Download Nonsurgical periodontal therapy reduces coronary heart disease

J Clin Periodontol 2012; 39: 1065–1074 doi: 10.1111/j.1600-051X.2012.01942.x
Non-surgical periodontal therapy
reduces coronary heart disease
risk markers: a randomized
controlled trial
Bokhari SAH, Khan AA, Butt AK, Azhar M, Hanif M, Izhar M, Tatakis DN.
Non-surgical periodontal therapy reduces coronary heart disease risk markers: a
randomized controlled trial. J Clin Periodontol 2012; 39: 1065–1074. doi: 10.1111/
j.1600-051X.2012.01942.x.
Abstract:
Aim: Periodontal disease elevates systemic inflammatory markers strongly associated with coronary heart disease (CHD) risk. The aim of this randomized controlled trial was to investigate the effect of non-surgical periodontal therapy on
systemic C-reactive protein (CRP), fibrinogen and white blood cells in CHD
patients.
Materials and Methods: Angiographically proven CHD patients with periodontitis (n = 317) were randomized to intervention (n = 212) or control group
(n = 105). Primary outcome was reduction in serum CRP levels; secondary outcomes were reductions in fibrinogen and white blood cells. Periodontal treatment
included scaling, root planing and oral hygiene instructions. Periodontal and
systemic parameters were assessed at baseline and at 2-month follow-up. Intentto-treat (ITT) analysis was performed.
Results: Study was completed by 246 subjects (intervention group = 161; control
group = 85). Significant improvements in periodontal and systemic parameters
were observed in intervention group. The number of subjects with CRP > 3mg/L
in intervention group decreased by 38% and in control group increased by 4%.
ITT analysis gave a significant (v2=4.381, p = 0.036) absolute risk reduction of
12.5%.
Conclusion: In CHD patients with periodontitis, non-surgical mechanical periodontal therapy significantly reduced systemic levels of C-reactive protein, fibrinogen and white blood cells.
Conflict of interest and source of
funding statement
Authors declare that they have no
conflict of interest. Grant No: 20-685,
R & D 06/1959, Higher Education
Commission, Government of Pakistan,
Islamabad.
Clinicaltrials.gov
01746.
identifier:
© 2012 John Wiley & Sons A/S
NCT012
Periodontitis (PD) is a chronic inflammatory disease of infectious nature
(Williams 1990, Tatakis & Kumar
2005). PD contributes to systemic
inflammation (Friedewald et al. 2009)
and has been strongly associated with
elevation of systemic inflammatory
markers, such as C-reactive protein
(CRP) (Paraskevas et al. 2008, Fisher
et al. 2010), fibrinogen and white blood
Syed A. H. Bokhari1, Ayyaz A. Khan2,
Arshad K. Butt3, Mohammad Azhar4,
Mohammad Hanif5, Mateen Izhar6 and
Dimitris N. Tatakis7
1
University Medical & Dental College, The
University of Faisalabad, Faisalabad,
Pakistan; 2Department of Oral Health
Sciences, Sheikh Zayed Federal
Postgraduate Medical Institute & Hospital,
Lahore, Pakistan; 3Department of
Gastroenterology, Sheikh Zayed Federal
Postgraduate Medical Institute & Hospital,
Lahore, Pakistan; 4Department of Cardiology,
Punjab Institute of Cardiology, Lahore,
Pakistan; 5Department of Statistics, National
College of Commerce, Business
Administration & Economics, Lahore,
Pakistan; 6Department of Pathology, Sheikh
Zayed Federal Postgraduate Medical Institute
& Hospital, Lahore, Pakistan; 7Division of
Periodontology, College of Dentistry, Ohio
State University, Columbus, USA
Key words: coronary heart disease; CRP;
periodontal therapy; randomized controlled
trial; risk
Accepted for publication 17 July 2012
cells (Kweider et al. 1993). CRP is considered as an independent predictor of
cardiovascular disease (CVD) (Wang
& Hoy 2010), including coronary heart
disease (CHD) (Wang et al. 2002).
Fibrinogen and white blood cell levels
have also been significantly associated
with CHD (Danesh et al. 1998).
Systematic reviews and metaanalyses provide evidence for the
1065
1066
Bokhari et al.
association of PD and CHD (Janket
et al. 2003, Bahekar et al. 2007,
Humphrey et al. 2008). The potential mechanisms implicated in this
association are diverse (Meurman
et al. 2004, Kebschull et al. 2010).
Oral microbial burden (Beck et al.
1996, Noack et al. 2001), inflammatory burden (Beck et al. 1996,
Noack et al. 2001, Montebugnoli
et al. 2004) and haemostatic factors
(Kweider et al. 1993, Montebugnoli
et al. 2004) have been implicated in
the PD-CHD association. The effects
of periodontal therapy on systemic
CHD risk markers have been evaluated in a number of intervention
studies; the results are inconsistent,
with some studies reporting a treatment-induced reduction in systemic
markers (Iwamoto et al. 2003, D’Aiuto et al. 2004, 2005, 2006, Seinost
et al. 2005, Hussain Bokhari et al.
