Article

The Periodontitis and Vascular Events (PAVE) Pilot Study: Recruitment, Retention, and Community Care Controls

Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27514, USA.
Journal of Periodontology (Impact Factor: 2.71). 02/2008; 79(1):80-9. DOI: 10.1902/jop.2008.070216
Source: PubMed
ABSTRACT
Population-based clinical and laboratory studies have reported findings providing support for a possible relationship between periodontal disease and cardiovascular disease. The Periodontitis and Vascular Events (PAVE) pilot study was conducted to investigate the feasibility of a randomized secondary prevention trial to test whether treatment of periodontal disease reduces the risk for cardiovascular disease.
Five clinical centers recruited participants who had documented coronary heart disease and met study criteria for periodontal disease. Eligible participants were randomized to receive periodontal therapy provided by the study or community dental care. Follow-up telephone calls and clinic visits were planned to alternate at 3-month intervals after randomization, with all participants followed until at least the 6-month clinic visit. Participants were followed for adverse events and periodontal and cardiovascular outcomes.
A total of 303 participants were randomized. Recruitment that involved active participation of a cardiologist with responsibility for the patients worked best among the strategies used. Of those who had not withdrawn, 93% completed the 6-month contact. During follow-up, 11% of the 152 subjects in the community dental care group reported receiving periodontal therapy outside of the study.
If appropriate recruitment strategies are used, this pilot study demonstrated that it is feasible to conduct a secondary prevention trial of periodontal therapy in patients who have had coronary heart disease. If a community dental care group is used, sample size estimation needs to take into account that a non-trivial proportion of participants in this group may receive periodontal therapy outside of the study.

Full-text

Available from: Gerardo Maupomé, Aug 31, 2015
The Periodontitis and Vascular Events
(PAVE) Pilot Study: Recruitment,
Retention, and Community Care Controls
David J. Couper,* James D. Beck,
Karen L. Falkner,
Susan P. Graham,
§
Sara G. Grossi,
i
John C. Gunsolley,
Theresa Madden,
#
** Gerardo Maupome,
††
Steven Offenbacher,
‡‡
Dawn D. Stewart,* Maurizio Trevisan,
§§
Thomas E. Van Dyke,
ii
and Robert J. Genco
Background: Population-based clinical and laboratory studies have
reported findings providing support for a possible relationship between
periodontal disease and cardiovascular disease. The Periodontitis and
Vascular Events (PAVE) pilot study was conducted to investigate the fea-
sibility of a randomized secondary prevention trial to test whether treat-
ment of periodontal disease reduces the risk for cardiovascular disease.
Methods: Five clinical centers recruited participants who had documented
coronary heart disease and met study criteria for periodontal disease. Eligible
participants were randomized to receive periodontal therapy provided by the
study or community dental care. Follow-up telephone calls and clinic visits
were planned to alternate at 3-month intervals after randomization, with all
participants followed until at least the 6-month clinic visit. Participants
were followed for adverse events and periodontal and cardiovascular out-
comes.
Results: A total of 303 participants were randomized. Recruitment that in-
volved active participation of a cardiologist with responsibility for the patients
worked best among the strategies used. Of those who had not withdrawn,
93% completed the 6-month contact. During follow-up, 11% of the 152 sub-
jects in the community dental care group reported receiving periodontal ther-
apy outside of the study.
Conclusions: If appropriate recruitment strategies are used, this pilot study
demonstrated that it is feasible to conduct a secondary prevention trial of peri-
odontal therapy in patients who have had coronary heart disease. If a com-
munity dental care group is used, sample size estimation needs to take
into account that a non-trivial proportion of participants in this group may re-
ceive periodontal therapy outside of the study. J Periodontol 2008;79:80-89.
KEY WORDS
Cardiovascular disease; controlled clinical trial; periodontal disease;
pilot study; subgingival scaling.
T
here is growing evidence
of a strong relationship
between chronic infec-
tion and atherosclerosis as
well as a specific link be-
tween periodontal infection
and heart disease. Over the
past 15 years, a substantial
number of population-based
clinical and laboratory studies
reported findings providing
support for a possible rela-
tionship between periodontal
disease and cardiovascular
disease (CVD).
A series of case-control
and cross-sectional studies
6-22
showed a significant associa-
tion between various indices
of poor dental health and cor-
onary heart disease (CHD),
stroke, subclinical athero-
sclerosis, endothelial func-
tion, and C-reactive protein
(CRP). A number of longitudi-
nal studies found positive ad-
justed associations between
oral status and some type of
cardiovascular outcome or
CRP.
