Medscape Medical News 2009. © 2009 Medscape

April 15, 2009 — Data from Chile show that there has been an increase in the rate of colorectal cancer since 2000, when the government introduced a mandatory program of fortification of wheat flour. A similar increase was reported in the United States and Canada in the late 1990s, after the introduction of folic-acid fortification there.

The aim of folic-acid fortification is to reduce neural tube defects, a result of folate deficiency during pregnancy and, in this, the programs have been successful. In Chile, these complications were reduced by 40% in 1 year.

But could the downside be an increase in the risk for colorectal cancer?

The latest data, published online February 2 in the European Journal of Gastroenterology & Hepatology, suggest that it might be. Sandra Hirsch, MD, MSc, and colleagues from the University of Chile, in Santiago, analyzed hospital-discharge data for two 4-year periods — before folic-acid fortification (1992–1996) and after (2001–2004) — and found a significant increase in reported cases of colon cancer. The increase was 162% in people 45 to 64 years and 190% in people 65 to 79 years.

Most other diseases showed no consistent patterns of change, they note. There was a small increase in breast cancer, smaller than that seen for colon cancer, but the authors note that this could probably be attributed to 2 programs for breast cancer introduced in 2000, one for early detection and the other guaranteeing universal access to treatment.

The researchers acknowledge that there could be other explanations for the finding, such as the rise in obesity (which increased from 19.7% in 1997 to 22% in 2003). However, Dr. Hirsch pointed out to Medscape Oncology that there were no changes in the hospital-discharge data for cardiovascular disease during that time.

"Our data provide new evidence that a folate-fortification program could be associated with an additional risk of colon cancer," Dr. Hirsch and colleagues conclude.

One problem with this study is that it uses indirect data for the incidence of colon cancer, say critics. There are no cancer registries in Chile, so the researchers used the diagnosis indicated on hospital-discharge forms as a proxy for disease incidence.

This is an important limitation of the study, said Reinhold Stockbrugger, MD, one of the editors of the European Journal of Gastroenterology & Hepatology. "Discharge rates are influenced by healthcare politics, increasing access to healthcare for new strata of the population with increased cancer risk, and so forth," he comments in a press release issued by the Journal.

"This study provides only a weak indirect indication of a causal relationship between folate enrichment and colorectal cancer," Dr. Reinhold said. However, he added that the finding is "similar to that reported in the United States and Canada."

Those data appeared nearly 2 years ago (Cancer Epidemiol Biomarkers Prev. 2007; 16:1325-1329), in a study by Joel Mason, MD, and colleagues from the Jean Mayor US Department of Agriculture Human Nutrition Research Center on Aging at Tufts University, in Boston, Massachusetts. That study used incidence data from nationwide cancer registries and showed significant increases in colorectal cancer rates in both the United States and Canada.

Folic-acid fortification began in the United States in 1996 and in Canada in 1997, and became mandatory in both countries in 1998, Dr. Mason and colleagues note. Concurrently, both countries experienced "abrupt reversals" of the downward trend in colorectal cancer incidence that they had enjoyed. In the United States, rates started to increase in 1996 and peaked in 1998; in Canada, rates began to rise in 1998 and peaked in 2000. Both rates have continued to exceed pre-1996/97 levels.

At the time, Dr. Mason and colleagues stressed that the observations did not prove a causal link, and they emphasized the "very compelling body of scientific evidence that has accrued over the past 15 years that indicates that supplemental folic acid protects against neural tube defects."

Total Amount of Folic Acid Important?

Dr. Mason and colleagues also note that there is evidence that "habitually high intakes of dietary folate are protective against colorectal cancer." They suggest, however, that the pharmaceutical form of folate (i.e., folic acid, which is used in fortification of foods and in vitamin tablets) might act differently than dietary folate, and they note that there is literature to suggest that a high intake of folic acid can accelerate the growth of established neoplasma. Adding substantial quantities of folic acid to the food supply in the mid-1990s might have facilitated the transformation of colorectal adenomas (which are found in 35% to 50% of Americans) into larger cancers, they suggest.

In the United States, folic acid was added to flour at a concentration of 140 μg/100 g (compared with 150 μg/100 g in Canada and 220 μg/100 g in Chile). But Dr. Mason and colleagues note that many breakfast cereals are fortified and that many Americans take vitamin supplements that include folic acid at a dose of 400 μg per pill.