2009, Offenbacher et al. 2009,
Vidal et al. 2009, Kamil et al. 2011,
Lopez et al. 2011) and others reporting no treatment effect (Ide et al.
2003, Yamazaki et al. 2005, Michalowicz et al. 2009, Correa et al.
2010).
A single-blind, parallel-arm randomized-controlled clinical trial was
designed with the aim to determine
the effect of conventional, mechanical, non-surgical periodontal therapy
on serum levels of high-sensitivity
CRP (primary outcome), fibrinogen
and white blood cells (WBCs) (secondary outcomes) in CHD patients
with periodontitis. The objectives of
this study were (a) to observe
changes in clinical periodontal
parameters and serum levels of
CRP, fibrinogen and WBCs following periodontal therapy of CHD
patients with periodontitis; (b) to
compare these changes to corresponding serum levels in periodontally untreated CHD patients; and
(c) to determine the effect-size of
conventional mechanical non-surgical periodontal therapy on the
reduction of CHD risk markers in
CHD patients.
Materials and Methods
Study design and study population
The present study was a single-blind,
parallel-arm, randomized controlled
clinical trial conducted between July
2008 and April 2009 in CHD
patients defined as having >50%
stenosis of 1 coronary artery
documented by coronary angiography (Malthaner et al. 2002, Briggs
et al. 2006). CHD patients screened
by hospital nurses in the angiography department, Punjab Institute of
Cardiology were invited to participate. General and medical inclusion
criteria were male or female; aged
>30 years; CHD case (as defined
above) having coronary angiography, or myocardial infarction, or
coronary artery bypass surgery or
angioplasty >3 months prior to entry
into study; and clinically stable in
the absence of any potentially confounding inflammatory condition (as
assessed clinically). Subjects were
non-smokers (never smokers) or former smokers (did not smoke at
inclusion time and had not used any
tobacco product for at least the last
12 consecutive months), able and
willing to comply with study procedures and available for the duration
of the study. Smoking history was
assessed from patient records and
self-reporting.
Oral/periodontal inclusion criteria
were as follows: at least 14
periodontally evaluable natural teeth
present (excluding third molars); 4
teeth with 1 sites with periodontal probing depth (PPD) 4 mm
and clinical attachment level (CAL)
3 mm at same site (Michalowicz
et al. 2006, Andriankaja et al. 2007);
baseline whole mouth bleeding on
probing (BOP) > 20% of sites; no
mechanical/antibiotic/anti-inflammatory/surgical periodontal therapy in
the last 6 months; no other oral diseases (e.g. oral/mucosal lesions and
oral infections); no immediate dental/
periodontal treatment needs (e.g.
extractions); and no recent (<2
months) tooth extractions.
Exclusion criteria were as follows:
not meeting any of the above inclusion criteria; CHD case diagnosed
3 months prior to start of study;
pregnant or lactating female; chronic
conditions associated with periodontitis or with changes in systemic
inflammation (e.g. diabetes mellitus,
rheumatoid
arthritis,
rheumatic
fever, malignancy, respiratory diseases, renal diseases, autoimmune
diseases and immunological deficiencies); acute conditions known to
affect systemic inflammatory markers
(orthopaedic
trauma,
surgery,
bacterial infections and viral infections, including common cold and
influenza); and medications (during
last 3 months) known to affect
systemic
inflammatory
markers
(systemic
steroids, non-steroidal
anti-inflammatory drugs, immunosuppressant, hormone replacement
therapy, contraceptives and systemic
antibiotics). Exit criteria were as
follows: failure to comply with treatment or follow-up visits; development of conditions meeting any of
the exclusion criteria; change in systemic medications; and expressed
desire
to
end
participation.
The study was approved by the
Punjab Institute of Cardiology
Ethics Committee.
Eligible patients who provided
written informed consent were
randomized into intervention group
(n = 212; immediate periodontal
therapy) or control group (n = 105;
delayed periodontal therapy) with a
2:1 ratio by computer generated simple random tables. The 2:1 ratio was
chosen to maximize the number of
patients receiving treatment and to
compensate for possible greater attrition in patients undergoing therapy
delivered in multiple appointments.
General and medical inclusion criteria were applied by two qualified
nurses trained for this study. Physicians performed clinical examinations (systemic exclusion criteria)
and recorded systemic medications.
Allocation of patients into intervention and control groups was concealed (sealed envelopes) and kept
masked from the periodontal examiner. Subjects’ enrolment, allocation
and follow-up record were maintained by the research assistant.
Sample analysis was performed by a
medical technologist blinded regarding subject group (coded samples).
Data were entered into SPSS program and analysed at primary level
by the statistician who was blinded
regarding study group identification.
Subjects were examined for periodontal and inflammatory parameters as outlined in the study timeline
(Fig. 1).