23-31
A few longitudinal
studies
32-37
reported no asso-
ciation or non-significant as-
sociation after adjustment.
Herzberg et al.
38
and Herzberg
and Meyer
39
proposed a direct
* Department of Biostatistics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Department of Dental Ecology, University of North Carolina at Chapel Hill.
Departments of Oral Biology and Microbiology, University at Buffalo, Buffalo, NY.
§ Department of Clinical Medicine, University at Buffalo.
i Brody School of Medicine, East Carolina University, Greenville, NC.
Department of Periodontics, Virginia Commonwealth University, Richmond, VA.
# Department of Periodontology, Oregon Health and Science University, Portland, OR.
** Department of Public Health and Psychosocial Studies, Auckland University of Technology, Auckland,
New Zealand.
†† Department of Preventive and Community Dentistry, Indiana University, Indianapolis, IN.
‡‡ Department of Periodontology, University of North Carolina at Chapel Hill.
§§ Department of Social and Preventive Medicine, University at Buffalo.
ii Department of Periodontology and Oral Biology, Boston University, Boston, MA.
doi: 10.1902/jop.2008.070216
Volume 79 Number 1
80
Page 1
effect of some of the bacteria found in dental plaque
that enter the bloodstream during bacteremic epi-
sodes. The oral Gram-positive bacteria Streptococcus
sanguis and the Gram-negative periodontal pathogen
Porphyromonas gingivalis induce platelet activation
and aggregation through the expression of collagen-
like platelet aggregation–associated proteins. The ag-
gregated platelets then may play a role in atheroma
formation and thrombosis. Haraszthy et al.
40
identi-
fied periodontal pathogens in human carotid ath-
eromas. These studies suggested that periodontal
pathogens may be present in arteriosclerotic plaques
where, like other infectious organisms, such as Chla-
mydia pneumoniae, they may play a role in the devel-
opment and progressionofatherosclerosis. In addition,
P. gingivalis is capable of invading the coronary and
carotid endothelium in cell culture
41,42
and promotes
foam cell formation.
43
Monocyte-derived cytokines,
such as tumor necrosis factor-alpha and interleukins
(IL-1, -6, and -8), may be released in response to a se-
ries of stimuli secondary to periodontal infection.
44,45
Studies by Wu et al.
46
and Slade et al.
11,47
provided
evidence that periodontal disease is associated with
cardiovascular risk factors, including acute-phase
proteins, CRP, and plasma fibrinogen. There is an ex-
tensive literature associating CRP and fibrinogen,
among other inflammatory factors, with CHD. Meta-
analyses of these studies
48
are consistent with highly
statistically significant associations of the acute-phase
proteins, CRP and fibrinogen, as well as elevated white
blood counts, with a subsequent risk for CVD
49-52
and
that CRP is an independent risk factor for CVD. A de-
tailed mechanism by which CRP participates in the
pathogenesis of atheromas is lacking. Periodontal in-
fections may be associated with an increased risk for
atherosclerotic processes, such as coronary artery
disease and strokes, in part, by the association of peri-
odontal infections with elevated levels of CRP. In a re-
cent randomized clinic trial,
53
intensive periodontal
treatment reduced systemic inflammatory markers
and systolic blood pressure and improved lipid pro-
files. Participants in the intensive periodontal treat-
ment group, which included adjunctive use of a
locally delivered antimicrobial, experienced signifi-
cant reductions in white blood count, CRP, IL-6, total
cholesterol, and low-density lipoprotein cholesterol at
1, 2, and/or 6 months compared to participants in the
standard periodontal therapy group. Changes in high-
density lipoprotein cholesterol and triglycerides did
not differ significantly between the groups.
The accumulation of epidemiologic and in vitro
evidence suggests a potential role for periodontal infec-
tion as a risk factor for CVD. The findings from cross-
sectional and longitudinal epidemiologic studies are
supported by in vitro studies describing plausible
mechanisms linking periodontal infection to athero-
sclerotic mechanisms and the triggering of clinical
coronary events.
The evidence of an association between periodon-
tal disease and CVD was sufficiently important for the
National Institute of Dental and Craniofacial Research
(NIDCR), National Institutes of Health, Bethesda,
Maryland, to fund the Periodontitis and Vascular
Events (PAVE) pilot study to investigate the feasibility
of conducting a randomized trial to test whether treat-
ment of periodontal disease reduces the risk for CVD.
The proposed model was a secondary prevention
trial, i.e., treating persons with documented CVD.
