Cardiovascular Correlations in Oral-Systemic Health: An Update. William J. Elliott, M.D., Ph.D. 27 JUL 18

Transcription

1 Cardiovascular Correlations in Oral-Systemic Health: An Update William J. Elliott, M.D., Ph.D. 27 JUL 18

2 Disclosure Statement This speaker s research and educational activities have been supported in the past (but NOT in the last 12 months) by essentially every pharmaceutical company that makes, markets or distributes antihypertensive drugs in the USA. The information presented is therefore likely to be biased. Healthcare providers are therefore strongly cautioned NOT to use the information presented in their daily practices (see, for example, The People of the United States of America v [the late] Peter Gleason) until and unless the specific agent or therapy receives formal approval from the US FDA for exactly the indication under consideration by the healthcare professional. Specifically, the FDA has NOT approved any drug or intervention for oral diseases to improve outcomes in cardiovascular disease.

3 Disclosure Statement In the last 12 months, the speaker has received: Grants/Research Support: None. Consultant Payments: None. Speakers Bureau Payments: None. Major Stock Shareholder: None. Royalties: Elsevier (editor, author); UpToDate (editor, author) for published work related to hypertension.

4 Disclaimers The speaker has participated (with known experts in the field) in writing a Scientific Statement from the American Heart Association on the topic of Treatment of Hypertension in Patients with Coronary Heart Disease. Some would argue that the speaker s ties to the American Heart Association have influenced the choice of information presented, much of which is summarized in two Scientific Statements from the American Heart Association (referenced below), but the audience is cautioned that this presentation does NOT reflect opinion, consensus, or recommendations from the American Heart Association.

5 Affidavit of Originality The following material is based exclusively on the speaker s own opinion, knowledge and expertise. There is no organization, company, or entity that has exercised any control or influence over the content of this presentation, nor has any other person or organization had any part in drafting, scripting or designing its content. The information presented is based on the principles of Evidence-Based Medicine, and is intended to avoid promotion of any specific commercial interest, product, or company.

6 Educational Objectives-1 At the end of this 50-minute presentation, the awake audience member should be able to: 1) Discuss the pathophysiology of, and current guidelines regarding, the most widely-recognized link between oral health and cardiovascular disease. 2) Name three (3) potential confounders for the proposed link between periodontal disease and atherosclerotic cardiovascular disease. 3) Using the criteria proposed by Sir Austin (Tony) Bradford Hill, evaluate the strength of the current evidence supporting a causal association between periodontal disease and atherosclerotic cardiovascular disease.

7 Educational Objectives-2 At the end of this 35-minute presentation, the awake audience member should be able to: 4) Summarize the results of three (3) recent, large, prospective cohort studies that examined the relationship of periodontitis (clinical, radiological, or self-reported) and coronary heart disease outcomes (especially fatal and non-fatal myocardial infarction). 5) Explain at least one possible confounder for the negative results of three (3) trials of chronic oral azithromycin therapy in patients with known coronary heart disease, and one (1) trial of periodontal therapy vs. non-surgical control in patients with periodontal disease and coronary heart disease.

8 Oral-Systemic Health Links Few reasonable people would deny that oral health is important to whole-body health, and especially cardiovascular disease. The clearest example is bacterial endocarditis, which can be caused by dental manipulations (including some intended to improve oral health), to see how oral and heart health can be related. Indeed, many guidelines cover the use of antibiotics to decrease the risk of dental procedures (including just brushing teeth) that allow the bloodstream to be invaded by normal oral flora, which can take up residence on diseased or deformed heart valves.

9 Dental Procedures & Endocarditis? A population-based case-control and casecrossover study of 16,315 Taiwanese people with infective endocarditis from The odds ratios (ORs) for having had an invasive dental procedure in the previous 16 weeks were non-significant: 1.07 ( ) and 1.12 ( ), respectively. The authors concluded that antibiotic prophylaxis before invasive dental treatments to prevent infective endocarditis is not required for Taiwanese people. irculation. 2018;epub 19 APR 18; doi: /CIRCULATIONAHA

10 Oral-CV Health Links This link may extend beyond bacteremia: A self-controlled, time-series, study of 1175 US Medicaid enrollees showed a transiently increased risk (1.50, 95% CI: ) of myocardial infarction (MI) or stroke within the first 4 weeks after invasive dental procedures (dental surgery or periodontal therapy), which returned to baseline over the next weeks. Ann Intern Med. 2010;153:

11 Routine Antibiotics before Any Dental Procedure? Before 2007, essentially anyone with a known or suspected cardiac valvular disorder was recommended to receive ampicillin or another antibiotic an hour before any dental manipulation. Since 2007, prophylaxis is indicated only for: Prosthetic cardiac valve History of infective endocarditis Certain forms of congenital heart disease Cardiac transplant recipients with valvular disease. Circulation. 2007;116:

12 Epidemiology Oral disorders (especially periodontitis, or periodontal disease, PD) and cardiovascular disorders (especially atherosclerotic cardiovascular disease, ASCVD) share many risk factors, including: Age, Smoking, Male gender, Socioeconomic status, and Many others.

13 Prevalence of Periodontal Disease (%) NHANES : PD Women Men J Clin Periodontol. 2013;40 (Suppl. 14):S20-3 Age Range (years)

14 Age-Related Prevalence of "Other Forms of PD" Similar, age-related increases in periodontal disease are: Seen for less severe forms of periodontitis (overall prevalence = 46%), Seen for gingitivitis (defined as the lack of substantial inflammatory destruction of supporting structures for teeth). Significantly different across races/ethnicities: Hispanics (63.5%), blacks (59.1%), Asian Amerians (50%), Non-Hispanic whites (40.8%). J Periodontol. 2015;86:

15 Prevalence of Cardiovascular Disease (%) NHANES : CVD Women Men Circulation. 2018;137:e Age Range (years)

16 Prevalence of Periodontal Disease (%) NHANES : PD Women Men J Clin Periodontol. 2013;40 (Suppl. 14):S20-3 Age Range (years)

17 Cardiovascular Disease-USA CHD Stroke 7.2 M, 2.7% 16.5 M, 6.3% HF 6.5 M, 2.5% million, 46% Updated from Circulation. 2018;137:e Hypertension

18 Causes of Death 2016, USA n=2,744,248 Other 26% 23% Heart Disease Suicide Nephritis 2% 2% 2% Diabetes Alzheimer's 3% 4% 5% Stroke COPD 5% CHS Data Brief. 2017;No. 293:4. 6% 22% Accidents Cancer

19 Prevalence of Coronary Heart Disease (%) NHANES : CHD Women Men Circulation. 2018;137:e Age Range (years)

20 Prevalence of Coronary Heart Disease (%) NHANES : CHD Women Men Circulation. 2018;137:e Age Range (years)

21 Risk Factors for PD & CVD Both diseases are found more often in people with: Tobacco exposure, Alcohol use disorder (formerly "alcoholism"), Minority status, Diabetes mellitus, Overweight or obesity, and Lower educational attainment (or socioeconomic status). The effects of these confounders are difficult to separate in nearly all epidemiological studies of the association of these two very common conditions.

22 Cost of PD & CVD PD: $14 Billion CVD: $329 Billion Other Procedures (31%) Hospitals Indirect Costs 28% 39% Periodontology :29: Circulation. 2018;137:e430. Meds 10% Home Health Outpatient visits 13% EDs

23 Peer-Reviewed Papers/ Year *Annualized PD & CVD: Publications

24 Links: PD & CVD? Over the last 50 or so years, there have been efforts to more strongly link oral health (and common oral pathogens) to heart disease, the predominant pathophysiology of which is the atherosclerotic process. Although many types of normal oral flora have been implicated, several lines of evidence have attempted to fulfill Koch s postulates regarding a common microorganism linking dental plaque and atherosclerotic plaques.

25 Koch's Original Postulates 1) The microorganism must be found in abundance in all patients suffering from the disease, but should not be found in healthy people (added later: "except for asymptomatic carriers"). 2) The microorganism isolated from a diseased patient must be able to be grown in pure culture. 3) The cultured microorganism should cause disease when introduced into healthy people. 4) The microorganism can be reisolated from the inoculated person who developed the disease, and must be identical to the original microorganism.

26 Microbiology of PD & CVD? The most compelling data are for Chlamydophilia pneumoniae, which is common in patients with both periodontal disease and cardiovascular disease, as shown by: Serological studies, Immunocytochemistry signatures in both oral and cardiac tissues, Electron microscopy in both oral and cardiac tissues, Microbial nucleic acid signatures in tissues (demonstrated by polymerase chain reaction amplification), In situ hybridization in dental tissue and atheromatous plaque, Experimental animal models of both periodontitis and atherosclerosis, Cell cultures that implicate bacteria in the pathogenesis of atherosclerosis, and Recovery of viable microorganisms in cultures of human atheromata.