Sample size
Sample size was calculated for a
two-tailed, two-sample t-test, based
on the results of a pilot study
(Hussain Bokhari et al. 2009) for the
© 2012 John Wiley & Sons A/S
Periodontal therapy and CHD risk markers
1067
(a) Study time line
INTERVENTION group
Day-10 (start of treatment) ___ Day-0 _____________ 30 ± 3 days__________________________30 ± 3 days
1-month follow-up
(Baseline/1st Examination)
1-month follow-up
(2nd examination)
(3rd examination)
CONTROL group
Day-0 _______________________________________30 ± 3 days___________________________30 ± 3 days
1-month follow-up
1-month follow-up
(Baseline/1st Examination)
(2nd examination)
(3rd examination)
(b) Study Flow Diagram
CHD subjects screened = 1963
Excluded = 1609
(General /Medical and oral/periodontal
exclusion criteria)
Declined to participate = 37
Recruited = 317
1st periodontal examination
+ Blood collection
Intervention group = 212
Received periodontal therapy = 201
Did not complete periodontal therapy = 11
Randomization
(Concealed allocation)
Periodontal
therapy
Control group = 105
Did not receive periodontal therapy = 105
Lost to follow up = 21
Received periodontal examination
and gave blood sample = 180
1st Follow up (1-month)
(2nd Examination)
Lost to follow up = 11
Received periodontal examination
and gave blood sample = 94
Lost to follow up = 14
Received periodontal examination
and gave blood sample = 166
2nd Follow up (1-month)
(3rd Examination)
Lost to follow up = 7
received periodontal examination
and gave blood sample = 87
Incomplete serum data = 5
Analyzed = 161
Data
analysis
Incomplete serum data = 2
analyzed = 85
Fig. 1. Study design: Panel 1A: study timeline; Panel 1B: study flow diagram.
primary endpoint (post-treatment
serum CRP values). Based on a=0.05
and assuming a mean difference
(CRP level) between groups of
0.2 mg/dL with group A (intervention group) r = 0.3 and group B
(control group) r = 0.5, a study with
158 subjects in group A and 79 subjects in group B (2:1 ratio) would
have 90% power to detect a significant inter-group difference. Assuming a 25% drop-out rate, 212
subjects were randomized to the
intervention group and 105 subjects
to the control group.
© 2012 John Wiley & Sons A/S
Measures
Demographic and medical parameters
Demographic and medical parameters were recorded from patient
interviews and patient hospital files.
Education level was categorized as
uneducated,
higher
secondary
( 12 years schooling) and university (>12 years schooling). Socio-economic status was defined according
to monthly income (Rs. <10,000/or
Rs. 10,000–20,000/- or Rs. >20,000/) and occupation (unskilled, skilled
and professional). Obesity was
defined
through
BMI
(obese
30 kg/m2 or overweight 25–29 kg/
m2 or desirable/underweight <25 kg/
m2). Smoking status was classified as
non-smoker (never smoker) and former smoker.
Clinical periodontal parameters
Clinical periodontal parameters were
recorded by a sole trained and calibrated examiner. The examiner was
trained against a reference examiner,
and calibration resulted in 85.5%
intra-examiner and 83.3% interexaminer reliability. BOP, PPD and
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Bokhari et al.
CAL were recorded for all teeth
present, excluding third molars. BOP
was noted within 30 s of probing at
six sites (mesiobuccal, mid-buccal,
disto-buccal, mesio-lingual, mid-lingual and disto-lingual) per tooth.
PPD and CAL were measured at the
aforementioned six sites using a
UNC15 probe (Hu-Friedy, Chicago,
IL) and recorded to the nearest mm.
BOP was recorded at baseline (first
examination) and at the 1-month
(second examination) and 2-month
(third examination) follow-up visits.
PPD and CAL were recorded only
at first examination (baseline) and at
third examination (2-month followup). Periodontal parameters were
recorded in a single/two visit(s),
completed within 48 h, depending on
patient comfort or need to remove
calculus to adequately probe (for
baseline examination only).
Serum inflammatory markers
Random blood samples (10 ml) were
obtained between 8 AM and12 noon
(to control diurnal variations) by a
hospital phlebotomist, following venipuncture (antecubital fossa), at baseline and at the 1- and 2-month
follow-up evaluations. Blood was collected in tubes with clot activator,
3.2% sodium citrate and EDTA for
CRP, fibrinogen and WBC analysis
respectively. Samples for CRP and
fibrinogen were centrifuged and
stored ( 20°C) for analysis within a
week. CRP levels (mg/L) were analysed using a high-sensitivity assay
following the manufacturer’s instructions (Dimension® CardioPhase®
CCRP Flex® reagent kit; Dade Behring Ltd, Atterbury, Milton Keynes
MK, UK). Fibrinogen (mg/L) was
analysed using a commercially available kit on a semi-automated analyser
(KC4 Delta; Trinity Biotech GmbH,
Lemgo, Germany). WBC counts
(9109/L) were obtained within
4 hours of blood collection, using
an automated haematology analyser
(KX-2; Sysmex Corp., Singapore).