The specific aims of the PAVE pilot study were: 1)
to organize field centers and the administrative infra-
structure necessary to perform a definitive clinical trial
of periodontal treatment in the secondary prevention
of CVD; 2) to use these field centers and the clinical
trial administrative infrastructure to design and imple-
ment a pilot randomized controlled trial with the pri-
mary goal of testing the efficacy of the infrastructure
in recruiting and enrolling patients, and in data man-
agement; and 3) to obtain information from the pilot
trial on feasibility, including data on compliance, peri-
odontal and cardiovascular outcomes, and adverse
events.
MATERIALS AND METHODS
The PAVE pilot study was a multicenter randomized
trial with two treatment groups: periodontal therapy
and community dental care. The study planned to
enroll 600 participants, 300 in each arm, over an
18-month period, with follow-up through the end of
the 18-month period. This corresponded to a target
enrollment rate of 33.3 participants per month. Follow-
up clinic visits were scheduled to occur every 6 months.
Telephone follow-up contacts were scheduled to oc-
cur 3 months after randomization and every 6 months
thereafter. These calls were to assess whether adverse
events or cardiovascular endpoints had occurred.
Baseline and follow-up clinic visits included a peri-
odontal examination; blood, subgingival plaque, and
crevicular fluid specimen collection; and medical
and dental histories.
The study was conducted at five field centers: the
University at Buffalo, the University of North Carolina
at Chapel Hill, Boston University, Kaiser Permanente
Center for Health Research (KPCHR)/Oregon Health
and Science University (OHSU), and the University
of Maryland, Baltimore, Maryland. It also had an oper-
ations office, central microbiology laboratory, and bi-
ologic specimen bank at the University at Buffalo and
a data and statistical coordinating center and central
cytokine laboratory at the University of North Carolina
at Chapel Hill.
To be eligible for the study, participants had to be
£75 years of age and satisfy cardiac and periodontal
J Periodontol January 2008 Couper, Beck, Falkner, et al.
81
Page 2
inclusion criteria. For the cardiovascular criteria, par-
ticipants had to have 50% blockage of one coronary
artery or have had a coronary event within 3 years but
3 months previously, including myocardial infarction,
coronary artery bypass graft surgery, or coronary
transluminal angioplasty with or without a stent. Rel-
evant information, such as coronary angiography
reports, was obtained from medical records. CHD,
rather than CVD more generally, was used for at least
three reasons: ease of defining the inclusion criteria un-
ambiguously; unpublished analyses of data from the
Atherosclerosis Risk in Communities (ARIC) Study;
and similar restrictions in other secondary prevention
trials of CVD, such as the Enhancing Recovery in Cor-
onary Heart Disease Patients Study.
54
The periodontal
inclusion criteria were: the presence of at least six nat-
ural teeth, including third molars, with at least three
teeth with probing depths 4 mm; at least two teeth
with interproximal clinical attachment loss 2mm;
and 10% of sites having bleeding on probing. The cri-
teria were applied after accounting for tooth extractions
that were deemed necessary. Potential participants
generally were screened first by telephone, with those
passing the telephone screen and consenting to fur-
ther screening being screened at a clinical center.
Randomization was stratified by clinical center and
smoking status (whether subjects were smokers in the
past 5 years). A permuted block randomization scheme
was used with a random mixture of block sizes within
each stratum. Clinical center staff obtained treatment
assignments through a Web-based system designed
and maintained by the coordinating center. When a
participant was deemed eligible, a staff member used
the Web interface to enter the eligibility information,
and the system returned the treatment assignment.
Participants in both treatment groups were given
personal oral hygiene instructions by trained and
standardized hygienists, instruction brochures of suc-
cessful techniques, plus toothbrushes, dental floss,
and other hygiene aids as necessary. Each clinical
center used its own brochures and supplied its own
hygiene aids. Participants randomized to the commu-
nity dental care group were given a copy of their oral
radiographs and a letter stating the tentative diagno-
sis. They were recommended to seek the opinion of a
dentist. Participants in the periodontal therapy group
received local periodontal treatment, including com-
plete subgingival debridement with scaling and root
planing under local anesthesia using hand and ultra-
sonic instruments with continuous irrigation with wa-
ter. Hopeless teeth, such as those with deep furcation
involvement, were extracted. At least three clinic
visits were required to provide the treatment: the first
visit consisted of standard dental prophylaxis and oral
hygiene instructions; the second visit involved com-
plete scaling and root planing on half (two quadrants
on one side) of the mouth under local anesthesia; and
the third visit was for similar treatment of the other half
of the mouth. An optional fourth visit was allowed for
suture removal and post-treatment evaluation. The
treatment was supposed to be completed within 2
months of randomization.
