associations between periodontitis and chd/stroke – how

Associations between periodontitis and CHD/Associations between periodontitis and CHD/stroke – how strong is the evidencestroke – how strong is the evidence

Thomas DietrichThomas Dietrich

Boston University School of Dental MedicineBoston University School of Dental Medicine

“old news” 1997

Associated Press, July 9, 1997

Meta-analysis of nine studies on CHD RR= 1.19 (95% CI: 1.08 - 1.32)

rr.5 1 1.5

Combined

DeStephano

Hujoel

Matilla1

Wu_cvd

Morrison

Howell

Joshipura

Beck

Genco

Janket et al., O.O.O. 2003;95:559

Meta-analysis (6 studies) for CHD risk in younger adults (RR = 1.4)

rr.5 1 1.5

Combined

Morrison2

Wu_2

Hujoel2

DeStephano2

Matilla1

Genco

Janket et al., O.O.O. 2003;95:559

Meta-analysis of 5 studies using fatal cardiac events as outcome (RR = 1.5)

rr.5 1 1.5

Combined

Howell_fatal

Hujoel_fatal

Morrison_fatal

Wu_fatal

Beck_fatal

Janket et al., O.O.O. 2003;95:559

Meta-analysis of studies using Stroke/TIA events as outcome

Summary RR = 2.85

95% CI: 1.78 – 4.56Wu et al., Arch Intern Med 2000;160:2749-2755

Beck et al., J Periodontol 1996;67:1123-1137

Janket et al., O.O.O. 2003;95:559

HyperinflammatoryPhenotype

Chronic Periodontitis

CHD

Indirect(e.g. CRP )

Established CVD risk factors

(e.g. smoking, diabetes)

Direct(bacteremia)

Beck et al. 1996, Danesh 1997

Conceptual model

Issues with observational studies

• Issues with epidemiologic studies of periodontitis-CHD association– Exposure measure

• misclassification/measurement error– Self-report vs. clinical measures– Baseline exposure status only

• Conceptualization– (e.g. clinical vs. serological measures)

– Confounding• Residual confounding (smoking)• Unmeasured confounders

– Interpretation• Causal vs. non-causal?

Confounding

Exposure Disease

b+ca+c

c+ddcE -

a+bbaE +

D -D +

?

Relative Risk = Risk exposed / Risk unexposed

RR crude = (a / a+b) / (c / c+d)

Example: Periodontitis and CHD

1000800200

900723177Perio -

1007723Perio +

CHD -CHD +

Relative Risk = Risk exposed / Risk unexposed

RR crude = (a / a+b) / (c / c+d)

10-year cohort study

Baseline: 1000 subjects (10% periodontitis) free of CHD


1000800200

900723177Perio -

1007723Perio +

CHD -CHD +

Relative Risk = (23/100) / (177/723)

RR crude = 1.17

Conclusion: Risk for CHD 17% increased if Perio+

10-year cohort study

Baseline: 1000 subjects (10% periodontitis) free of CHD


1005050

804040Perio -

201010Perio +

CHD -CHD +

Relative Risk = (10/20) / (40/80)

RR crude = 1.00

Conclusion: no association

What about diabetes?

-10% of cohort had diabetes mellitus at baseline

-For diabetics:


900750150

720600120Perio -

18015030Perio +

CHD -CHD +

Relative Risk = (30/180) / (120/720)

RR crude = 1.00

Conclusion: no association


-10% of cohort had diabetes mellitus at baseline

-For non-diabetics:


Conclusions?

1. 17% increase of risk for Perio+ in entire cohort

2. No increase of risk for Perio+ among diabetics

3. No increase of risk for Perio+ among non-diabetics

What?


Answer:

- Diabetes is a confounder (of the Perio/CHD association)

- The crude RR is biased

- There is no independent association between Perio and CHD (independent of diabetes mellitus)


1000900100

90082080Perio -

1008020Perio +

DM -DM +

Odds Ratio = (20/80) / (80/820)

OR = 2.56


-Association between Periodontitis and Diabetes


1000800200

900750150DM -

1005050DM +

CHD -CHD +

Relative Risk = (50/100) / (150/900)

RR = 3.0


-Association between Diabetes and CHD

Confounding

• Is a source of bias• Exists because confounder is related to

BOTH the exposure and outcome• can go in either direction

– Crude RR can overestimate true RR– Crude RR can underestimate true RR

Confounding

• What to do about confounding ?