Manufacturer instructions were followed for blood sampling, sample
preparation, storage and analysis.
Periodontal therapy
Mechanical non-surgical periodontal
therapy included supra- and sub-gingival scaling and root planing
and oral hygiene instructions. Scaling
was performed by dentist or dental
hygienist
using
ultrasonic
instrumentation, whereas root planing was performed using Gracey
curettes. Oral hygiene instructions
were given by dental hygienist, using
dental educational materials. Scaling
and root planing was performed in 2–
4 visits and completed within 10 days
of enrolment, under local or topical
anaesthesia as needed (Michalowicz
et al. 2006). Upon completion of periodontal therapy, subjects received at
no charge five tubes of toothpaste
(CROTA) and manual toothbrush
for oral home care. Oral hygiene
instructions were reinforced at each
follow-up visit. No adjunctive local
or systemic chemotherapeutics were
used as part of periodontal therapy.
Subjects were asked to call/visit the
dental clinic if any oral/systemic complication arose during the follow-up
period. Periodontal therapy was considered successful when BOP was
reduced to 20% and the number of
PPD 4 mm was reduced by 50%
at follow-up.
Data analysis
Bleeding on probing, PPD and CAL
site measurements were calculated for
whole mouth. Subjects were stratified
for periodontal disease severity/extent
and also grouped according to CHD
risk category based on CRP cut-off
levels; moderate/low-risk ( 3.00 mg/
L) and high-risk (>3.00 mg/L) (Pearson et al. 2003). The primary outcome measure was CRP reduction,
and secondary measures were reductions in fibrinogen and WBCs.
Intent-to-treat (ITT) analysis was
performed as primary analysis, utilizing the last values carried forward
approach. Data were analysed
using SPSS software (version 13.0,
SPSS, IBM, Chicago, IL, USA) and
presented as mean±SD for continuous variables and percentages for
categorical variables. Comparison of
periodontal
and
inflammatory
parameters in intervention and control groups at first (baseline), second
(1-month follow-up) and third (2month follow-up) examinations was
performed using a t-test and paired
t-test and repeated measure design
for continuous data as test of significance for inter- and intra-group
comparisons. The differences in proportions of subjects with periodontal
outcome measures (changes in BOP,
PPD and CAL) and systemic inflam-
matory parameter outcomes (CRP,
fibrinogen and WBCs) between
intervention and control groups
were analysed using chi-square test
at first and third examinations.
Level of significance was considered
at 95% (p 0.050). In addition to
ITT, per-protocol (PPT) analysis
was also performed (data partially
reported).
Results
Study population and study protocol
One thousand nine hundred and
sixty-three patients of the same ethnic origin were screened (July 2008–
February 2009). Four hundred and
thirty patients fulfilling the general
and medical inclusion criteria were
invited for oral/periodontal evaluation. Sixty-nine patients did not fulfil
the oral/periodontal inclusion criteria, 37 patients declined to participate
and seven were not recruited because
the approved enrolment number had
been met. The enrolled 317 CHD
patients with periodontitis were randomized into intervention (n = 212)
and control (n = 105) groups (Fig. 1).
Two hundred and fifty-two (79.8%)
subjects completed the study with 166
(78.3%) subjects in the intervention
group and 87 (82.8%) in the control
group. Sixty-four (20.1%) subjects
(46 from intervention and 18 from
control group) dropped out in the
course of the study (Fig. 1). The 11
subjects who did not complete periodontal therapy refused to continue
for logistic reasons. Of the 32 subjects
lost during the first month of followup, 19 (12 in intervention and seven
in control group) failed to report for
personal reasons, while the remaining
were exited from the study. Of the 13
subjects exited during this period,
eight (six in intervention and two in
control group) were exited because of
changes in cardiac medications, three
(all three in intervention group)
because they received anti-inflammatory medications and two (both in
control group) because they received
percutaneous cardiac intervention
(PCI). During the second month of
follow-up, 21 subjects (14 in intervention and seven in control group) were
lost; eight (six in intervention and two
in control group) because they
received PCI or other cardiac
intervention, five (three intervention
© 2012 John Wiley & Sons A/S
Periodontal therapy and CHD risk markers
and two control) for personal reasons, four (two intervention and two
control) because they received antibiotics and four (three intervention and
one control) because they developed
systemic illnesses. Five subjects from
intervention group and two from the
control group were dropped from
analysis because of incomplete serological data (Fig. 1). Data analysis
was based on the complete data from
161 intervention group and 85 control
group subjects and the incomplete
data of 71 (51 intervention and 20
control) subjects (last values carried
forward).
