. Thus, within the limits of the above‐reported studies, there is some limited evidence, suggest‐ ing that statins may have a positive impact on periodontal health.

Very few clinical studies have been designed to evaluate the effect of adjunctive systemic statin intake in conjunction with periodontal therapy (Fajardo, Rocha, Sanchez‐Marin, & Espinosa‐Chavez, 2010; Fentoglu et al., 2012; Sangwan, Tewari, Singh, Sharma, & Narula, 2016). In a randomized placebo‐controlled pilot study in 38 patients with chronic periodontitis, adjunctive statin intake led to beneficial effects on radiological bone loss and tooth mobility after 3 months (Fajardo et al., 2010). Another 3‐month study compared the treatment response to nonsurgical periodontal therapy in 107 chronic periodon‐ titis patients (35 normolipidaemic as control, 36 hyperlipidaemic on non‐pharmacological therapy and 36 hyperlipidaemic on statins) and found a greater improvement in gingival index in the normolipidaemic control and in the statin groups (Sangwan et al., 2016). Based on this limited evidence, two recent systematic reviews with meta‐analysis on the effects of (local and systemic) statins on periodontal treatment concluded that systemic statin intake does not enhance the outcomes of periodontal therapy (Bertl et al., 2017; Muniz et al., 2018).

5   |   C A R D I O VA S C U L A R R I S K S A N D C O M P L I C AT I O N S O F P E R I O D O N TA L T H E R A P E U T I C I N T E R V E N T I O N S

5.1 | Is there an ischaemic cardiovascular risk for patients undergoing periodontal therapy?

Non‐surgical treatment of periodontitis involving supra‐ and subgingi‐ val instrumentation of the affected dentition (under local anaesthesia) is often delivered in several short sessions. Alternatively, full‐mouth non‐surgical periodontal treatment can be performed within 24 hours.

Delivering periodontal treatment in a full‐mouth fashion (i.e. within 24 hours) triggers a one‐week acute systemic inflammatory response associated with transient impairment of endothelial function (Orlandi et al., 2019). This distant effect is not observed when periodontal treat‐ ment is delivered across several separate sessions (Graziani et al., 2015). This is achieved by limiting the number of teeth involved and the time devoted to completing the dental instrumentation. These findings raise the question of whether performing longer sessions of periodontal treatment could contribute to an individuals’ inflammatory burden/risk and increase their short‐term risk of suffering from a vascular event.

T A B L E 1   Summary of the evidence on the effect of periodontal therapy on surrogate markers of cardiovascular diseases

Topic Outcome

Number of RCTs and SR since last consensus References Effect

Overall Level of Evidence

Effect of Periodontal Therapy on Lipids

Lipids (multiple) 6 RCTs Caula, Lira‐Junior, Tinoco, and Fischer (2014); D'Aiuto et al. (2018); Deepti, Tewari, Narula, Singhal, and Sharma (2017); Fu, Li, Xu, Gong, and Yang (2016); Hada, Garg, Ramteke, and Ratre (2015); Kapellas et al. (2014)

No Moderate

Effect of Periodontal Therapy on Blood Pressure

Systolic, diastolic 3 RCTs D'Aiuto et al. (2018); Hada et al. (2015); Zhou et al. (2017)

Yes Limited

Effect of Periodontal Therapy on Endothelial Function

Endothelial Function (multi‐ ple measures)

2 RCTs D'Aiuto et al. (2018); Saffi et al. (2018) Yes Moderate

1 SR Steffel et al. (2018b)

Effect of Periodontal Therapy on interleukin (IL)−6

IL−6 3 RCTs Fu et al. (2016); Kapellas et al. (2014); Zhou et al. (2017)

Yes Moderate

Effect of Periodontal Therapy on C‐Reactive Protein (CRP)

CRP 5 SR Demmer et al. (2013); Freitas et al. (2012); Ioannidou, Malekzadeh, and Dongari‐Bagtzoglou (2006); Paraskevas, Huizinga, and Loos (2008); Teeuw et al. (2014)

Yes Moderate

7 RCTs following 2014

D'Aiuto et al. (2018); Deepti et al. (2017); Kaushal, Singh, Lal, Das, and Mahdi (2019); Caula et al. (2014); Hada et al. (2015); Kapellas et al. (2014); Zhou et al. (2017)

Effect of Periodontal Therapy on Pulse Wave Velocity (PWV)

PWV 1 RCT Kapellas et al. (2014) No Limited

Effect of Periodontal Therapy on carotid intima‐media thickness (cIMT)

Common cIMT 1 RCT Kapellas et al. (2014) Yes Limited

Abbreviation: RCT, randomized clinical trial; SR, systematic review.

276  |     SANZ et Al.