– Randomization (Design)– Matching (Design & Analysis)– Restriction (Design & Analysis)– Adjustment, Stratification (Analysis)

Confounding

Periodontitis CHD

What are important confounders?

Confounder

Confounding

Periodontitis CHD

RR crude is confounded (biased)

Bias depends on:

3. strength of association with exposure

4. strength of association with outcome

5. prevalence of confounder

Smoking

+ +

Smoking !

Confounding

• Residual confounding ?

– Measurement error/misclassification of confounder• Spiekerman et al., J Dent Res 82(5): 345-349, 2003

– Imperfect modeling of confounder• Dietrich et al., J Dent Res 83(11):859-863, 2004

Confounding

Spiekerman et al., J Dent Res 82(5): 345-349, 2003

linear association remaining between mean AL and serum cotinine after adjustment for self-reported intensity (cig/d), age, race and gender (1507 current smokers, NHANES III) .

Confounding


• Measurement error/misclassification of confounder– Simulation experiments using joint distribution

of smoking and periodontal variables

– Time to fictional morbid event:t = X•exp(-ß•cotinine/287)

– Cox PH models to estimate association between AL and morbid event (true independent RR = 1)

– Adjustments for self-reported smoking vs. cotinine

Confounding

53.21.0419.81.02self-reported smoking (log cigs/day)

5.21.004.91.00cotininen = 10,000


5.11.005.21.00cotininen = 500025%


4.81.005.11.00cotininen = 10,000


5.01.004.71.00cotinine (perfecte)n = 50005%

RR=1.9 RR=3.8

CI n variable adjusted RR FP RR FP


Confounding• Imperfect modeling of confounder

– Simulation experiments using joint distribution of smoking and periodontal variables

– Time to fictional morbid event:t = X•exp(-ß•CSI)

– Cox PH models to estimate association between AL and morbid event (true independent RR = 1)

– Adjustments for self-reported smoking vs. cotinine

Confounding

1.40.961.50.961.60.96

1.60.961.80.962.20.97

1.60.961.50.962.80.98

7.11.095.21.053.91.01

111.148.21.115.71.06

551.41511.38421.34

FPHRFPHRFPHR

10 yrs

5 yrs1 yrτ

Crude model (no adjustment for smoking)

Confounding

1.40.961.50.961.60.96

1.60.961.80.962.20.97

1.60.961.50.962.80.98

7.11.095.21.053.91.01

111.148.21.115.71.06

551.41511.38421.34

FPHRFPHRFPHR

10 yrs

5 yrs1 yrτ

Never, former, current

Confounding

1.40.961.50.961.60.96

1.60.961.80.962.20.97

1.60.961.50.962.80.98

7.11.095.21.053.91.01

111.148.21.115.71.06

551.41511.38421.34

FPHRFPHRFPHR

10 yrs

5 yrs1 yrτ

Never, Former, Current 0 – 10 /d, 11 – 20 /d, > 20 /d

Confounding

1.40.961.50.961.60.96

1.60.961.80.962.20.97

1.60.961.50.962.80.98

7.11.095.21.053.91.01

111.148.21.115.71.06

551.41511.38421.34

FPHRFPHRFPHR

10 yrs

5 yrs1 yrτ

packyears / former, current, intensity, duration / CSI (perfect)

Bias due to misclassification of periodontitis

• AL and PD of mesiobuccal sites from 12,976 subjects in NHANES III• Bootstrap samples (n=5000)• time to fictional morbid events: t = X * exp (-ln(1.5) * AL)

– X : exponential random variable– AL: mean AL per subject– RR of morbid event for an increase in mean AL of 1 mm was 1.5

• fixed censoring time was chosen to yield a cumulative incidence of 5%

• Periodontal disease defined using three previously used criteria: – (1) at least 1 site with PD 4 mm– (2) at least 4 sites with PD 4 mm– (3) at least 1 site with PD 6 mm.