Study parameters at baseline
A comparison of intervention and
control groups at baseline, with
respect to demographic and medical
(Table 1) and periodontal and serum
inflammatory (Table 2) parameters
revealed no significant differences
(p 0.055) between the groups. Subjects of both groups were categorized
based on threshold levels of periodontal and inflammatory parameters; it
was observed that the proportion of
subjects with BOP > 20% sites,
PPD 4 mm at > 30% sites,
CAL 3 mm at >30% sites and
proportion of subjects with serum levels of CRP > 3 mg/L, fibrinogen levels of >300 mg/L and WBC counts of
>7.00 9 109/L was not significantly
different (p 0.055) between the
groups (Table 2). Similarly, there was
no significant difference (p 0.45)
between groups regarding prescribed
cardiac medications. The distribution
of subjects with respect to various
medications was 97.5% were on antiplatelets; 77% b-blockers; 27% angiotensin
receptor
blockers
or
angiotensin converting enzyme inhibitors; 46% calcium channel antagonists; 76% lipid lowering agents
(statins); 9% diuretics; and 33%
nitrates. Subjects were monitored for
change in cardiac medicines at baseline and during follow-up period. As
detailed
herein,
subjects
were
excluded from study at follow-up
visits due to change in medications.
Periodontal and inflammatory parameter
changes from baseline to 1-month and
2-month follow-up
Figure 2 shows the trend line graphs
for changes (mean ± SE) in BOP,
© 2012 John Wiley & Sons A/S
1069
Table 1. Demographic and medical parameters of study population at baseline
Demographic and medical
parameters of study
Age† (years)
Gender
M/F (%)
Marital status
Married (%)
Education (% subjects)
Uneducated/secondary/
university
Income (% subjects)
Rs. <10,000/10-20,000/
>20,000.00
Occupation (% subjects)
Unskilled/skilled/professional
Body Mass Index (BMI) (% subjects)
Desirable/overweight/obese
BMI†
Smoking (% subjects)
Non-smoker/former smoker
% CHD patients with 1/2/ 3
coronary vessels with >50% stenosis
Cardiac procedures (% subjects)
PCI/CABG/no procedure
Hypertensive/non-hypertensive
(% subjects)
Blood pressure†
Systolic/diastolic
†
Intervention
group (n = 212)
Control group
(n = 105)
t-test*,
Chi-square
test**
49.0 ± 0.6
50.1 ± 0.9
*p = 0.303
85/15
88.5/11.5
**p = 0.399
97.2
97.1
**p = 0.612
22.5/67.6/9.9
15.4/69.2/15.4
**p = 0.163
85.4/11.7/2.8
88.5/8.7/2.9
**p = 0.707
52.5/23.0/24.5
51.3/23.9/24.8
**p = 0.452
26.5/41.7/31.8
28.3 ± 0.5
25/41.3/33.7
28.4 ± 0.7
**p = 0.931
*p = 0.843
54.8/45.2
30/42/28
**p = 0.222
**p = 0.884
53.5/18.3/28.2
56/44
40.4/20.2/39.4
47/53
**p = 0.069
**p = 0.152
123.7 ± 0.7/
84.2 ± 0.5
123.5 ± 0.9/
83.8 ± 0.8
*p 0.861
62.4/37.6
27/43/30
Values expressed as Mean ± SE.
Table 2. Periodontal and serum inflammatory parameters of study population at baseline
Periodontal and inflammatory parameters
Intervention
group
(n = 212)
Control
group
(n = 105)
t-test*,
Chi-square
test**
Bleeding on probing (BOP)† % sites
% Subjects with BOP > 20% sites
Periodontal probing depth (PPD)† in mm
% Subjects with PPD 4 mm at >30%
sites/ 30% sites
Clinical attachment loss (CAL)† in mm
% Subjects with CAL 3 mm at >30%
sites/ 30% sites
hsC-Reactive Protein (hsCRP)† in mg/L
% Subjects with CRP levels >3/ 3 mg/L
Fibrinogen† in mg/L
% Subjects with Fibrinogen levels > 300
mg/L/ 300 mg/L
White blood cells (WBCs)† 9 109/L
% Subjects with WBC counts
>7.00 9 109/L/ 7.00 9 109/L
42.1 ± 1.0
100
3.5 ± 0.1
71/29
39.1 ± 1.5
100
3.4 ± 0.1
65/35
*p = 0.092
–
*p = 0.216
**p = 0.241
3.4 ± 0.1
88/12
3.3 ± 0.1
88.5/11.5
*p = 0.734
**p = 0.728
4.4 ± 0.2
58.5/41.5
367.1 ± 10.4
65/35
4.2 ± 0.3
46.5/53.3
339.6 ± 10.5
67/33
*p = 0.316
**p = 0.055
*p = 0.097
**p = 0.803
7.8 ± 0.1
66/34
7.9 ± 0.2
63/37
*p = 0.898
**p = 0.617
†
Values expressed as Mean ± SE.
PPD, CAL and serum levels of
CRP, fibrinogen and WBCs for the
317 subjects. BOP was 42.1 ± 1.0%
at baseline, 27.5 ± 0.9% at second
examination and 23.6 ± 0.9% at
third examination in intervention
group; respective values for control
group
were
39.1 ± 1.5%,
36.1 ± 1.8% and 35.6 ± 1.6%. Intragroup analysis showed that BOP
changes from baseline were significant (p = 0.001) only for intervention
Bokhari et al.