For the community care group, mean SD of mea-
sures of periodontal disease at baseline and of the
change in each measure from baseline to the 6-month
follow-up visit were calculated. Paired t tests were
used to test whether the changes were significantly
different from zero. The corresponding statistics for
the periodontal therapy group are the focus of a sep-
arate article.
55
The study was approved by the Institutional Review
Board (IRB) at each participating center. It also was
monitored by a Data and Safety Monitoring Board
(DSMB) appointed by the NIDCR. All participants pro-
vided informed consent.
RESULTS
Recruitment
Screening of potential participants began early in
2003, and the first randomization was on March 18,
2003. The final randomization occurred in December
2004, and the final follow-up visit took place in June
2005.
Throughout the enrollment phase, the number of
participants randomized lagged well behind the tar-
get rate. Despite regular discussions about recruiting
strategies, a change to the eligibility criteria, and ex-
tending screening for 3 months beyond the planned
18-month enrollment period, just 303 participants
were randomized: 151 to periodontal therapy and
152 to community dental care. The average enroll-
ment rate was 14.4 participants per month. Even
the number who attended clinic screening was less
than the original randomization goal.
A variety of recruitment methods were used by the
clinical centers. The study did not deliberately set out
to compare various recruitment methods, instead al-
lowing each clinical center to use whatever methods
were available to it. The yield of participants from
among those screened by telephone varied widely
(Table 1). Initial screening at KPCHR was done by
searching its database of health maintenance organi-
zation (HMO) members for potentially eligible people
among members with dental and medical benefits.
Many of those identified were unwilling to participate
in the study. The recruitment performance improved
markedly through adding manual review of the med-
ical records by the study cardiologist, beyond the
computer searches of cardiovascular conditions,
and by adding the HMO members without dental ben-
efits to the pool of potential participants. When the
Health Insurance Portability and Accountability Act
The Periodontitis and Vascular Events (PAVE) Pilot Study Volume 79 Number 1
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regulations came into force in April 2003, the Univer-
sity of Maryland’s IRB would not permit the PAVE
study to examine medical records to look for potential
participants. After that, the University of Maryland
field center had to use advertising as its primary re-
cruitment method. In this case, the first contact usually
was made by the potential participants; therefore, the
proportion that was unwilling to participate was much
lower than when clinical centers cold-called potential
participants identified by database/records search-
ing. The other centers recruited through cardiology
practices and cardiac catheterization laboratories.
Each clinical center started out with a periodontal
principal investigator and a cardiology principal inves-
tigator. The center with the most active participation
by a practicing cardiologist fared best at recruitment.
In an attempt to increase the yield of participants,
the periodontal eligibility criteria were changed ;6
months into the recruitment phase. Analysis of data
from the ARIC Study suggested that the modified cri-
teria presented above would increase the yield from
screened subjects without having a negative impact
on the risk for cardiovascular endpoints. The old cri-
teria were presence of 12 natural teeth and interprox-
imal clinical attachment loss 5 mm on two or more
teeth (excluding third molars) and one or more teeth
(excluding third molars) with probing depths 5 mm.
The change was approved by the DSMB and all rele-
vant IRBs. Because of the small number of potential
participants screened prior to the change, it is not clear
how large of an effect the change had on enrollment.
There was some evidence, both anecdotal and in
monthly data, of seasonal variation in recruitment.
January and June/July tended to be poorer than other
months. The January effect was attributed to winter
weather and the June/July effect to summer travel
and vacations of potential participants and of clinic
staff. There often was a substantial delay between ini-
tial screening and randomization (Table 2). Part of this
was because the study had separate clinic screening
and baseline visits that needed to be completed before
randomization. Both of these visits included a peri-
odontal examination. Any necessary urgent dental
care, such as endodontics, oral surgery, and restora-
tive dentistry, which was identified at the clinic screen-
ing visit had to be carried out before a participant
could be enrolled.
Demographics of the randomized participants are
presented in Table 3. The demographics varied across
Ta b l e 1 .
Number of People Telephone- and Clinic-Screened Per Participant Randomized
and Percentage of Subjects Ineligible for Various Reasons
Clinical Center
Telephone
Screened
Clinic
Screened
Unwilling to
Participate (%)
Insufficient
Teeth (%)
Medically Ineligible
at Phone Screen (%)
Did Not Meet
Periodontal Criteria (%)
Other
Reason (%)
Boston University 2.6 1.3 29.5 23.9 15.9 14.8 15.9
KPCHR/OHSU 19.5 2.9 63.3 15.8 7.0 4.1 9.8
University at Buffalo 6.8 1.2 51.5 13.2 27.1 1.8 6.5
University of Maryland 2.7 1.2 20.0 6.7 41.9 5.7 25.7
University of North Carolina 5.9 1.8 25.6 25.6 16.1 15.3 17.4
Overall 7.0 1.6 50.0 16.3 16.9 5.6 11.2
Only one reason for ineligibility was allowed, prioritized in the order in which screening occurred.