• randomly misclassified periodontal disease variables• Cox PH regression models, median HR of 1000 repetitions• relative bias: 1-(ln HRm /ln HRp)


1.61/55%1.28/59% 1.53/14%90%100%

2.90/0.0%1.80/1.8 % 1.63/1.2% 100%90%

1.55/59%1.26/61%1.49/19%90%90%

2.9/-1.82/-1.64/-100%100%

1+ PD6+

HR / Bias

4+ PD4+

HR / Bias

1+ PD4+

HR / Bias

SPECSENS


1.35/72%1.16/75%1.43/28%80%100%

2.87/1.0%1.80/1.8%1.58/7.5%100%80%

1.26/78%1.12/81%1.32/44%80%80%

2.9/-1.82/-1.64/-100%100%

1+ PD6+

HR / Bias

4+ PD4+

HR / Bias

1+ PD4+

HR / Bias

SPECSENS


1.16/86%1.07/89%1.17/68%90%30%

1.37/70%1.18/72%1.34/41%90%60%

1.09/92%1.04/94%1.12/77%80%40%

2.9/-1.82/-1.64/-100%100%

1+ PD6+

HR / Bias

4+ PD4+

HR / Bias

1+ PD4+

HR / Bias

SPECSENS

Meta-analysis of nine studies on CHD RR= 1.19 (95% CI: 1.08 - 1.32)

rr.5 1 1.5

Combined

DeStephano

Hujoel

Matilla1

Wu_cvd

Morrison

Howell

Joshipura

Beck

Genco

Janket et al., O.O.O. 2003;95:559

New Epidemiologic Studies

• Case control study• 303 incident cases of acute cerebral ischemia• 300 population controls• 168 hospital controls• Periodontal status assessed clinically and

radiographically• periodontal probing at 4 sites in all teeth• Subjects were categorized into 4 categories based on

means clinical attachment levels (CAL), which allowed evaluation of the dose-response pattern.

Grau et al., Stroke 2004

Grau et al., Stroke 2004

1 a SR with homogeneity of RCTs b Individual RCT with narrow Confidence Interval c All or none

2 a SR with homogeneity of cohort studies b Individual cohort study (including low quality RCT; e.g., <80% follow-up) c "Outcomes" Research; Ecological studies

3 a SR with homogeneity of case-control studies b Individual Case-Control Study

12 Case-series and poor quality cohort and case-control studies

13 Expert opinion without explicit critical appraisal, or based on physiology, bench research or "first principles"

Hierarchy (levels) of evidence

Efficacy of AB for secondary CVD prevention: major RCT

• antibiotic arm of the PROVE-IT trial• Inclusion: patients with an acute coronary syndrome• randomized to placebo (n=2,086) or monthly courses of

gatifloxacin (n=2,076) • 2 year follow-up• composite primary endpoint (death, MI, unstable AP,

revascularization, stroke) • cum. Incidence: placebo: 25.1%; treatment: 23.7%• Stratification by baseline CRP:

– CRP above median: placebo: 24.9%; treatment: 25.2%– CRP below median: placebo: 21.6%; treatment: 24.4%

• no other subgroup could be identified in which the treatment was effective

Cannon et al., New Engl J Med 2005

Efficacy of AB for secondary CVD prevention: major RCT

• Inclusion: patients with documented stable CHD• Randomiyed to placebo (n=2,008) or 600mg azithromycin once per

week for a year (n=2,004)• Patients followed for up to 4.5 years • composite primary endpoint (fatal MI, revascularization, unstable

AP)• Cumulative incidence identical: placebo: 22.4%; treatment: 22.3%• Conclusion: no clinically significant benefit in the secondary

prevention of CHD events from one year of weekly azithromycin treatment

• neither Chlamydia pneumoniae nor another organism susceptible to azithromycin plays an important role in the pathogenesis of CHD events in subjects with advanced CHD.

Grayston et al., New Engl J Med 2005

Hill’s Criteria for Causality

• Strength • Consistency• Specificity• Temporality• Biologic gradient• Biologic plausibility • Experimental evidence

A.B. Hill (1965) “The environment and disease: association or causation? Proc. Roy. Soc. Med. 58:295-300.