Intervention group
p > 0.05
**
PPD (mm)
3.5
CAL (mm)
n = 105
*
4.5
**
4
a
3.5
b
c
2.5
E2
E3
Control group
n = 212
E1
(e)
n = 105
p > 0.05
p > 0.05
a
b
p > 0.05
p > 0.05
3.3
a
3.1
a
3
n = 105
P > 0.05
b
b
E2
E3
Control group
n = 212
n = 105
p > 0.05
8
7.5
*
a
Intervention group
8.5
Control group
p > 0.05
(f)
n = 105
E3
n = 212
E1
Control group
n = 212
E2
Intervention group
400
380
360
340
320
300
280
260
240
220
200
E3
3.4
3.2
Control group
n = 212
3
Intervention group
3.6
**
c
E1
(c)
Intervention group
5
p > 0.05
b
Intervention group
3.8
3.7
3.6
3.5
3.4
3.3
3.2
3.1
3
2.9
2.8
(d)
n = 105
a
E1
(b)
Control group
n = 212
CRP (mg/l)
50
45
40
35
30
25
20
15
10
5
0
FIB (mg/l)
BOP (percentage)
(a)
WBC (x109/l)
1070
*
**
a
7
b
6.5
c
6
5.5
2.9
5
E1
E3
E1
E2
E3
Fig. 2. Comparison of (a) bleeding on probing (BOP), (b) periodontal probing depth (PPD), (c) clinical attachment level (CAL), (d)
C-reactive protein (CRP), (e) fibrinogen (FIB), and (f) white blood cells (WBC) in intervention (▲; n = 212) and control
(■; n = 105) groups at three examinations: E1 (Baseline), E2 (1st month follow-up) and E3 (2nd month follow-up). Values are
presented as Mean ± SE. * denotes significant intergroup difference at the specific examination (*p 0.05, **p 0.01). Different
small letters (a,b,c) between examinations indicate significant intra-group differences (p 0.05) , observed in intervention group
for BOP, PPD, CRP, FIB and WBC. Intra-group differences were non-significant in control group.
group, at both follow-up examinations
(Fig. 2a).
Inter-group
analysis
showed that BOP differences were
significant at second and third examinations (p < 0.001).
In the intervention group, PPD
was 3.5 ± 0.1 mm and 3.1 ± 0.0 mm
at baseline and 2-month follow-up
respectively;
the
corresponding
values for the control group were
3.4 ± 0.1 mm and 3.3 ± 0.1 mm.
Intra-group comparisons showed
that PPD was significantly (p
= 0.001) reduced in intervention
group, without significant change in
control group (p > 0.05) (Fig. 2b).
Inter-group PPD differences were
not significant (p > 0.05), either at
baseline or at third examination.
Mean CAL of intervention group
was 3.4 ± 0.1 mm at baseline and
3.3 ± 0.1 mm at the 2-month followup; the respective values in control
group were 3.3 ± 0.1 mm and 3.3 ±
0.1 mm. Intra-group and inter-group
CAL comparisons revealed no significant differences, either between
examinations (p > 0.5) or between
groups (p > 0.7) (Fig. 2c).
Serum CRP levels in intervention
group changed from 4.4 ± 0.2 mg/L
at baseline to 3.4 ± 0.2 mg/L and
3.1 ± 0.2 mg/L at the 1- and 2-month
follow-up visits; both follow-up values were significantly different from
baseline (p < 0.001) (Fig. 2d). In
contrast, control group serum CRP
levels (baseline: 4.2 ± 0.3 mg/L; 1month: 4.1 ± 0.3 mg/L; and 2month: 4.1 ± 0.3 mg/L) remained
unchanged over time (p > 0.8)
(Fig. 2d). Inter-group differences
were significant at the 1-month
(p = 0.043) and 2-month follow-up
visit (p = 0.007).
Serum fibrinogen levels in intervention and control groups were
367.1 ± 10.4 mg/L and 339.6 ± 10.5
© 2012 John Wiley & Sons A/S
Periodontal therapy and CHD risk markers
mg/L, respectively, at baseline,
305.3 ± 8.7 mg/L and 325.5 ± 9.6
mg/L at the 1-month follow-up, and
299.3 ± 8.0 mg/L and 335.9 ± 11.8
mg/L at the 2-month follow-up.
Intra-group differences in fibrinogen
levels were significant between baseline and follow-up visits only for the
intervention group (Fig. 2e). Intergroup comparisons for serum fibrinogen revealed significant differences
between groups only at the 2-month
follow-up (p = 0.010).