Table 2.
Number of Participants Randomized
and Statistics for the Interval Between
Telephone Screening and Randomization
Days From Telephone Screening
to Randomization
Clinical
Center* Randomized Median Mean SD
A 88 40.5 59.3 58.3
B 46 64.0 71.4 33.0
C 61 40.0 43.7 26.8
D 52 63.0 99.6 89.1
E 56 41.0 77.9 100.7
Overall 303 48.0 68.3 69.2
* In this and subsequent tables, clinical centers are identified by a letter
only, not by name, because the intention is to show the variation across
centers rather than to be critical of the performance of any centers. The
order of the centers is different from that in Table 1.
J Periodontol January 2008 Couper, Beck, Falkner, et al.
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Page 4
the centers. For instance, the percentage of men varied
from 60.7% to 80.4% and that of African Americans
from 1.1% to 28.8%. The high percentages of subjects
with CVD and on blood pressure and cholesterol med-
ication are to be expected because of the cardiovas-
cular eligibility criteria.
Follow-Up
Clinic follow-up visits originally were scheduled to oc-
cur every 6 months. To extend the recruitment period
without an increase in the budget, this was changed
later to requiring just the first 6-month follow-up visit.
Because of this, unless specified otherwise, results re-
ported are at or by the 6-month follow-up visit. By the
time of the 6-month visit, 14 participants had with-
drawn consent and seven had been lost to follow-up
(Table 4). If cardiovascular events had been a primary
endpoint of this pilot study, more resources would
have been expended on trying to obtain event infor-
mation on these participants. Among those who had
not withdrawn consent or been lost to follow-up by
the time of the 6-month contact, 93% of the contacts
were completed. For 13% of these, a telephone inter-
view was conducted instead of a clinic visit. The con-
tact was deemed late if it occurred >14 days beyond
the scheduled time. This occurred for 41% of the
6-month contacts. Neither completion of the 6-month
contact nor whether it was late differed significantly
by treatment group. For 20% of subjects who had the
6-month contact, the contact was >2 months later
than scheduled. Although the difference was not sta-
tistically significant, the community dental care group
had fewer visits that were 2 months late than the
periodontal therapy group (16% versus 24%, respec-
tively).
Details of study safety and cardiovascular out-
comes are addressed in a separate article.
55
Briefly,
the application of periodontal therapy in participants
with CVD did not raise any safety concerns.
Compliance
Table 5 provides information about compliance with
the study-provided periodontal therapy among those
participants randomized to the periodontal therapy
group. More than 90% of participants in this group re-
ceived at least some periodontal therapy, with >80%
having two or more clinic visits for the initial therapy.
At three of the clinical centers, more than half of the
participants had their treatment completed within
two treatment visits. Participants with evidence of
Table 3.
Demographics of Randomized Participants by Clinical Center
Clinical Center
A B C D E Overall
Age (mean SD) 62.5 8.0 60.9 8.1 58.5 8.8 58.1 9.6 56.8 8.9 59.6 8.8
Male (%) 72.7 69.6 60.7 73.1 80.4 71.3
Non-Hispanic (%) 98.9 100.0 100.0 100.0 91.1 98.0
White (%) 96.6 93.5 83.6 69.2 73.2 84.5
African-American (%) 1.1 4.3 11.5 28.8 19.6 11.2
Other (%) 2.3 2.2 4.9 1.9 7.1 4.3
Smoking
Current (%) 11.4 13.0 21.7 13.5 25.0 16.6
Former (%) 60.2 56.5 46.7 59.6 41.1 53.3
Never (%) 28.4 30.4 31.7 26.9 33.9 30.1
On medication for:
High blood pressure (%) 90.9 73.9 80.3 69.2 62.5 77.2
High cholesterol (%) 92.0 82.6 80.3 92.3 83.9 86.8
Blood thinning (%) 78.4 60.9 27.9 32.7 85.7 59.1
Prior CVD:
50% blockage of a coronary artery (%) 96.6 78.3 46.7 100.0 87.3 82.7
Angioplasty or stent (%) 70.5 73.9 51.7 66.7 67.9 66.1
Bypass surgery (%) 28.4 8.7 31.7 21.2 33.9 25.8
Myocardial infarction (%) 31.8 45.7 39.3 36.5 50.9 39.7
Regular dental visits (%) 67.0 67.4 54.1 46.2 46.4 57.1
Prior gum treatment (%) 27.3 37.0 41.0 50.0 28.6 35.6
The Periodontitis and Vascular Events (PAVE) Pilot Study Volume 79 Number 1
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progression of periodontal disease at follow-up visits
received further treatment, with 60.7% being retreated
at 6 months. The initial set of treatment was supposed
to be completed within 2 months of randomization.