Hill’s Criteria for Causalityvs. EBM levels of evidence

• Can RCT prove causality?– Proof of what?– Theoretically? – Practically? (feasibility)

• Clinical study of PD patients (n=30) and healthy controls (n=31), matched for age, sex and cardiovascular risk factors

• Flow-mediated dilation (FMD) of brachial artery• Periodontal treatment: SC/RP, CHX (14 days), systemic antibiotics

(7 days: Augmentin, metronidazole)• Measures at baseline and at 3-month f/u• Perio tx improved FMD and lowered CRP

Periodontal treatment improves endothelial dysfunction in patients with

severe periodontitisG Seinost et al Am Heart J 2005; 149:1050-1054

Periodontal treatment improves endothelial dysfunction in patients with severe periodontitis

G Seinost et al Am Heart J 2005; 149:1050-1054

Tonetti et al., Treatment of Periodontitis and Endothelial Function

N Engl J Med 2007; 356:911-920.

Periodontitis and age-related risk of Periodontitis and age-related risk of coronary heart disease in mencoronary heart disease in men

T. DietrichT. Dietrich11, M. Jimenez*, M. Jimenez*1,2,31,2,3, E.A. Krall, E.A. Krall11, , P.S. VokonasP.S. Vokonas44, R.I. Garcia, R.I. Garcia1,41,4

1 1 Boston University School of Dental MedicineBoston University School of Dental Medicine

2 2 Harvard School of Dental Medicine Harvard School of Dental Medicine 3 3 Harvard School of Public HealthHarvard School of Public Health

4 4 VA Boston Healthcare SystemVA Boston Healthcare System

Objective

• Evaluate strength of periodontitis-CHD association in long-term cohort study– Clinical measures of periodontal disease over

time– Time-varying effects of exposure and

potential confounders

MethodsMethods

• PopulationPopulation

– 1,231 male participants of both the Veterans’ Affairs Normative Aging (NAS) and Dental Longitudinal Study (DLS)

– DLS began in 1968– men are not VA patients– medical/dental exams every 3 years

• Outcomes:Outcomes: – Physician diagnosed CHD (MI, angina pectoris)

• ECG, biomarkers, history– fatal CHD

• ICD-8 410-414, primary cause of death

MethodsMethods

• Exposure:Exposure: (dental exam every 3 yr)– Full mouth radiographs

• Bone loss (Schei score) assessed by single reader (0-5 in 20% increments)

• Mean per subject bone loss score

– Probing pocket depth (PD)• calibrated examiners• Maximum PD per tooth recorded as score

(0-3 mm, >3-5 mm, >5 mm)• Cumulative PD calculated as sum of max. PD of all present teeth

– Edentulism

MethodsMethods

Exclusions:• participant with prevalent CHD at DLS baseline

Potential confounders assessed: • Baseline: Age, education & occupation • Time-varying effects of:

– Smoking: using a comprehensive smoking index (Dietrich & Hoffmann 2004)

– Body mass index (BMI) – Cholesterol:

• Total cholesterol & High density lipoprotein cholesterol (HDL) – Triglycerides– Hypertension – Blood Pressure:

• mean systolic & mean diastolic separately – Diabetes: Diagnosis of diabetes, fasting glucose level, 2 hour glucose

level– Alcohol consumption

MethodsMethods

Statistical analysis:• Cox PH regression with time-varying covariates• Time from baseline until

– CHD event (total or fatal)– loss to follow-up– last NAS exam

• Age-adjusted and multivariate adjusted (“kitchen sink”) models• Models stratified by age (< 50, 50+ years)