27 Koch's Postulates: PD & CVD? Although most oral pathogens would NOT be susceptible to antibiotic therapy (because they exist within a biofilm that is relatively impervious to most drugs), several clinical trials have given either placebo or azithromycin (a drug with excellent activity against Chlamydophilia in other tissues) or other antibiotics to patients with various types of cardiovascular disease, for various periods of time (e.g., 6-24 months), without any significant decrease in cardiovascular events.

28 Meta-Analysis of 11 Trials Analyzing data from more than 19,000 patients showed no significant reductions in: 1) All-cause mortality, 2) MI (myocardial infarction), or 3) MI or unstable angina pectoris. These trials can be criticized for their enrollment of many subjects without a proper dental examination, their relatively short follow-up period, crossovers, and dropouts. JAMA. 2005;293:2641-7

29 Association vs. Causation In 1965, the famous British epidemiologist, Sir Austin (Tony) Bradford Hill ( ) proposed a set of criteria that helped solidify a link between an exposure and a clinical outcome, with a greater number of fulfilled criteria usually indicating a higher likelihood of causality. These are commonly used to evaluate such associations today in many areas of medicine. Proc Royal Soc Med. 1965;58:

30 Bradford Hill's Criteria Strength of association: the higher the relative risk, the greater the chance of causation. Consistency: Similar findings in different studies under different conditions. Specificity: One cause is associated with only one effect. Temporal sequence: Cause precedes effect in time. Biological gradient: The greater the exposure, the greater the risk. Biologic plausibility: Is consistent with current understanding of the mechanism of disease. Analogy: A similar process is known to occur in another disease. Coherence: Consistent with previously known information about the disease. Experiment: After reduction of exposure, does the disease occur less often?

31 Hierarchy of Medical Evidence Systematic Review or Meta-analysis uses quantitative methods to summarize previous studies. Clinical Trials controlled experiments, in which baseline differences across groups are equalized by randomization. Cohort Study controls known confounders by statistical adjustment; cannot adjust for unknown or unmeasured baseline differences across groups. Case-Control Study choice of controls is key: contemporaneous are better than historical controls. Case Series usually a larger number of patients studied than case reports. Expert Opinion useful when the research question is too new, too controversial, or too complex to have been addressed by clinical investigation. Personal Experience usually not published.

32 Prospective Observational Studies Many of these studies reported significant associations (with odds ratios or relative risks in the range), but few had sufficient statistical power to adjust for many demographic and other potentially important covariates. A 2017 systematic review of these types of observational studies found 22 such reports, involving 129,630 participants. Overall, subjects with PD had a 2.02-fold (95% CI: ) risk of MI, with substantial heterogeneity across studies. The OR in 4 cohort studies was 1.18 ( ). The OR in 6 cross-sectional studies was 1.71 ( ). The OR in 12 case-control studies was 2.93 ( ). BMC Cardiovasc Dis. 2017;17:50.

33 Tooth Loss & Types of CVD A 2018 meta-analysis of tooth loss (perhaps the most easily quantifiable outcome of periodontal disease), of 17 studies involving 879,084 subjects and 43,750 incident cases of cardiovascular disease, also showed a significant, graded, increased risk for cardiovascular events, with every 2 teeth lost increasing by 3% the risk of MI or stroke (separately). Most of these studies can be criticized because they usually involved a self-report of lost teeth, seldom included a dental examination, and did not include less severe forms of periodontal disease. PLOS One. 2018;13(3):e

34 PLOS One. 2018;13(3):e

35 PLOS One. 2018;13(3):e Tooth Loss & CVD Risk

36 Very Recent (Foreign) Studies A population-based report from Australia involving 172,630 allegedly healthy people aged 45 or older linked questionnaires about missing teeth and self-reported teeth and gum health to records of hospitalizations or deaths 3.9 years later. Significantly higher risk of hospitalization or death from ischemic heart disease, heart failure, peripheral vascular disease, and all-cause mortality were seen with increasing numbers of teeth lost. Self-rated teeth and gum health correlated with hospitalization for ischemic heart disease, peripheral vascular disease, and all-cause mortality. BMJ Open. 2016;6:e

37 A Danish Study A recent cohort of all 17,691 patients hospitalized in Denmark with a diagnosis of periodontitis during were matched with 83,003 controls from the general population, and followed administratively for cardiovascular events and all-cause mortality. Concerns about the study design were: they excluded obesity from the covariates (since it is not recorded in Danish registries), found only a 0.4% prevalence of periodontitis among the hospitalized cohort (compared to up to 50% in other nations!), and presumed that their controls did not have periodontitis.