There is consistent and strong observational evidence that common acute infections/inflammatory responses are associated at a popula‐ tion level with an increased risk of vascular events within the first 4 weeks of the infectious/inflammatory event (Smeeth et al., 2004).

5.1.1 | At population level

There is no evidence for specific effects of periodontal treatment pro‐ cedures on increasing ischaemic cardiovascular risk. Two observational studies reported no effect of “invasive dental treatment” in elevating is‐ chaemic cardiovascular risk (Chen et al., 2019; Nordendahl et al., 2018), and one study suggested a minimal increased risk within 4 weeks fol‐ lowing treatment (Minassian, D'Aiuto, Hingorani, & Smeeth, 2010).

Chen et al. (2019) performed a case‐crossover and self‐controlled case series using the Taiwanese National Health Insurance Research Database, including over 110,000 Myocardial Infarction cases and 290,000 ischaemic stroke patients between 1999 and 2014. They reported a non‐significant increase in the incidence of myocardial infarction within the first 24 weeks following “invasive dental treat‐ ment” (including periodontal procedures) except for a modest risk of myocardial infarction during the first week for patients without other comorbidities (OR = 1.31, 95% CI [1.08; 1.58], after 3 days).

A registry‐based case–control study between 2011 and 2013 in‐ cluding 51,880 cases who underwent an “invasive dental procedure” compared to 246,978 controls reported no association with an in‐ creased incidence of myocardial infarction (OR 0.98, 95% CI [0.91; 1.06]) (Nordendahl et al., 2018).

Minassian et al. (2010) performed a self‐controlled case series in‐ cluding nearly 10 million participants included in an insurance data‐ base from 2002 and 2006 in the United States. The analysis showed that invasive dental treatment (largely comprising of tooth extractions and only 4% being non‐surgical and surgical periodontal procedures) is associated with an increased risk of incident acute cardiovascu‐ lar events (IR = 1.5, 95% CI [1.09; 2.06]) within the first 4 weeks of treatment recorded.

In summary, the Group concluded that delivering periodontal treatment is safe with regard to cardiovascular risk.

5.1.2 | In patients with established CVD

There is limited evidence on the effects of “invasive dental treatment” on the incidence of ischaemic events in patients with established CVD or after an event.

A small RCT on the effects of the treatment of periodontitis on CVD biomarkers in patients with established CVD (Montenegro et al., 2019) showed no cardiovascular adverse events within 3 months of completion of scaling and root planing (periodontal therapy).

In the PAVE feasibility randomized secondary prevention trial, provision of periodontal scaling and root planing treatment in pa‐ tients with established CVD did not increase the incidence of car‐ diovascular events compared to the control group (community treatment) within 6 months (Beck et al., 2008).

In summary, the Group concluded that delivering periodontal treatment is safe with regard to cardiovascular risk in patients with established CVD.

5.2 | What is the perioperative bleeding risk when performing periodontal therapy?

Periodontal treatment consists of numerous procedures with differ‐ ent levels of bleeding risk. This risk of bleeding is however low in the vast majority of procedures, and it can be easily controlled with local haemostatic measures.

Perioperative bleeding risk varies according to the extent and invasiveness of the periodontal procedure performed. The majority of periodontal procedures may be grouped within the ESC/AHA/EHRA (Steffel et al., 2018a, 2018b). Low bleeding risk group (frequency less than 1% of post‐operative bleeding) group: supragingival polishing, non‐surgical periodontal treatment, con‐ ventional surgical periodontal treatment (conservative, resective or regenerative), tooth extractions and dental implant placement. Moderate bleeding risk (frequency between 2 and 5%) may be ob‐ served in major autogenous bone augmentation procedures such as block bone harvesting, sinus floor elevation and procedures where healing is by secondary intention, such as free gingival grafting. Appendix S1 summarized the main recommendations for patients with antithrombotic therapy when performing periodon‐ tal therapy.

5.2.1 | In patients undergoing antiplatelet therapy

Individuals undergoing single acetylsalicylic acid (ASA) therapy (aspirin) in different therapeutic dosages, as well as therapy with clopidogrel, ticlopidine or ticagrelor, show no statistically significant differences in frequency of bleeding events when compared to con‐ trols, that is subjects not undergoing antiplatelet therapy (Doganay, Atalay, Karadag, Aga, & Tugrul, 2018; Lillis, Ziakas, Koskinas, Tsirlis, & Giannoglou, 2011).

Dual antiplatelet therapy, most commonly ASA in combination with clopidogrel, may pose a certain risk for post‐operative bleeding complications; however, it appears that these haemorrhagic events may be managed safely with local haemostatic measures (Napenas et al., 2009; Nathwani & Martin, 2016).

Thus, current evidence does not support discontinuation of antiplatelet therapy before dental procedures, irrespective of the type of therapy employed (single or dual antiplatelet therapy) or the type of procedure performed (single, multiple tooth extractions, non‐surgical and surgical periodontal therapy and dental implant procedures).