Results

17%8%5% Edentulous

63%74%78% >20

Number of teeth

19%20%23%Alcohol Use

24%22%25%Smokers

10%7%6%Diabetes

77.6 ± 9.977.7 ± 9.176.1 ± 8.8Diastolic Blood Pressure

131.1 ± 19.1126.8 ± 16.0122.8 ± 14.8Systolic Blood Pressure

17%14%10%Hypertension

178.1 ± 129.9168.6 ± 114.3147.8 ± 66.1Triglycerides

42.1 ± 11.8945.7 ± 14.449.4 ± 13.7HDL

235.2 ± 48.9232.9 ± 51.8220.7 ± 44.38Total Cholesterol

26.4 ± 3.426.5 ± 3.226.0 ± 3.0BMI

55 ± 9.950 ± 8.948 ± 9.3Age

109364839 N

Fatal CHDCHDNon-CHD

Baseline characteristics by CHD

Fatal & non-fatal CHD – bone loss

p=0.91p=0.87 Trend

p=0.02p=0.001 Trend

1.0 (Reference)1.0 (Reference)37260.30- 0.5

1.0 (Reference)1.0 (Reference)52270.24- 0.5

0.9 (0.6, 1.4)1.0 (0.6, 1.5)47240.75>0.5 – 1

0.9 (0.6, 1.5)1.1 (0.7, 1.6)43211.21> 1 - 1.5

1.1 (0.7, 1.8)1.2 (0.7, 1.9)30151.90> 1.5

1.6 (0.9, 2.8)1.9 (1.1, 3.2)260-Edentulous

50+ years

1.3 (0.6, 2.8)1.5 (0.7, 3.1)80-Edentulous

1.7 (1.1, 2.8)2.0 (1.3, 3.3)26181.81> 1.5

1.6 (1.1, 2.5)1.8 (1.2, 2.8)35221.21> 1 - 1.5

1.5 (1.0, 2.2)1.6 (1.1, 2.3)60250.73>0.5 – 1

< 50 years

Multivariate

HR (95% CI)Age Adjusted HR (95% CI)# events# teethMedianBL Score

Fatal & non-fatal CHD – bone loss

0

0.5

1.0

1.5

2.0

2.5

3.0

0.3 0.7 1.3 1.9edentulous

< 50 years 50+ years

mean bone loss score [mm]

HR

(95

% C

I)

Fatal CHD – bone loss

0

1

2

3

4

5

0.3 0.8 1.2 1.9edentulous

mean bone loss score [mm]

HR

(95

% C

I)

50+ years

Fatal & non-fatal CHD – cumulative PD

p=0.54p=0.94 Trend

p=0.002p=0.001 Trend

1.0 (Reference)1.0 (Reference)442300

1.0 (Reference)1.0 (Reference)452400

1.1 (0.7, 1.7)1.2 (0.8, 1.9)4822124 – 20

1.4 (0.9, 2.1)1.6 (1.0, 2.4)44233020 – 40

0.8 (0.5, 1.4)1.0 (0.6, 1.7)20246040 - 164

1.7 (1.0, 2.9)2.1 (1.3, 3.5)260-Edentulous

50+ years

1.2 (0.6, 2.6)1.3 (0.6, 2.8)80-Edentulous

1.6 (1.0, 2.4)1.7(1.1, 2.6)43266040 - 164

1.2 (0.8, 2.0)1.2 (0.8, 1.9)32263020 – 40

1.3 (0.9, 2.0)1.3 (0.9, 2.0)5125124 – 20

< 50 years

Multivariate

HR (95% CI)Age Adjusted HR (95% CI)# events# teethMedianCum. PD

0

0.5

1.0

1.5

2.0

2.5

3.0

0 12 30 60edentulous

mean cumulative PD [mm]

Fatal & non-fatal CHD – cumulative PDH

R (

95%

CI)

< 50 years 50+ years

Discussion / Conclusions

• Moderate association between periodontitis and CHD among younger men only

• Consistent evidence for effect-modification by age• DeStefano, BMJ 1993• Geismar, J Periodontol 2006• Indirect evidence

• Feasibility of RCT?• Association between edentulism and CHD among older

men• Mean bone loss vs. cumulative PD: similar results• Common pro-inflammatory phenotype may be important

(dominant) component of observed association

HyperinflammatoryPhenotype

Chronic Periodontitis

CHD

Indirect(e.g. CRP )

Established CVD risk factors

(e.g. smoking, diabetes)

Direct(bacteremia)

Beck et al. 1996, Danesh 1997

Directed acyclic graph

Acknowledgements

NIDCR GrantsNIDCR Grants: R03 DE016357 K24 DE00419

T14 DE017284

US Dept. of Veterans' AffairsUS Dept. of Veterans' Affairs

associations between periodontitis and chd/stroke – how

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