Scheduling difficulties for the clinic or the participant
resulted in 30% of the treatments being completed
>2 months after randomization. The proportion with
treatment completed late varied substantially by clin-
ical center, from 10.3% to 65.0%.
At each follow-up visit, participants were asked
about dental care received elsewhere since the previ-
ous visit. No validation was undertaken of this self-
reported information. Substantially more participants
in the community dental care group than in the
Ta b l e 4 .
Status at the 6-Month Follow-Up Contact
6-Month Contact Late
Clinical
Center
Withdrew
Consent
Lost to
Follow-Up
6-Month Contact
Completed (%)*
6-Month Contact by
Telephone (%)
Periodontal Therapy
Group (%)
Community Dental Care
Group (%)
A 4 0 89 8 40 43
B 2 1 95 7 100 45
C83 92 11 46 40
D00 94 20 28 37
E 0 3 98 6 15 32
Overall 14 7 93 13 42 40
* Percentage of subjects who had not withdrawn consent or been lost to follow-up by the 6-month visit.
† Percentage of subjects who completed 6-month contact.
‡ Contact was late if >2 weeks beyond 6 months after randomization.
Ta b l e 5 .
Treatment Received (%) by the Periodontal Therapy Group
Clinical Center
A B C D E Overall
Dental treatment provided (%) 93.2 86.7 96.7 88.5 96.4 92.7
For those receiving treatment:
One treatment visit 4.9 10.0 17.2 26.1 0.0 10.7
Two treatment visits 17.1 75.0 79.3 65.2 25.9 47.9
Three treatment visits 56.1 10.0 3.4 8.7 55.6 30.7
More than three treatment visits 22.0 5.0 0.0 0.0 18.5 10.7
Treatment completed late 29.3 65.0 10.3 17.4 37.0 30.0
Treatment received:
Supragingival scaling 97.6 90.0 100.0 9.1 85.2 85.0
Tooth extractions 7.3 5.0 13.8 17.4 14.8 11.4
Ultrasonic bactericidal curettage 92.7 95.0 96.6 100.0 100.0 96.4
Subgingival scaling and planing 2.4 95.0 96.6 95.7 96.3 68.6
Prophylaxis, fluoride 24.4 55.0 3.4 4.3 81.5 32.1
Oral hygiene instructions* 87.8 50.0 69.0 43.5 96.3 72.9
Retreated at 6 months 63.4 90.0 51.7 65.2 40.7 60.7
Treatment was scheduled to be completed within 2 months of randomization.
* All participants received oral hygiene instructions at randomization. This refers to instructions given at treatment visits.
J Periodontol January 2008 Couper, Beck, Falkner, et al.
85
Page 6
periodontal therapy group received dental care out-
side of the study (Table 6). In particular, 9% of com-
munity care group participants had received scaling
and root planing outside of the study by the 6-month
follow-up and 11% received it during the entire follow-
up. This is substantially more than the 5% that had
been assumed when planning this study. Table 7 pro-
vides summary statistics on the periodontal examina-
tions at baseline and change from baseline for the
community dental care group. The change was not
statistically significant for any of the measures. All
estimates were in the direction of improvement, which
may reflect the care some participants received out-
side of the study.
DISCUSSION
Recruiting an adequate number of participants turned
out to be the biggest challenge facing the pilot study.
There was substantial variation in the recruitment rate
across centers. Even the center most successful at re-
cruiting did not succeed in achieving the goal that had
been set at the outset. All clinical centers initially had a
periodontal and a cardiology principal
investigator. The participation of the
cardiology principal investigator
varied substantially across the cen-
ters. The center with the most active
participation from a practicing cardi-
ologist was the clear leader in the
number of participants randomized.
Twenty-one participants (6.9%)
withdrew consent or were lost to fol-
low-up by the 6-month clinic visit. Six-
teen of them were in the community
dental care group. The overall rate
and the differential between the two
treatment groups are larger than
would be reasonable for a definitive
clinical trial. The primary endpoints
for the pilot study required partici-
pants to return for follow-up visits,
rather than obtaining information
Table 6.