White blood cell counts in intervention and control groups were
7.8 ± 0.1 9 109/L and 7.9 ± 0.2 9
109/L, respectively, at baseline, 7.1 ±
0.1 9 109/L and 7.6 ± 0.2 9 109/L at
the 1-month follow-up, and 6.7 ±
0.1 9 109/L and 7.6 ± 0.1 9 109/L at
the 2-month follow-up. Intra-group
changes from baseline were significant in intervention group only, for
both examinations (Fig. 2f). Intergroup differences for WBC were significant at 1-month (p = 0.024) and 2month follow-up (p < 0.001).
Changes between baseline and 2month follow-up in the prevalence of
subjects (%) within specified categories of periodontal and inflammatory
parameters are depicted in Fig. 3.
The distributions differed significantly
between groups (p 0.047) at the 2month follow-up for all periodontal
and inflammatory parameters, except
CAL (Fig. 3).
Periodontal treatment effects on CRP risk
category
A risk reduction analysis was performed based on the number of subjects with serum CRP levels ( 3
mg/L or > 3 mg/L) at third examination. ITT analysis gave an absolute risk reduction (ARR) of 12.5%
(48.5%-36%), which was significant
p = 0.036).
Number
(v2=4.381,
needed to treat analysis (1/ARR)
showed that one of eight cardiac
patients with moderate to severe
periodontitis may benefit from
mechanical, non-surgical periodontal
therapy to lower serum CRP levels
to 3 mg/L. The relative risk ratio
was 1.34 and relative risk reduction
(RRR) 26%.
Per-protocol analysis gave an
ARR of 20% (49%–29%), which
was significant (v2=9.850, p = 0.002).
RRR was 41% and relative risk
ratio was 1.68.
© 2012 John Wiley & Sons A/S
Discussion
This randomized controlled trial
showed that in CHD patients with
periodontitis, conventional, mechanical and non-surgical periodontal
therapy results in significant reduction of systemic levels of inflammatory markers (CRP, fibrinogen and
WBCs) within 2 months of such
intervention and in the absence of
any changes in systemic medication
regimen. The provided treatment significantly improved the periodontal
health status of the CHD patients.
The CHD patient population of
this study is comparable to patients
included in non-periodontal cardiology studies (Jousilahti et al. 1999,
Fang et al. 2004, Jafar et al. 2005).
Randomization of recruited patients
resulted in intervention and control
groups that, at baseline, did not differ with respect to demographic,
medical, periodontal and inflammatory parameters. However, intervention and control groups differed
significantly in periodontal and systemic parameters at the end of the
trial.
Periodontal improvement compared with baseline was noted at
8 weeks
following
non-surgical
mechanical periodontal therapy.
Mean BOP was reduced by 44%,
while 49% of subjects with
BOP > 20% sites at baseline fell to
the BOP < 20% category after treatment. There was a 38% reduction in
the prevalence of subjects with
PPD 4 mm >30% sites. These
outcomes are consistent with studies
on patients with comparable periodontal disease severity and similarly
treated, whether patients were systemically healthy (Lindhe et al. 1982,
Pihlstrom et al. 1984), pregnant
(Michalowicz et al. 2006), or had
systemic disease (Hussain Bokhari
et al. 2009, Vidal et al. 2009).
The systemic outcomes of the
present study are consistent with
previous intervention trials in periodontitis patients without CHD
(Vidal et al. 2009, Nakajima et al.
2010, El Fadl et al. 2011), as well as
with CHD (Hussain Bokhari et al.
2009, Offenbacher et al. 2009). A
randomized trial in patients with
refractory hypertension found that
periodontal therapy resulted in significant reduction of CRP (35%)
and fibrinogen (14.5%) in the test
1071
group (n = 11) compared with the
control group (n = 11) after 3
months (Vidal et al. 2009). Periodontitis
and
vascular
events
(PAVE) study (Offenbacher et al.
2009) reported that in 303 CHD
patients, any periodontal therapy
resulted in significant decrease of the
odds of being in the high-risk
(>3 mg/L) CRP group at 6 months,
with obesity nullifying such effect.
The lack of lipid fractions analysis is
a limitation of this study and precludes calculation of Framingham
risk scores (Wilson et al. 1998); nevertheless, reduction of CRP levels by
pharmacological intervention has
been shown to significantly reduce
CHD risk, in the absence of hyperlipidaemia and regardless of Framingham risk (Ridker et al. 2008).
The greater extent and severity of
periodontitis and the higher mean
CRP levels at baseline in the present
trial, compared with the PAVE
study, might explain the more pronounced CRP reduction effect in a
CHD patient population that was
comparable in terms of obesity. In
the present trial, 58.5% of intervention group participants were in the
high-risk CRP group at baseline and
only 36% remained in the high-risk
category after periodontal therapy.
Although CRP risk categories refer
to populations without CHD, evidence suggests that higher CRP levels are associated with a significantly
increased risk for further cardiovascular events in CHD patients
(Momiyama et al. 2009).
The CRP response to mechanical
periodontal therapy in the present
trial (30% decrease in mean CRP
levels) compares favourably with
reported CRP changes in response
to pharmacological intervention for
non-periodontal reasons. Results
from 153 stable CHD patients treated with high-dose statin (80 mg)
showed that baseline CRP decreased
by 36.4% at 5 weeks and continued
to decrease over time (57.1%
decrease at 26 weeks) (Bonnet et al.
