In its “Centennial Series”, an article celebrating Periodontal Medicine appears in next month’s issue in the Journal of Dental Research. The authors James Beck, Panos Papapanou, K.H. Philips and late Steven Offenbacher scrutinize a number of so-called landmark, or “milestone”, studies regarding three pathologic conditions, cardiovascular disease, diabetes mellitus, and adverse pregnancy outcomes. As in every opinion piece, one needs careful reading in order to identify the authors’ bias .
The authors recapitulate the timeline beginning with W.D. Miller’s dental focal hypothesis of 1891. (When writing, I couldn’t get full access to the Lancet article of 1891 to which Beck et al. originally refer.)
They then turn to the stunning (then) observation by Finnish authors Mattila et al. (1989) who adopted a “dental index” of caries, marginal and apical periodontitis, and pericoronitis in a case-control study of hospital admitted patients with recent myocardial infarction and matched controls from official records inhabitants of Helsinki. These authors had set up a logistic regression model adjusted for traditional risks, in particular smoking (former and current smokers) and identified the “dental index” (as well as smoking and, negatively, HDL cholesterol) being statistically significantly associated with myocardial infarction (Odds ratio 1.2586, 95% confidence interval 1.1503; 1.3771, my calculation based on given coefficient and standard error estimates). In two subpopulations, medians of the dental index were 4 and 6. So, the observed odds ratio for increase of 1 score in the index (1.2586) must in fact be considered substantial. This was a single center, low quality (as of current standards) case-control study which had to be confirmed in larger observational and ultimately interventional studies.
The issue mentioned in the title was dealt with in a systematic review of the Cochrane Collaboration which was published 3 1/2 years ago. It confirmed that, since the publication of the PAVE pilot study in 2009, no further evidence had emerged. The authors of the Cochrane review concluded,
We found very low quality evidence that was insufficient to support or refute whether periodontal therapy can prevent the recurrence of CVD in the long term in patients with chronic periodontitis. No evidence on primary prevention was found.
Possible systemic effects of periodontal treatment had been claimed for a very long time, and lack of evidence, or evidence for their clinical irrelevance, had never been accepted by many colleagues, indeed.
The most recent attempt of reviving the largely lapsed interest by most of our medical colleagues in the Perio-Systemic link, in particular its cardiovascular branch, was launched earlier this week when a delegation of the European Federation of Periodontology (EFP) met colleagues of the World Heart Federation (WHF) in Madrid. The aim of the workshop was to “explore the links between periodontal disease and cardiovascular disease and draw up a series of recommendations.”
The November 2012 EFP and AAP workshop on systemic health and how it is affected by periodontal disease has resulted in the joint publication of a couple of valuable systematic reviews in both Journal of Clinical Periodontology and Journal of Periodontology. I have expressed my strong opinion here on this blog that, in essence, there was not so much new or surprising. That there is strong evidence for minor effects of periodontitis on, say, cardiovascular disease and that diabetes mellitus is affected by periodontal disease while it is a risk factor for gum disease itself has been known for decades. That, what organizers had claimed, there is now a need for intervention studies to show that the risk for cardiovascular events may be reduced, has been questioned on this blog and elsewhere.
I have criticized the workshop’s Manifesto, a press release which reduced the somewhat difficult to digest information to a message for the public (and I include here in particular most of the dental profession whose members may not be able or willing to read through the pages of documents, be it but systematic reviews let alone the original cohort studies). I have also suggested a brief example (based on a gut feeling of a possible risk ratio) in which the most relevant ethical problem of not treating huge cohorts for periodontal disease was mentioned while probably a great number of patients with periodontitis had to be treated successfully (number needed to treat) in order to prevent a single cardiovascular event (if the effect was causal) which renders the whole exercise probably irrelevant.
The recent joint enterprise by the American Academy of Periodontology and European Federation of Periodontology to address, once again, the meanwhile well-known connection between periodontal and systemic disease held at La Granja de San Ildefonso, Segovia in Spain in November last year has resulted in a number of review papers and consensus reports which have right now been published by the Journal of Clinical Periodontology and the Journal of Periodontology. Some are in fact informative and present lots of new information. In a press release (strangely called “manifesto”) on the occasion of the publication of supplements of the respective journals, and as regards epidemiological data on periodontitis and cardiovascular disease, it is stated that “[t]here is consistent epidemiological evidence that periodontitis imparts increased risk for future [sic!] cardiovascular disease, independently of other confounding factors.”
Well, while this statement seems to imply indeed a causal relationship (periodontitis increases the risk for future cardiovasuclar disease) the respective review article by Dietrich et al. (2013) explicitly studied (once again) the association between periodontitis and incident atherosclerotic cardiovascular disease (ACVD). However, association does not automatically mean causation, something which is nowadays fortunately known by most undergraduate medical and dental students.
In an attempt to focus on “the most robust studies” in terms of endpoint definition (incidence of ACVD) and exposure (clinically or radiographically assessed periodontal disease), the authors omitted, for example, the long considered large longitudinal studies based on early National Health and Nutrition Examination Surveys (NHANES) which had adopted now outdated measures of periodontal disease; but, apart from a number of well-conducted prospective studies which might be able to give a certain hint about possible causation, included several case-control studies. This is absolutely okay when assessing “association” and not addressing “causation” .