Dental Care Received Outside of the Study (%)
By 6 Months* Ever During Follow-Up*
Periodontal
Therapy
Community
Dental Care
Periodontal
Therapy
Community
Dental Care
Examination/checkup 9 31 14 37
Dental prophylaxis 3 25 13 34
Restorative treatment 7 11 15 16
Root canal 4 3 6 3
Extraction 3 11 4 10
Crown prosthesis 4 9 7 9
Scaling and root planing 1 9 1 11
* The percentage is of those randomized.
Table 7.
Periodontal Disease at Baseline and Change From Baseline to 6 Months for the
Community Care Group (mean SD)
Baseline (n = 102)* Change From Baseline
P Value
Teeth (N) 22.83 6.06 0.04 0.34 0.25
Probing depth (mm) 2.68 0.66 0.10 0.30 0.0009
Attachment loss (mm) 2.78 1.02 0.06 0.40 0.13
Plaque score 1.31 0.48 0.08 0.42 0.05
Gingival index 1.23 0.42 0.05 0.33 0.11
Calculus index 1.42 0.67 0.14 0.48 0.005
Bleeding on probing 0.49 0.26 0.06 0.19 0.002
Sites with probing depth 4 mm (%) 19.1 15.6 2.3 8.5 0.008
Sites with attachment loss 2 mm (%) 78.1 21.8 2.6 12.1 0.03
P value is for a t test of whether the mean change from baseline is zero and is not adjusted for multiple comparisons. The statistics were calculated after
accounting for teeth marked for extraction.
* Baseline statistics are restricted to the participants who also had 6-month data.
† Change is calculated as the baseline measurement minus the 6-month measurement; a positive value is an improvement (except for number of teeth).
The Periodontitis and Vascular Events (PAVE) Pilot Study Volume 79 Number 1
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about hospitalizations or death. The pilot study did not
put significant resources into trying to track those lost
to follow-up. Further, if follow-up were to be done
through cardiology offices rather than periodontal
clinics, we expect that the withdrawal and the loss
rates would be substantially lower. Among subjects
who were not lost/withdrawn, the response rate was
good, with 93% completing the 6-month contact.
Among subjects randomized to receive periodontal
therapy, compliance with the therapy was good, with
92.7% returning for at least one treatment visit. A key
factor in designing a full-scale trial is the cross-over
rate between the treatment groups. The particular
concern is the proportion of participants in the com-
munity care group that is likely to receive periodontal
treatment outside of the study. The higher this pro-
portion, the smaller the difference in treatment effect
is likely to be between the two groups. In the pilot
study, participants randomized to the community
care group were given a copy of their oral radio-
graphs and a letter stating the tentative diagnosis
of their periodontal status. They were recommended
to seek the opinion of a dentist and to follow the ad-
vice of this dentist. By the 6-month follow-up visit, 9%
of those in the community care group had received
periodontal therapy outside of the study. This is
larger than the prestudy guesstimate of 5%. It sug-
gests that a substantial allowance for cross-over will
need to be built into the sample size calculations for a
full-scale trial.
The periodontal status of the community care
group did not change significantly from baseline to
the 6-month clinic visit. There was no indication of
an overall decline in periodontal health. If anything,
there may have been a slight improvement, possibly
because some participants received treatment out-
side of the study.
The PAVE pilot study demonstrated that the big-
gest challenge in conducting a full-scale randomized
trial of periodontal therapy among patients with CHD
is to recruit and randomize sufficient participants. Ac-
tive participation from the cardiology community is
essential. The most practical approach seems to be
to have cardiology clinics responsible for recruitment,
with subjects eligible on the basis of their cardiovascu-
lar features being referred to dental clinics for peri-
odontal screening, randomization, and treatment. It
also would be logical to have follow-up for cardiovas-
cular endpoints being undertaken by the cardiology
clinics.
ACKNOWLEDGMENTS
The PAVE Study was funded by an NIDCR grant (U01
DE13940 to Dr. Genco). The investigators thank the
subjects for participating in the study and the staff at
the clinical centers for conducting the research. The
study was monitored by a data and safety monitoring
board (DSMB) appointed by the NIDCR. The investi-
gators thank the members for their service on the
DSMB and the valuable advice they provided. None
of the authors report any conflicts of interest related
to this study.