38 Results of Danish Study Crude Relative Risk Adjusted* Relative Risk Myocardial infarction 1.44 ( ) 1.16 ( ) Ischemic stroke 1.89 ( ) 1.51 ( ) Cardiovascular death 2.54 ( ) 2.02 ( ) MACE 2.03 ( ) 1.55 ( ) Death 3.20 ( ) 2.70 ( ) *After adjustment for baseline age, gender, smoking, medical comorbidities, medications, and socioeconomic status (based on self-reported annual gross income for the 5 years prior to enrollment). Am J Cardiol. 2016;118:

39 Recent American Studies In the NIH-funded Atherosclerosis in Communities (ARIC) Study, 6736 dentate subjects underwent full-mouth examinations; 299 had ischemic strokes over 15 years of follow-up. The periodontal examinations (6 per tooth) were graded, and showed a significant increase in stroke risk from "healthy" (1.29) to "severe periodontitits" (5.03 per 1000 person-years). Regular dental care was associated with a significantly lower adjusted stroke risk (ARR = 0.77, 95% CI: ). Stroke. 2018;49:

40 ARIC: Periodontitis & Stroke

41 Women's Health Initiative Observational Study In this NIH-funded study, 57,001 postmenopausal women without cardiovascular disease aged were asked in about dentist-diagnosed periodontitis, regular dental visits, and edentulism; cardiovascular events were recorded over 6.7 years. Periodontitis Edentulism Unadjusted Adjusted Unadjusted Adjusted CVD 1.00 ( ) 1.06 ( ) 1.86 ( ) 1.07 ( ) CHD 1.01 ( ) 1.08 ( ) 2.02 ( ) 1.10 ( ) Stroke 1.02 ( ) 1.11 ( ) 1.29 ( ) 0.77 ( ) Death 1.11 ( ) 1.12 ( ) 2.11 ( ) 1.17 ( ) CV Death 0.97 ( ) 1.09 ( ) 2.36 ( ) 1.07 ( ) J Am Heart Assoc. 2017;6:e

42 Surrogate Measures Much stronger associations have been found for various pathophysiological markers (or subclinical surrogates) for cardiovascular disease. Probably the easiest of these to understand is systemic inflammation, typically measured by a serum high-sensitivity C-reactive protein level. Although hs-crp is not specific to either periodontal or cardiovascular disease (and can in fact be elevated because of the common cold), several large studies have shown a significant correlation between an elevated hs-crp and both periodontal and cardiovascular diseases.

43 Endothelial Dysfunction, Carotid IMT Several studies have also examined endothelial dysfunction, which is also more common in patients with periodontal or cardiovascular diseases. Ultrasound examination of the carotid arteries provides a reasonably well-validated assessment of the whole-body atherosclerotic burden, and correlates (albeit imperfectly) with the risk of heart attack and stroke; not surprisingly, it also correlates with the presence and extent of periodontal disease, as assessed by a professional clinical examination.

44 PAROKRANK (Case-Control) 805 Swedish subjects who survived a first MI and 805 age-, gender-, and geographical area-matched controls underwent a standardized dental examination, including a Panorex. Data on more than 100 covariates were also collected. PD was found in 43% of the MI survivors, and 33% of the controls (P < 0.001); unadjusted odds ratio: 1.49, 95% CI: ). After statistical adjustment for covariates (e.g., smoking, diabetes, years of education, marital status), PD had an odds ratio of 1.28 (95% CI: ) for MI. Circulation. 2016;133:

45 PAROKRANK Limitations It was only a case-control study, the lowest ranking type of controlled study in the entire literature. Only 25% of the controls recruited into the study agreed to participate, which may have biased the control group toward healthier people. After enrollment, 13% of the MI survivors withdrew consent, so their data were largely "imputed." Having fewer than 1000 subjects in each group is likely to have made statistical adjustment for more than 50 covariates unstable. The adjusted odds ratio had a 95% CI that was dangerously close to unity (and non-significance). Circulation. 2016;133:

46 Experiments? Some results of interventions to treat periodontal disease and markers of cardiovascular risk have shown significant results. Although somewhat inconsistent across studies, several reports of hs-crp, endothelial dysfunction, or carotid intimalmedial thickness showed some worsening of these parameters immediately after mechanical dental debridement, which moderates over time and actually improves (compared to baseline) after 4-6 weeks.