5.2.2 | In patients undergoing anticoagulant therapy

Vitamin K antagonists

In patients taking oral anticoagulant therapy (vitamin K antagonists, VKA) and undergoing dental extraction, minor dental procedures

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and dental implant placement do not seem to increase the risk of bleeding compared to patients who discontinue oral anticoagulant therapy (Shi, Xu, Zhang, Zhang, & Liu, 2017; Yang, Shi, Liu, Li, & Xu, 2016). There may be a higher post‐operative bleeding risk in patients continuing VKA and undergoing either minor dental surgery or other higher‐risk procedures when compared to non‐VKA patients (Biedermann et al., 2017; Shi et al., 2017), but local haemostatic agents appear to be effective in controlling post‐operative bleeding (Madrid & Sanz, 2009).

Novel/direct anticoagulants (DOAC/NOAC)

Limited trials and evidence are available on the management of patients on novel oral anticoagulant (NOAC) therapy undergoing dental treatment; hence, the Group concluded that further stud‐ ies regarding dental procedures in these patients are strongly encouraged.

It appears there is no need for interruption of NOAC therapy in most dental treatments, due to a low incidence of bleeding compli‐ cations, which can be successfully managed with local haemostatic measures when comparing groups continuing NOAC and groups discontinuing NOAC therapy (Kwak et al., 2019; Lababidi et al., 2018; Patel et al., 2017; Yagyuu et al., 2017) and with reported timing of discontinuation and reinstitution varying greatly. When comparing NOAC patients with healthy individuals, there seems to be a higher incidence of delayed bleeding (2 days and later) in those patients who do not discontinue NOAC therapy (Miclotte et al., 2017).

6   |   R E C O M M E N D AT I O N S

6.1 | Recommendations for oral health professionals for use in dental practice/office for people with cardiovascular disease (CVD)

• Patients with periodontitis should be advised that there is a higher risk for cardiovascular diseases, such as myocardial infarction or stroke, and as such, they should actively manage all their car‐ diovascular risk factors (smoking, exercise, excess weight, blood pressure, lipid and glucose management, and sufficient periodon‐ tal therapy and periodontal maintenance).

• Patients with periodontitis and a diagnosis of CVD should be informed that they may be at higher risk for subsequent CVD complications, and therefore, they should regularly adhere to the recommended dental therapeutic, maintenance and preventive regimes.

• Patients collect a careful history to assess for CVD risk factors, such as diabetes, obesity, smoking, hypertension, hyperlipidaemia and hyperglycaemia. Patients suggest that the patient consults his/her physician if any of these risk factors are not appropriately controlled.

• Oral health education should be provided to all patients with peri‐ odontitis and a tailored oral hygiene regime, including twice‐daily

brushing, interdental cleaning and, in some cases, the use of ad‐ junctive chemical plaque control, may be appropriate.

• People presenting with a diagnosis of CVD should receive a thor‐ ough oral examination, which embeds a comprehensive periodon‐ tal evaluation, including full‐mouth probing and bleeding scores.

• If no periodontitis is diagnosed initially, patients with CVD should be placed on a preventive care regime and monitored regularly (at least once a year) for changes in periodontal status.

• In people with CVD, if periodontitis is diagnosed, they should be managed as soon as their cardiovascular status permits.

o Irrespective of the level of CVD or specific medication, non‐ surgical periodontal therapy should be provided, preferably in several 30‐ to 45‐min sessions, in order to minimize a spike of acute systemic inflammation

o Surgical periodontal and implant therapy when indicated should be provided in a similar manner as in patients without CVD.

However, attention should be paid to: • Hypertension. It is recommended to measure the patients’

blood pressure (after appropriate relaxation) before the sur‐ gical intervention, and in cases of high blood pressure (above 180/100 according to expert opinion), the surgery should be postponed until the patient's blood pressure is stabilized.

• Medication with antiplatelet and anticoagulant drugs. Since periodontal and implant surgical procedures usually impart only a low‐to‐medium risk of bleeding in general terms, the dentist should not change a patient's medication, or in cases of doubt, he/she should consult the physician/cardiologist prior to the surgical intervention. Consideration should also be given to the local management of bleeding complications that may arise.

Current AHA/ACC/SCAI/ACS/ADA/ESC/ACCP guidelines on periop‐ erative management of antithrombotic therapy do not suggest dis‐ continuation of anti‐platelet therapy for low bleeding risk procedures (Douketis et al., 2012; Grines, Bonow, & Casey, 2007; Kristensen et al., 2014).