2008). Gensini et al. (Gensini et al.
2010) reported that 80 mg of statin
(highest dose) resulted in 33.6%
reduction of mean CRP in 1345
statin-free patients, whereas in 772
statin-treated patients, the decrease
was 24.5%. In subgroups of 162 statin-free and 45 statin-treated patients
with baseline CRP levels 3 mg/L,
1072
Bokhari et al.
Subject distribution
100
100
100
IG: Baseline examination
IG: 3rd examination
CG: Baseline examination
CG: 3rd examination
92
89.5
85.7
88
90
81
80
71
Subjects (percent)
70
65
67
65
63
63
58.5
60
49
46.7
44
40
60
58
51
50
66
46
37
36
30
20
10
0
BOP>20%
PPD
CAL
CRP
FIB
WBC
Fig. 3. Intervention group (IG) (n = 212) and control group (CG) (n = 105) subject distribution at 1st (baseline) and 3rd (2-month
follow-up) examination. Periodontal parameters: Bleeding on probing (BOP) > 20% sites; periodontal probing depth
(PPD) 4 mm >30% sites; Clinical attachment level (CAL) 3 mm >30% sites. Systemic parameters: C-reactive protein
(CRP) > 3 mg/L; Fibrinogen (FIB) > 300 mg/L; White blood cells (WBC) > 7 9 109/L. Inter-group differences at baseline were
non-significant for all parameters. Inter-group differences at 3rd examination were significant for BOP, PPD, CRP, FIB and WBC
(p 0.040) and non-significant for CAL.
the 80 mg statin regimen resulted in
48% and 46% reduction respectively; the CRP lowering effects of
high-dose statin treatment were evident at 6 weeks (Gensini et al.
2010). Yu et al. (2007) reported that
in 112 angiographically documented
CHD patients, with mean CRP of
3.9 mg/L, high-dose statin resulted
in 65% reduction of mean CRP levels 26 weeks after onset of therapy;
most of the patients (97 of 112) were
on statin therapy prior to the trial,
which included a 1-week wash-out
period (Yu et al. 2007). In the present trial, the significant CRP lowering effects of periodontal therapy
were obtained in CHD patients who
were on anti-inflammatory, anticoagulant and lipid lowering drugs.
The present trial also resulted in statistically significant reduction of
median
CRP
levels
following
periodontal therapy (data not
shown), with the intervention group
experiencing a change of 1 mg/L in
median CRP levels (compared with a
change of -0.0 mg/L in the control
group). This non-pharmacological
reduction in median CRP levels is
less than the JUPITER study results,
where the statin group experienced a
2 mg/L reduction in median CRP
levels (Ridker et al. 2008).
The findings of the present study,
where
periodontal
therapy
significantly reduced serum levels of
inflammatory (CRP and WBCs) and
haemostatic (fibrinogen) risk markers of CHD, lend further support to
the association between PD and
CHD. Untreated or inadequately
controlled moderate to severe periodontitis increases the systemic
inflammatory burden, and periodontitis may independently increase the
risk for cardiovascular disease
(Friedewald et al. 2009). The longevity of the systemic outcomes in
response to mechanical periodontal
therapy cannot be ascertained from
the present trial. However, the
periodontal outcomes of such therapy are sustainable long-term when
appropriate home care is performed
by the patients and professional oral
health maintenance care is provided
(Westfelt et al. 1983).
Acknowledgements
The authors acknowledge the assistance and expertise offered by the
following individuals affiliated with
the Punjab Institute of Cardiology:
M. Abubakar and I. Waheed (cardiologists); M. Aamir Chaudhary,
A. Shoab and A. Waqar (dentists);
M. Niazi and N. Jehan (staff
nurses); M. Tahir (medical technologist); M. Hamza (research assistant); and R. Alam (statistician)
affiliated with the University of
Lahore. Woodwards (Pvt) Ltd.,
Karachi and Roomi Enterprises
(Pvt) Ltd., Karachi, kindly provided free toothpaste and toothbrush samples respectively.
© 2012 John Wiley & Sons A/S
Periodontal therapy and CHD risk markers
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Clinical Relevance
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tis. Treatment studies have reported
conflicting results regarding the systemic effects of mechanical periodontal therapy.
Principal findings: In the absence of
any changes in systemic medication
regimen, mechanical periodontal
therapy significantly reduced the systemic levels of C-reactive protein,
fibrinogen and white blood cells in
coronary heart disease patients.
Practical implications: Treatment of
coronary heart disease patients
with periodontitis using non-surgical mechanical periodontal therapy
can result in significant reduction
of coronary heart disease risk
markers.
Address:
Syed Akhtar Hussain Bokhari
22- Rewaz Garden
Lahore 54000
Pakistan
E-mail: [email protected]
© 2012 John Wiley & Sons A/S