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  • Source
    • "Study participants were randomized to either community care or SRP in University settings. Despite being only a feasibility trial, after 1 year of follow-up , no difference was observed in CVD events rate between the community control and the treatment groups (23 versus 24) (Beck et al. 2008). Recently reported in the AHA position paper, we confirm that there is limited evidence on the effects of periodontal therapy on CVD events including myocardial infarction or stroke (Lockhart et al. 2012). "
    [Show abstract] [Hide abstract] ABSTRACT: Aim: The aim of this review was to critically appraise the evidence on the impact of periodontal treatment of cardiovascular diseases (CVDs) biomarkers and outcomes. Methods: A systematic search was performed in Cinhal, Cochrane, Embase and Medline for relevant articles up to July 2012. Duplicate screening and reference hand searching were performed. Data were then summarized and evidence graded in tables. Results: The search resulted in: (a) no evidence on the effects of periodontal therapy on subclinical atherosclerosis, serum levels of CD40 ligand, serum amyloid A and monocyte chemoattractant protein-1, (b) limited evidence on the effects of periodontal therapy on arterial blood pressure, leucocyte counts, fibrinogen, tissue necrosis factor-a, sE-selectin, von Willebrand factors, d-dimers, matrix metalloproteinases, oxidative stress and CVD events, and (c) moderate evidence suggesting a negligible effect of periodontal therapy in reducing interleukin-6 and lipids levels, whilst a positive effect in reducing serum C-reactive protein levels and improving endothelial function. Conclusions: Periodontal therapy triggers a short-term inflammatory response followed by (a) a progressive and consistent reduction of systemic inflammation and (b) an improvement in endothelial function. There is however limited evidence that these acute and chronic changes will either increase or reduce CVD burden of individuals suffering from periodontitis in the long term.
    Preview · Article · Apr 2013 · Journal of Periodontology
  • Source
    • "In response, multi-center trials have begun. One multi-center trial is the Periodontitis and Vascular Events study, which randomly assigned patients to periodontal therapy or community dental care, but found no difference in outcomes in their pilot study (Couper et al., 2008; Beck et al., 2008). Although this pilot was not designed to be long enough nor large enough for an adequate estimate of treatment effects, another potential reason for this finding is that periodontal therapy was received by at least 11% of the control group. "
    [Show abstract] [Hide abstract] ABSTRACT: Studies show a relationship between oral inflammatory processes and cardiovascular risk factors, suggesting that dental care may reduce the risk of cardiovascular disease (CVD) events. However, due to the differences between men and women in the development and presentation of CVD, such effects may vary by sex. We use a valid set of instrumental variables to evaluate these issues and include a test of essential heterogeneity. CVD events include new occurrences of heart attack (including death from heart attack), stroke (including death from stroke), angina, and congestive heart failure. Controls include age, race, education, marital status, foreign birthplace, and cardiovascular risk factors (health status, body mass index, alcohol use, smoking status, diabetes status, high-blood-pressure status, physical activity, and depression). Our analysis finds no evidence of essential heterogeneity. We find the minimum average treatment effect for women to be -0.01, but find no treatment effect for men. This suggests that women who receive dental care may reduce their risk of future CVD events by at least one-third. The findings may only apply to married middle-aged and older individuals as the data set is only representative for this group.
    Full-text · Article · Oct 2011 · Health Economics
  • Source
    • "Randomized controlled trials, using populations at higher risk for future cardiovascular events, with more severe periodontal disease might enlighten us as regards several unresolved issues on the association between periodontitis and CAD. To implement such a project, close collaboration of cardiologists and periodontologists is imperative and the design of future studies should appropriately assess the extent of the exposure variable [16] [42]. "
    [Show abstract] [Hide abstract] ABSTRACT: Periodontitis is a bacterially-induced, localized chronic inflammatory disease destroying both the connective tissue and the supporting bone of the teeth. In the general population, severe forms of the disease demonstrate a prevalence of almost 5%, whereas initial epidemiological evidence suggests an association between periodontitis and coronary artery disease (CAD). Both the infectious nature of periodontitis and the yet etiologically unconfirmed infectious hypothesis of CAD, question their potential association. Ephemeral bacteremia, systemic inflammation and immune-pathological reactions constitute a triad of mechanisms supporting a cross-talk between periodontal and vascular damage. To which extent each of these periodontitis-mediated components contribute to vascular damage still remains uncertain. More than twenty years from the initial epidemiological association, the positive weight of evidence remains still alive but rather debated, because of both the presence of many uncontrolled confounding factors and the different assessment of periodontal disease. From the clinical point of view, advising periodontal prevention or treatment targeting on the prevention of CAD it is unjustified. By contrast, oral hygiene including periodontal health might contribute to the overall well-being and healthy lifestyle and hence as might at least partially contribute to cardiovascular prevention.
    Full-text · Article · Jan 2011 · American Journal of Cardiovascular Disease
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