Various approaches for peri‐operative management of anti‐ coagulant therapy have been suggested. The Group reviewed the guidelines on perioperative management of vitamin K antagonists (VKA) and suggested discontinuation of medication treatment if the INR is 4 or below for low or medium bleeding risk procedures (Perry, Noakes, Helliwell, & British Dental, 2007). However, if the INR (in‐ ternationalized normalized ratio) is 3.5 or above, the expert group recommends that dental clinicians seek advice and consult with the responsible medical professional. Management of high thrombo‐ embolic risk cases should be collaborative in consultation with the medical professional responsible for VKA therapy (Kristensen et al., 2014; Valgimigli et al., 2018).

After reviewing novel anticoagulant (non‐VKA) and direct anti‐ coagulant (NOAC/DOAC) therapies guidelines, the Group concluded that for low bleeding risk periodontal procedures no discontinuation of anticoagulants is recommended (Steffel et al., 2018a, 2018b). These

278  |     SANZ et Al.

procedures could be performed 18‐24 hrs after the last intake (de‐ pending on a renal function assessment for the medication in question) and then restart 6 hrs following treatment. The expert group, however, strongly recommends that the dental clinician should consult with the responsible medical professional. When a medium bleeding risk peri‐ odontal procedure is planned, discontinuation of therapy should be agreed with the medical professional responsible for and/or prescrib‐ ing the anticoagulant therapy.

Lastly, in cases of combined antiplatelet and anticoagulant thera‐ pies that pertain patients with the highest thrombotic and ischaemic risk (i.e. chronic atrial fibrillation or after an acute myocardial infarc‐ tion or recent coronary stenting), when periodontal procedures (ei‐ ther of low or medium bleeding risk) are required, any alterations in medication should be discussed and agreed upon with the respon‐ sible medical professional (Steffel et al., 2018a, 2018b). In elective periodontal procedures, the operation should be delayed until after treatment stabilization and appropriate consultation with the medical specialist.

In cases of triple therapy (dual antiplatelet and one anticoagulant) or one anticoagulant plus one antiplatelet, such patients need individu‐ alized management by the responsible medical professional according to their thrombotic and haemorrhagic risk (Valgimigli et al., 2018).

It is important to highlight that local haemostatic agents (such as oxidized cellulose, absorbable gelatin sponges, sutures, tranexamic acid mouthwashes, compressive gauze soaked in tranexamic acid) should be used and dental clinicians should consider the confound‐ ing effect of local anaesthetic with vasoconstrictors.

• Patients with a risk of endocarditis should be premedicated with antibiotics following current guidelines (such as the European or the American guidelines).

• People with cardiovascular disease who have extensive tooth loss should be encouraged to pursue dental rehabilitation to restore adequate mastication for proper nutrition.

People without a diagnosis of CVD, but with risk factors for CVD should be informed about their CVD risk and referred to a physician for appropriate risk assessment, diagnostic testing and follow‐up care. For oral health professionals, risk assess‐ ment may be performed based upon the recommendations of the European Society of Cardiology (Systematic COronary Risk Evaluation, SCORE) (Sixth Joint Task Force of the European Society of Cardiology & Other Societies on Cardiovascular Disease Prevention in Clinical Practice, 2016).

6.2 | Recommendations for physicians and other medical health professions for use in cardiology practice

Because of the potential negative impact of periodontitis on CVD complications, the following recommendations are made:

• Patients with CVD should be advised that periodontitis may have a negative impact on CVD and may also increase the risk of CVD events.

• Patients should be advised that effective periodontal therapy may have a positive impact upon CV health.

• For people with CVD, physicians should ask about a prior diag‐ nosis of periodontitis. If a positive diagnosis has been made, the physician should seek to ascertain that appropriate periodontal care and maintenance are being provided.

• Patients with CVD should be asked about any signs and symp‐ toms of periodontitis, including bleeding gums during brushing or eating, loose teeth, spacing or spreading/drifting of the teeth, oral malodor and/or abscesses of the gums or gingival suppuration. o If a positive history is elicited, then a prompt periodontal eval‐

uation should be recommended before their scheduled annual check‐up.

o In the case of a negative history, people with CVD should be advised to check for the above symptoms, and if a positive sign appears, they should visit their dentist at least once per year.

• For all patients with newly diagnosed CVD, referral for a peri‐ odontal examination should occur as part of their ongoing man‐ agement of CVD. Even if no periodontitis is diagnosed initially, an annual oral/dental check‐up is recommended.

• The physician should liaise with the dental surgeon over peri‐ odontitis management in CVD patients on anticoagulant/anti‐ platelet therapy prior to the oral intervention and/or periodontal surgery, to avoid excess bleeding or the risk of ischaemic events.

6.3 | Recommendations for patients at the dental surgery/ office who have CVD or are found to be at risk of CVD

• People with CVD must be aware that gum disease is a chronic condition, which may aggravate their CVD and requires lifelong attention and professional care.

