148 Journal of Indian Society of Periodontology - Vol 14, Issu

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: [email protected]
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 pr esent
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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Dhadse, et al.: The link between periodontal and cardiovascular
disease…
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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Jul-Sep 2010 151
disease…
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
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
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
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
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
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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Jul-Sep 2010 153
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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disease…
Author Institution Mapping (AIM)
Please note that not all the institutions may get mapped due to
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For AIM of other

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
mailto:
https://orcid.org/0000-0002-6293-5755
https://orcid.org/0000-0002-4160-5837
https://orcid.org/0000-0003-0935-5601
https://orcid.org/0000-0001-8780-7306
https://orcid.org/0000-0002-5554-2777
https://orcid.org/0000-0002-8794-552X
https://orcid.org/0000-0003-0935-5601
https://orcid.org/0000-0001-9145-5155
https://orcid.org/0000-0002-2743-0137
mailto:[email protected]
http://creativecommons.org/licenses/by-nc-nd/4.0/
| 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 (Herrer a,
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).
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).
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).
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 onl y
par‐
tially reduces the cytokine hyper‐ reactivity with some evidence
of a
constitutively elevated response (Ling, Chapple, & Matthews,
2016).
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).
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).
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 br ushed
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 limi ted
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
| 275SANZ et Al.
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
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)
interleukin (IL)−6
IL−6 3 RCTs Fu et al. (2016); Kapellas et al. (2014);
Zhou et al. (2017)
Yes Moderate
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)
Pulse Wave Velocity (PWV)
PWV 1 RCT Kapellas et al. (2014) No Limited
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
| 277SANZ et Al.
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.

148 Journal of Indian Society of Periodontology - Vol 14, Issu

148 Journal of Indian Society of Periodontology - Vol 14, Issu

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148 Journal of Indian Society of Periodontology - Vol 14, Issu