In an interview with Medscape Oncology, Dr. Mason said that the new data from Chile "contribute to this concern that the total amount of folic acid present in the food stream can potentially contribute to an increase in certain types of cancer." However, he also said that the Chilean data are "weak in some regard," in that they rely on a surrogate end point of hospital-discharge data rather than cancer-incidence data.

Another recent publication has added to the concern about folic acid and cancer, he noted. New data from the Aspirin/Folate Polyp Prevention Study, published last month (J Natl Cancer Inst. 2009;101:432-435), show a 3-fold increase in prostate cancer among men who took the folate supplement, compared with men who took placebo.

This is cancer in a different organ, and the folic acid was in a supplement rather than in fortified foodstuff, but this observation "contributes to the concern," Dr. Mason commented. "There is a real concern that there are certain types of cancers common in the older population that are in an indolent phase of slow development, but their development may be accelerated by too much folic acid," Dr. Mason said. One example is the colorectal adenoma, "which sits in the colon for a decade before it evolves into a cancer, as far as anyone can tell." A second example is dysplastic prostatic nodules, which are seen in most men when they reach 70 to 90 years of age; the majority of these do not become clinically significant, and these men die of other causes, he added.

"In both situations, these are indolent precancerous lesions, which, with a bit of tweaking, might be pushed over the edge to evolve into clinically significant cancer," Dr. Mason said.

Is folic acid one of the factors that could push an indolent lesion into cancer?

"We cannot prove causality," Dr. Mason said, "but this is highly biologically plausible." This is a "smoldering concern," but at the moment there are not enough data to lead to any changes in the current policy of folic-acid fortification in those countries that have already implemented it, Dr. Mason said. But the matter is being debated, particularly by countries around the world (and the European Union) that are considering whether or not to implement such a policy. Dr. Mason recently took part in a meeting of experts in Sweden to discuss these matters, and has written a comprehensive review of the issue (Nutr Rev. 2009,67;206-212).

It is not just a question of folic-acid fortification of food, however; there is also the issue of folic-acid supplementation, such as in multivitamin pills. Dr. Mason noted that recent data from the US Centers for Disease Control suggest that 70% to 80% of the general adult population has detectable levels of folic acid in the blood, but "under more natural conditions, folic acid would not even be present in the blood."

Dr. Mason said he is attracted to the proposal that has been suggested in the United Kingdom, namely that, if folic-acid fortification goes ahead, there should be a reduction in the folic-acid component of vitamin and other supplement products. The dose of folic acid would need to be cut quite dramatically, he suggested, from the current 400 μg in a daily tablet to around 50 to 100 μg.

The researchers have disclosed no relevant financial relationships.

Eur J Gastroenterol Hepatol. Published online before print February 2, 2009. Abstract

Medscape Medical News 2009. © 2009 Medscape

April 14, 2009 (updated with commentary April 17, 2009) — The number of patients with mild cognitive impairment (MCI) who progress to dementia is at least half of what it was previously believed to be, new research suggests. A large meta-analysis showed that the cumulative risk over 10 years ranged between 30% and 50%, depending on whether the studies that were analyzed used a definition of MCI that included subjective memory complaints.

Until now, the prevailing opinion was that the progression rate from MCI to dementia was about 10% per year, or a 100% conversion to dementia over 10 years.

This research suggests that instead of always being an invariable transitional state between normal aging and dementia, MCI is a condition in which some patients stay static and some even improve, principal investigator Alex J. Mitchell, MD, from the University of Leicester, in the United Kingdom, told Medscape Psychiatry.

The review is published in April issue of Acta Psychiatrica Scandinavica.

Still Not Good News

But even with this study's more optimistic estimates of dementia risk, doctors should be careful when interpreting this information for patients, said Dr. Mitchell. "Let's say a patient is in a high-risk group, and the risk is 50% over 10 years, that's still not good news," he said. "Telling someone they have half the risk of developing a condition that is greatly feared is not generally good news, even if it was worse news before."

In a search of various databases, researchers found 41 studies that fit their criteria for inclusion in the analysis. Among other things, the studies had to last a minimum of 3 years and include at least 20 subjects.

Researchers excluded case-control studies with no longitudinal period of observation. They also excluded studies of Lewy-body dementia or frontotemporal dementia because of the lack of data. The 41 studies included 25 that were conducted using strict Mayo Clinic criteria for MCI and 16 with non-Mayo criteria. The researchers also categorized studies into those carried out in a specialist setting and population studies carried out in the community. Three of the studies that used the Mayo Clinic definition of MCI were randomized trials. Of the remaining 22 studies, 14 were clinical studies conducted in specialist centers and 8 were population-based studies. Of the 16 studies conducted using non-Mayo Clinic criteria, 4 took place in specialist centers and 12 were population studies.