• There is a need to clean the teeth and gums very carefully at home. Personalized advice will be provided by the oral health professional.

This may include the following: • Twice‐daily brushing with either a manual or electric

toothbrush; • Cleaning between teeth using interdental brushes where they

fit, and where they do not fit, then flossing may be useful; • Use of specific dentifrices and/or mouth rinses with proven

activity against dental plaque, if advised by oral health professionals;

• If left untreated, gum disease can lead to tooth loss and may also make CVD preventive measures harder to control;

• Gum disease may be present and deteriorate with no apparent symptoms, so the dentist should advise their patient that even without current gum disease, they should still receive regular dental check‐ups as part of managing their CVD.

Dentists should be able to identify the early signs of gum disease, but patients should also suspect gum disease if noticing:

     |  279SANZ et Al.

• Red or swollen gums; • Bleeding from the gums or blood in the sink after toothbrushing; • Foul taste; • Longer looking teeth; • Loose teeth; • Increasing spaces between teeth/ teeth moving apart; • Calculus (tartar) on teeth.

Patients should inform their dentist about the outcome of their visits to the physician and provide an update on their CVD history and any changes in medications. Patients should inform the dentist if they are on anticoagulant therapy.

Patients should understand that it is important to keep their mouth and whole body as healthy as possible with regular dental and medical visits.

6.4 | Recommendations for patients with CVD at the physician's practice/office

6.4.1 | Why should I have my gums checked?

If your physician has told you that you have cardiovascular disease (CVD), you should make an appointment with a dental surgeon to have your mouth and gums checked.

This is because people with CVD may have a higher chance of getting further complications when they have gum disease. The ear‐ lier you seek help, the better the outcome will be.

6.4.2 | What should I look for that may tell me I have problems with my gums?

You may have gum disease if you have ever noticed:

• Red or swollen gums; • Bleeding from your gums or blood in the sink after you brush your

teeth; • Foul taste; • Longer looking teeth; • Loose teeth; • Increasing spaces between your teeth, or your teeth drifting

apart; • Calculus (tartar) on your teeth.

If you have noticed any of these problems, it is important to see a den‐ tist as soon as possible.

6.4.3 | Can I have gum disease without these signs being present?

Gum disease may also be present and get worse with no apparent signs to you that you have it, especially if you smoke, so even if you do not think you have gum disease now, you should still have annual check‐ups of your mouth as part of managing your CVD. Your dentist will be able to pick up early signs of gum disease.

6.4.4 | What can I do to prevent gum disease?

You need to clean your teeth and gums twice daily at home for a minimum of 2 min. Also, cleaning between your teeth daily is important and your oral health professional will show you how to do this. You should visit a dental surgeon as soon as possible for a diagnosis and advice on what you need to do. It is important to keep your mouth as healthy as possible with regular oral and dental care, according to the recommendations of your oral health professional.

O R C I D

Mariano Sanz https://orcid.org/0000‐0002‐6293‐5755

Søren Jepsen https://orcid.org/0000‐0002‐4160‐5837

Filippo Graziani https://orcid.org/0000‐0001‐8780‐7306

David Herrera https://orcid.org/0000‐0002‐5554‐2777

Bruno Loos https://orcid.org/0000‐0002‐8794‐552X

Phoebus Madianos https://orcid.org/0000‐0003‐0935‐5601

Lior Shapira https://orcid.org/0000‐0001‐9145‐5155

Maurizio Tonetti https://orcid.org/0000‐0002‐2743‐0137

Israel Gotsman https://orcid.org/0000‐0003‐0935‐5601

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jop.2017.160447

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A N T I T H R O M B O T I C T H E R A P Y: W H E N , H O W A N D W H Y. C O M P R E H E N S I V E A P P R O A C H F O R O R A L H E A LT H P R O F E S S I O N A L S

Introduction

The use of antithrombotic therapy is one of the cornerstones of cardiovascular medicine, as the main pathophysiological event is thrombus formation. The widespread use of antithrombotic agents is an indisputable fact and is increasing everyday with the ageing of the general population and the unstoppable growth of cardiovascu‐ lar diseases (CVD) prevalence. Altogether, the number of available agents, indications and timing of these therapeutic interventions is a matter of constant discussion and controversy. This document pretends to complement the current recommendations of the Joint Committee of the European Federation for Periodontology (EFP) and the World Heart Federation (WHF) with an overview of the rationale of the antiplatelet and anticoagulant therapies in the set‐ ting of cardiovascular disease, to increase awareness of the dos and don´ts of these medications and optimize the thrombotic and bleed‐ ing of patients with CVD that undergo periodontal interventions.