Unsurprisingly, Dietrich et al. (2013)  arrived at similar conclusions (when it comes to the desired “association”) as the recent extensive systematic review by Lockhart et al. (2012) , of which I have written before, see here. Lockhart et al. (2012) fortunately warn, in addition, that “statements that imply a causative association between PD and specific ASVD [atherosclerotic vascular diseases]events or claim that therapeutic interventions may be useful on the basis of that assumption are unwarranted.” Dietrich et al. (2013) claim that the findings suggest that intervention studies would not be suitable in older subjects, say 60+ years, due to general weaker associations, which “present yet another formidable challenge for the design and conduct of future clinical trials that aim to address the question of benefits of periodontal therapy on adverse cardiovascular events.”
So, what’s the meaning of this new effort. No new attempt to prove a causal relationship has been or can be made at the moment. After 25 years, intervention studies which might reveal the more interesting aspect (causality) are still by and large missing. At least for the time being, one may trumpet once more that “[a] large body of research has indicated a relationship between periodontal disease and other systemic diseases” as Nancy L. Newhouse (the AAP’s new president) informed me before yesterday in an email. Well, how long have we been told this news now?
One comment on the sloppy presentation of the findings in the review paper by Dietrich et al. (2013). While the absolutely necessary information about the 12 selected studies (to get information about the prospective or case-control design, the duration, the size of the study, its outcome) is buried in the supplementary material, the main tables in the review itself are completely messed up. Important measures of associations can hardly be found. Figures were even manipulated (rounded), which was revealed only after checking the referred original paper .
I am afraid that the common cursory reader of either JCP or JP can only miss these data, does not understand and is not informed that inconsistent results in several studies and multiple testing may only weaken any desired conclusion in favor of a substantial association. In the worst case, he or she has to rely on the, well misleading EFP “manifesto” which seems to suggests indeed causality .
 Dietrich T, Sharma P, Walter C, Weston P, Beck J. The epidemiological evidence behind the association between periodontitis and incident atherosclerotic cardiovascular disease. J Clin Periodontol 2013; 40(Suppl 14): S70-S84: “Observational studies to date support an association between PD and ASVD independent of known confounder.” While the authors mention that “meta-analyses were not attempted due to heterogeneity of studies in terms of virtually all study characteristics”, which had been done in the past when looking at these huge prospective, long-term studies, but with rather sobering, weak associations between periodontal and cardiovascular disease, it is amazing that risk ratios, relative risks, hazard ratios and odds ratios in the presently selected studies, where subgroup analyses were a common feature, were low or at most pretty moderate, inconclusive and frequently even insignificant. So, whether a decade old studies with crude methodologies had been omitted or not did not really matter for the current conclusions.
 Lockhart PB, Bolger AF, Papapanou PN Osinbowale O, Trevisan M, Levison ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, Wilson WR, Smith SC Jr, Baddour LM. Periodontal disease and atherosclerotic vascular disease: Does the evidence support an independent association?: a scientific statement from the American Heart Association. Circulation 2012;125:2520-2544, conclude [pdf] “[T]he current evidence supports the notion that the incidence of ACVD, as represented by incident CHD, cerebrovascular disease and periopheral arterial disease is higher in subjects with PD or with better periodontal status, independent of many established cardiovascular risk factors.”
 For instance, a not significant hazard ratio in younger than 60-yr old subjects in the original paper by Dietrich, Jimenez, Krall Kaye et al. (Circulation 2008; 117: 1668-1674) of 1.55 for a bone score of 1 to less than 1.5 had been rounded up to 1.6 in the systematic review by Dietrich et al. (2013).
 When scrolling down, the first recommendation for practitioners is in fact misleading. The U.S. Preventive Services Task Force had already in 2009 recommended not to screen asymptomatic subjects with no history of coronary heart disease for non-traditional risk factors such as periodontitis to prevent respective events. Remaining recommendations sound, on the other hand, rather moderate, just reflecting that there is nothing new in the Perio-Cardio relationship:
“Practitioners should be aware of the emerging and strengthening evidence that periodontitis is a risk factor for developing [sic!] atherosclerotic cardiovascular disease, advising patients of the risk of periodontal inflammation to general as well as oral health.
Based on the weight of evidence, periodontitis patients with other risk factors for atherosclerotic cardiovascular disease, such as hypertension, overweight/obesity, smoking, etc. who have not seen a physician within the last year, should be referred for medical examination.
Modifiable lifestyle associated risk factors for periodontitis (and atherosclerotic cardiovascular disease) should be addressed in the dental surgery/office and within the context of comprehensive periodontal therapy, i.e. smoking cessation programs and advice on lifestyle modifications (diet and exercise). This may be better achieved in collaboration with appropriate specialists and may bring health gains beyond the oral cavity.
Treatment of periodontitis in patients with a history of cardiovascular events needs to follow American Heart Association (AHA) guidelines for elective procedures.”
5 May 2013 @ 12:55 pm.
Last update May 5, 2013.