The mean observation period was 4.57 years for studies using a Mayo Clinic MCI definition and 4.59 years for those with a non-Mayo definition.

Across all studies, researchers analyzed the rates of conversion from MCI to dementia. After adjustment for sample size, in the studies adhering to the Mayo Clinic MCI definition, the cumulative risks over approximately 5 years in specialist settings were: 39.2% for progression to dementia; 33.6% for progression to Alzheimer's disease (AD); and 6.2% for progression to vascular dementia (VaD). In population studies, the respective cumulative risks for dementia, AD, and VaD were: 21.9%, 28.9%, and 5.2%.

Higher Risk in Clinical Setting

The cumulative risks were higher in specialist settings because patients are typically referred to these clinics by primary-care physicians concerned about memory problems, whereas patients in the community setting are sought out by researchers conducting population-based cognition studies, said Dr. Mitchell.

"You would be at high risk by the very nature of that process of being seen in a clinical setting," he said.

The respective cumulative risks in studies using the non-Mayo Clinic definition of MCI were, as expected, generally lower than those using this definition. The cumulative rate averaged 32.3% for those with Mayo Clinic–defined MCI and 24.1% for those with non-Mayo criteria. The cumulative proportion that progressed to dementia rarely exceeded 50%, even in long-term studies. In the 6 studies with an observational period of 5 years or more, the cumulative conversion rate was only 38.2%.

As for the annualized conversion rate (ACR), in studies adhering to the Mayo Clinic definition of MCI, after sample size was corrected for, these rates in specialized settings were: 9.6% for dementia, 8.1% for AD, and 1.9% for VaD.

The adjusted ACR in community settings was 4.9% for dementia, 6.8% for AD, and 1.6% for VaD. Again, these rates were generally lower in studies using non–Mayo Clinic criteria

Across all 41 studies, the overall ACR was 6.7% for progression to dementia, 6.5% for AD, and 1.6% for VaD.

The relative risk for progression was 15.9 (MCI Mayo type) and 6.2 (MCI non-Mayo type) for dementia and 9.5 (MCI Mayo type) and 4.7 (MCI non-Mayo type) for AD when compared with healthy elderly patients.

Modeling the development of dementia over time showed a "plateau" at 10 years of 50%, said Dr. Mitchell.

Challenging Accepted Progression Rate

This study challenges the previous accepted annual progression rate of 10%, which, if true, would mean that all surviving MCI sufferers would have dementia within 10 years.

"The chances of developing dementia with MCI, at least for the foreseeable future — which is the length of a study and in this case is up to 10 years — is somewhere between 30% and 50%, depending on the relative risk," said Dr. Mitchell. "Before, most people thought that the cumulative risk was basically 100%."

The cumulative risk is roughly arrived at by using a simple model of multiplying the annual rate of progression to dementia by the number of years studied. However, the actual numbers do not always add up, because, as Dr. Mitchell explained, the risk continues after the end of the study; there are outcomes other than dementia; and ACR and cumulative-risk statistics have different weightings.

Those previous rates were arrived at using short-term studies or small samples, said Dr. Mitchell. He added that it is only now that there are sufficient studies with large samples that followed subjects for long enough to make a solid meta-analysis possible.

MCI Has Subgroups

The study suggests that instead of being a homogenous transitional phase between normal aging and dementia, MCI includes several subgroups, some of which go on to develop dementia, some of which stay static, and some of which even improve, said Dr. Mitchell.

"This paper is just another piece of evidence that this MCI group is not just 1 explanation (for memory problems), that there are different things going on; the groups may look the same at certain points, but they will have slightly different trajectories," he said.

As an example, Dr. Mitchell used patients with MCI whom experts presume are destined to develop AD. "If you're able to examine brain pathology in life, you'll find that many individuals with MCI are not in a pre-Alzheimer's group at all, that there are other explanations for their memory decline." One common cause for such memory decline is depression, and when the depression is treated, the memory decline is reversed, he said. Another possible explanation for memory problems is "silent" cerebral infarction. In many cases, patients suffer a stroke and do not present to the hospital or, if they do, their stroke is not picked up on magnetic resonance imaging, said Dr. Mitchell. "It's only when you test their memory that you find they have these memory complaints."