Pharmacology of antithrombotic agents

Thrombus prevention is based on the interruption of the haemosta‐ sis, and this can be achieved by intervening in the primary haemosta‐ sis (namely, platelet function) or secondary haemostasis (basically, humoral factors). Agents whose main target is primary haemostasis are usually called antiplatelet drugs and are widely used in circum‐ stances in which the main phenomenon is local thrombosis (e.g. myocardial infarction, non‐embolic strokes, etc.). On the other hand, drugs that alter secondary haemostasis are generally referred to as anticoagulants and are used in conditions that increase the risk of clot formation with subsequent embolization (e.g. atrial fibrillation, deep vein thrombosis, etc.).

Antiplatelet drugs

The currently commercialized antiplatelet drugs of common use are:

• Acetylsalicylic acid (ASA ‐ Adiro®) • AntiP2Y12: usually, these medications are used as adjuvants in

situations of abnormally high thrombotic risk, such as the months after a myocardial infarction (MI) or the placement of a coronary stent. When compared with ASA, all of these drugs have a higher antithrombotic power and, thus, a higher bleeding risk. That is why it is of no surprise that, when used as adjuvants therapies together with ASA, the final risk of bleeding arises from a synergistic effect of both drugs and is markedly elevated compared with single an‐ tiplatelet therapy. As the thrombotic risk in the aforementioned situations (recent MI, recent coronary stent placement) decreases with time, the use of these agents is almost always limited for a number of months after the event. These group includes:

o Clopidogrel (Plavix®) o Ticagrelor (Brilique®, Brilinta®, Ticalog®) o Prasugrel (Efient®, Effient®, Agrepres®, Prasugil®, Prasita®)

The last two agents, namely ticagrelor and prasugrel, were released several years after the commercialization of clopidogrel due to some concerns regarding the efficacy of the latter in selected populations with resistance its biological effect. Both medications have shown a higher platelet inhibition when compared to clopidogrel with a logically expected increase in the bleeding rates. No studies have addressed the comparative risk of ticagrelor against prasugrel.

There are other available antiplatelet drugs, but their use is re‐ stricted to very specific and rarely situations that are beyond of the scope of this review and, thus, would not be review.

Anticoagulant drugs

The span of anticoagulant drugs is broader, as it included both oral and parenteral families. The oral anticoagulant medications include:

• Vitamin K antagonists (VKA): These anticoagulants were the first oral agents in the market and have been available for more than 20 years. Their use is widely extended, as they are very cheap agents and the medical community is very comfortable with its use. Another positive feature is that the dose can be titrated to achieve higher or lower anticoagulant effect, depending on the thrombotic risk of the patient. However, they have some setbacks that are to be considered. Firstly, the dose is not predictable, so the patient must routinely undergo haemostasis checks at least monthly to adjust the dosage regime. In addition, these agents are tightly bound to plasmatic proteins and tend to interact with medications that displace them from that union (e.g. non‐steroi‐ dal anti‐inflammatory drugs, antibiotics, etc.). Also, their effect varies widely with vitamin K intake with the diet. All in all, these medications can be quite uncomfortable for both the patient and the doctor: the patient has to be disciplined with the diet and the dosage regime, and should be aware of all the medications that can interact. Physicians, on the other hand, have to check these patients up monthly to adjust the dose. The active principles of this group are:

o Warfarin (Coumadin®, Farin®, Aldocumar®) o Acenocumarol (Sintrom®)

While in North America the use of warfarin is much more frequent, acenocumarol is the preferred choice in Europe.

• Direct Oral Anticoagulants (DOACs): this group encompasses four different drugs divided into direct thrombin inhibitors and Xa factor inhibitors. The benefits these medications have in compar‐ ison with VKA is that their dose is predictable, so no dose moni‐ toring is necessary. Also, their interactions are limited and much more infrequent. Regarding outcomes, these drugs have shown to be at least non‐inferior to acenocumarol in embolic prevention with a better safety profile as measured by a lower bleeding risk.

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This better overall profile is the reason why DOACs are now the first line therapy with patients with atrial fibrillation (AF) accord‐ ing to the current clinical practice guidelines. However, not all the AF patients are candidates for these medications. This group includes:

o Dabigatran (Pradaxa®): available as 110 mg or 150 mg tablets. It is used twice a day.

o Rivaroxaban (Xarelto®): available as 15 mg or 20 mg tablets. It is used once daily.

o Apixaban (Eliquis®): available as 2.5 mg or 5 mg tablets. It is used twice a day.

o Edoxaban (Lixiana®): available as 30 mg or 60 mg tablets. It is used once daily.

Other than the above, sometimes patients can be on parenteral an‐ ticoagulant therapies such as low molecular weight heparins. These medications are normally used during short periods of time while bridging in between drugs. Indications

For single antiplatelet therapy (SAPT)

Every patient with any form of CVD that belong to the atheroscle‐ rotic spectrum (coronary artery disease, cerebrovascular disease or peripheral artery disease) should start indefinite treatment with an antiplatelet agent. For this indication, the most extended practice is to use ASA, but also clopidogrel can be used. Ticagrelor and prasug‐ rel are never used in monotherapy (Neumann et al., 2008; Task Force Members et al., 2018).