47 Periodontitis And Vascular Events In contrast, one (Periodontitis and Vascular Events, PAVE) trial randomized 303 patients with periodontitis (on dental examination) and a history of coronary heart disease (recent MI, coronary obstruction by angiogram, or recent coronary revascularization) to either community dental care or periodontal therapy (including, but not limited to, scaling and root planing). The primary outcome was hs-crp, which did not differ significantly between randomized groups at 6 months after enrollment. There were significant differences in hs-crp among nonobese subjects, even after adjustment for smoking, marital status, and gender; addition of obesity to the model nullified the treatment effect.

48 PAVE Results There was limited improvement in periodontal status in those who received the more intensive therapy at 6 months, but this was not sustained after either 12, or 24 months. Furthermore, 48% of the subjects randomized to community care received preventive or periodontal treatments (an example of the Hawthorne effect? ). Lastly, during 25 months of mean follow-up, there were 23 cardiovascular events in the community care group and 24 in the intensively-treated group (P = 0.85). Periodontol. 2008;80:

49 PAVE Shortcomings? Most critics would cite as issues: The confounding effect of obesity, Low incidence of the hard endpoint, Large proportion of crossovers, and The single intervention (vs. annual?). These might be parameters that could be improved if funding to perform a second study of this type can be acquired. Periodontol. 2008;80:

50 Periodontal Therapy & CV Events A 2017 systematic review of periodontal therapy to reduce cardiovascular disease events in patients with chronic periodontitis identified no clinical trials with hard endpoints. It concluded that only very low quality evidence exists, which was insufficient to address whether such therapy prevents CVD events in patients with chronic periodontitis. Cochrane Database Syst Rev. 2017;11:CD

51 What Do US Guidelines Say? A 2012 American Heart Association Scientific Statement, endorsed by the World Heart Foundation, and with concurrence from the American Dental Association Council on Scientific Affairs, concluded: "Observational studies to date support an association between PD and ASVD independent of known confounders. They do not, however, support a causative relationship. Although periodontal interventions result in a reduction in systemic inflammation and endothelial dysfunction in short-term studies, there is no evidence that they prevent ASVD or modify its outcomes." Circulation. 2012;125:

52 US Preventive Services Task Force US Preventive Services Task Force A July 17, 2018 report from the USPSTF that reviewed non-traditional risk factors in cardiovascular risk assessment, concluded, There are insufficient adequately powered clinical trials evaluating the incremental effect of the ankle:brachial index, high-sensitivity C-reactive protein level, or coronary artery calcium score in risk assessment and initiation of preventive therapy. Furthermore, the clinical meaning of improvements in measures of calibration, discrimination, and reclassification risk prediction studies is uncertain. It is likely they would say the same about measures of periodontitis. JAMA. 2018;320:

53 Conclusions My conservative interpretation of the reasonably large body of evidence attempting to link periodontal disease and cardiovascular disease would be: 1) Both diseases are important to the public health because of their high prevalence, especially in older individuals. 2) Both diseases share many risk factors, making statistical associations very likely, but causative relationships more difficult to prove.

54 Conclusions-2 3) Both diseases are correlated to systemic inflammation, endothelial dysfunction, and markers of subclinical cardiovascular disease. 4) Systematic reviews and meta-analyses of prospective observational studies are consistent with a link between the two diseases, but correlation and associations do not necessarily prove causation. 5) Clinical trials of antibiotic therapy (to reduce colonization with C. pneumoniae, among other microbes), or direct periodontal therapy for patients with clinically apparent periodontal disease and a recent cardiovascular event have failed to show a significant improvement in cardiovascular outcomes in those given active treatment.

55 The Scientific Process As with all things scientific, there are many lessons to be learned from these trials, and many gaps in our knowledge base regarding these two common problems. This is exactly why the process is called, RE-search! A Scottish civil court might consider the proposition that PD causes CVD, but would/should/could rule, Not Proven, based on multiple lines of circumstantial evidence, but no smoking gun.