Although this has been widely discussed during several decades, the use of ASA in primary prevention is currently not justified and should be avoided.

Other than the above, there are several conditions that also re‐ quire the utilization of ASA, such as some cases of antiphospholipid syndrome or the presence of intracardiac structural devices (mitral clip, atrial and/or ventricular septal defect occluders, bioprosthetic valves, etc.)

For double antiplatelet therapy (DAPT)

• Coronary artery disease (CAD): patients with CAD require DAPT in the following situations (Ibanez et al., 2014; Neumann et al., 2008): o Chronic angina pectoris: after the implantation of a coro‐

nary stent, it is generally recommended to use DAPT for 6 months, after which the patient can discontinue the sec‐ ond antiplatelet drug and stay only on ASA. In some cases of high risk of bleeding, the duration can be shortened to three months. The only combination approved for this scenario is ASA + clopidogrel.

o Acute coronary syndrome (myocardial infarction): after a myocardial infarction, is it recommended to use DAPT for a duration of 12 months. However, in some cases, the duration

can be shortened to only one month, after which the patient should discontinue the second agent and remain on ASA in‐ definitely. First month after stent implantation is particularly critical, so no patient should suspend DAPT within this time window. Preferably, the patient should be on ASA + ticagrelor/ prasugrel, but ASA + clopidogrel is also acceptable if there are contraindications for the other agents.

• Cerebrovascular disease (CeVD): patients with CeVD require DAPT in the following situations: o Chronic carotid disease: in symptomatic patients with carotid

stenosis that undergo carotid stenting, ASA + clopidogrel is recommended for one month. After that, the patient can dis‐ continue one of the two agents and remain indefinitely on the other (usually clopidogrel is discontinued).

o Acute ischemic stroke: the use of DAPT for secondary preven‐ tion of stroke has not shown consistent positive results in this scenario. Thus, it is not routinely recommended.

• Peripheral artery disease (PAD) (European Stroke Organisation et al., 2012): o Chronic lower extremity artery disease: in symptomatic pa‐

tients that undergo lower limb percutaneous revascularization (stenting), ASA + clopidogrel is recommended for one month. After that, the patient can discontinue one of the two agents and remain indefinitely on the other (usually clopidogrel is discontinued).

o Acute ischemic lower limb event: the use of DAPT for second‐ ary prevention of lower limb occlusions has not shown consis‐ tent positive results in this scenario. Thus, it is not routinely recommended.

Chronic Oral Anticoagulation (COA)

There are three main indications for anticoagulation:

• Deep vein thrombosis (DVT) and pulmonary embolism (PE) (Konstantinides et al., 2019): both VKA and DOACs are autho‐ rized for this indication. The duration of the therapy depends on whether it is assumed to be a spontaneous case (3–6 months) or secondary to a non‐solvable condition (may even be indefinite). When using VKA, the optimal international normalized ratio (INR) range is 2 to 3.

• Atrial arrhythmias with high risk of systemic embolism (AF, Atrial Flutter): the indication for chronic anticoagulation in the set‐ ting of AF/AFlutter is guided by the risk of embolism. Although the method for the risk estimation varies worldwide, European Society of Cardiology (ESC) guidelines recommend the use of CHADSVASc scale. Generally, it is accepted that the following patients with a score equal to 2 or higher must use chronic oral anticoagulant therapy. For this indication, again, both VKA and DOAC can be used, being the latter the first line therapy. When using VKA, the optimal INR range is 2 to 3.

• Valve heart diseases with high risk of systemic embolism: this sit‐ uation includes significant mitral stenosis and mechanical valve

     |  287SANZ et Al.

prosthesis. Tissue valves are not at a high risk of systemic embo‐ lism. These situations are the ones with the highest thrombotic risk in the whole area of cardiovascular medicine. As the “power” of the anticoagulation with DOACs was proven to be insufficient in these patients and entailed an increased thrombotic risk, VKA are the only option. In the case of mitral mechanical prosthesis, the optimal INR range is 2.5–3.5, while aortic valve prosthesis can be handled between 2–3. However, some older prosthetic models are known to be more thrombogenic than newer ones and could require INR of up to 4.

Combined Therapies: SAPT/DAPT with COA

Usually, patients with indication for chronic SAPT with either ASA or clopidogrel and indication for COA are encouraged to take COA alone. This strategy has been assessed is several studies and proved to be safe from a secondary prevention point of view, with a reduced risk of bleeding when compared with concomitant SAPT and COA.

On the other hand, the management of patients with indication for DAPT and COA is normally seen in patients that are undergo‐ ing coronary stent implantation and have either atrial arrhythmias (more frequent) or mitral stenosis/mechanical valves (less frequent). Depending on the bleeding risk of the patients, two different ap‐ proaches can be chosen:

• Normal bleeding risk: short period of triple therapy (1‐3 months of DAPT+COA) and a transition period with SAPT and COA (3‐12 months). After that, it is recommended to downgrade to simple COA therapy.

• High bleeding risk: the short period is either reduced to 1 month or omitted, leaving the patient on SAPT+COA for a minimum of 12 months.

Treatment withdrawal: safety and rationale

It is not the purpose of this paper to give recommendations on tim‐ ing and indications of withdrawal, but rather explain the changes/ effects that the antithrombotic withdrawal entails.

Risks of antiplatelet withdrawal

The main risk of SAPT withdrawal is, of course, the increase in thrombotic risk as explained by a higher chance of MI, stroke or pe‐ ripheral artery thrombosis. It should be noticed that patients with implanted stents are at a much greater risk of acute events after SAPT withdrawal.

Regarding DAPT, the crucial thing to be understood is that when‐ ever DAPT is used, an abnormally high thrombotic risk underlies. The duration of DAPT regimes depends on several factors, but there should be always a preestablished goal (e.g. 6 months, 12 months, etc.). Transitioning from DAPT to SAPT before the preestablished goal should always be performed under cardiological supervision. Specially, the first month after a coronary stent implantation is of

vital importance, as discontinuation of antiplatelet therapy can eas‐ ily lead to stent thrombosis, a complication that could be fatal.

After discontinuing an antiplatelet agent, the effect does not wear off immediately:

• ASA: 10 days until absence of effect. • Clopidogrel: 3 days for significant decrease in effect. 5 days for

absence of effect. • Ticagrelor: 3 days for significant decrease in effect. 5 days for ab‐

sence of effect. • Prasugrel: 5 days for significant decrease in effect. 7 days for ab‐

sence of effect.

Risks of anticoagulation withdrawal

Patients with indication for COA that stop taking these medications are at an increased risk for thromboembolic complications. The over‐ all risk of the thrombotic complications highly depends on the indi‐ cation for COA.

In patients with mitral stenosis or mechanical heart valves, the discontinuation of VKA leads to an extremely thrombotic risk, spe‐ cially for patients with mechanical valves in mitral position. Thus, discontinuation of this therapy in such patients such always be su‐ pervised by cardiovascular professionals and usually requires bridg‐ ing treatment with heparin (Baumgartner et al., 2008).

On the counterpart, patients without those conditions, can nor‐ mally be off DOAC/VKA for brief periods of time with an assumable thromboembolic risk, specially in patients with CHADSVASc scores between 2‐6. However, discontinuation of VKA is not recommended anymore for procedures other that those with high bleeding risk. After an oral cavity intervention with significant bleeding, DOACs can be safely restarted 24 hours later.

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Title Author & Affiliation Abstract (a summary of the paper)

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Minimum requirements for the

review paper

·

Page Requirement

: Minimum 10 pages not including references, 1 inch margin, font 12, double space, no

additional space between paragraphs.

·

References Requirement:

Minimum 10 peer

-

reviewed journal research papers. Among these, minimum five

were published within the past

5 years. References are typed with single space.

·

Format

: Follow a journal style

.

·

Content

:

The paper reviews current research of a selected topic. Research data from primary papers should be included to

support ideas or arguments presented in the paper.

·

Organization

:

Literature Review (following

the format of a review journal paper)

Title Author & Affiliation Abstract

(a summary of the paper)

Introduction

(briefly overview the importance of the main topic, state the purpose of the paper and preview the

structure (what will be reviewed) of the pap

er)

Text with headings

Materials and Methods

Results and Discussion

(

include appropriate tables and/or graphs to illustrate results, data interpretation

)

Conclusions

References

(following a required format and typed reference using single space)

Minimum requirements for the review paper

 Page Requirement: Minimum 10 pages not including references, 1 inch margin, font 12, double space, no

additional space between paragraphs.

 References Requirement: Minimum 10 peer-reviewed journal research papers. Among these, minimum five

were published within the past 5 years. References are typed with single space.

 Format: Follow a journal style.

 Content:

The paper reviews current research of a selected topic. Research data from primary papers should be included to

support ideas or arguments presented in the paper.

 Organization:

Literature Review (following the format of a review journal paper)

Title Author & Affiliation Abstract (a summary of the paper)

Introduction (briefly overview the importance of the main topic, state the purpose of the paper and preview the

structure (what will be reviewed) of the paper)

Text with headings

Materials and Methods

Results and Discussion (include appropriate tables and/or graphs to illustrate results, data interpretation)

Conclusions

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