Progression from MCI to dementia is fraught with "gray areas," said Dr. Mitchell. For 1 thing, while patients who complain of memory problems are considered at increased risk to develop dementia, just because a patient does not complain of memory problems does not mean these problems do not exist.

Such patients may not want to talk about their memory problems or prefer to minimize them out of embarrassment. "Many of these people are functioning reasonably well and many are still working," said Dr. Mitchell. "They want to be doing as well as they can for as long as possible."

He pointed out that other factors that were not measured in the meta-analysis — including biological and psychological factors — could pose additional risks in terms of progression to dementia.

While these results are more favorable than previously thought, they should be interpreted carefully, said Dr. Mitchell. "I would cautiously say that this is not as bad news as it once was, but I wouldn't go so far as to say that all patients do well."

A good reason to be cautious is that patients with MCI are at higher risk for mortality and other negative outcomes than the general population, said Dr. Mitchell. He and his colleagues will investigate these risks more closely in future research.

Results Should Be Considered With Caution

Asked by Medscape Psychiatry to comment on the meta-analysis, Ronald Petersen, MD, PhD, principal investigator of the Mayo Clinic Study of Aging, said the findings should be considered with a little caution, as some of the studies included relatively young patients.

"A study that includes people in their 40s and 50s in the overall analysis will get very different conversion rates than a study that includes people in their 70s and 80s. If you're evaluating a set of criteria, that's an important factor to take into account," he said.

He noted the 50% conversion rate indicated in the study is perhaps "a little too optimistic. If I diagnose someone who is 75 years old with MCI and they don't have depression, the conversion rate is a lot higher than 50% over 10 years."

However, Dr. Petersen added, if the study findings result in physicians having more discussions about cognitive problems with their patients, then that is a good thing. "That would be wonderful, and I wouldn't detract from that message."

The authors report no relevant conflicts of interest.

Acta Psychiatr Scand. 2009;119:252-265. Abstract

Heartwire 2009. © 2009 Medscape

April 10, 2009 (Munich, Germany) — A new study using platelet-aggregometry testing to assess the effects of different proton-pump inhibitors (PPIs) on platelet response to clopidogrel suggests that omeprazole might be alone in adversely interacting with the widely used antiplatelet therapy [1]. The study, published in the April issue of Thrombosis and Haemostasis, hints that other PPIs tested--pantoprazole and esomeprazole--might be a safer bet for minimizing gastrointestinal side effects and bleeding in patients requiring long-term clopidogrel treatment.

But the authors also caution that their study was restricted to testing platelet response, using just one of many tests developed to evaluate platelet function and that it included no hard clinical end points. "Specifically designed and randomized clinical studies are needed to define the impact of concomitant PPI treatment on adverse events after percutaneous coronary intervention," Dr Dirk Sibbing and colleagues (Deutsches Herzzentrum, Munich, Germany) write.

Sibbing et al performed platelet-function testing (using the Dynabyte Multiplate point-of-care impedance aggregometer) in 1000 patients who had undergone PCI and stenting and were taking dual antiplatelet therapy (aspirin and clopidogrel 75 mg/day). Of these, 268 patients were also taking PPIs at the time of testing (162 were taking pantoprazole, 64 omeprazole, and 42 esomeprazole); the remainder were not taking a PPI.

As the authors report, platelet aggregation was significantly different between the four groups, with platelet aggregation significantly higher in the omeprazole group than in the group not taking a PPI. By contrast, patients in the pantoprazole and esomeprazole groups had similar platelet aggregation to those in the group not taking a PPI. In multivariate analyses, only administration of omeprazole was associated with a reduced response to clopidogrel, they note.

"This is the first study comparing the impact of concomitant treatment with three different PPIs (pantoprazole, omeprazole, and esomeprazole) on platelet response to clopidogrel treatment in a large cohort of patients with previous coronary stent placement," Sibbing told heartwire "Diverging effects on clopidogrel response for different PPIs in one and the same study population have never been demonstrated before and are now shown by our study."

An Important Contribution

The role and relative value of different platelet-function tests continue to prompt debate; the authors of the current study point out that their findings corroborate those of the OCLA study, which used a different type of assay to gauge clopidogrel responsiveness. "Both assays provided similar results regarding the impact of omeprazole on clopidogrel response, which is a strong clue for the effect observed," they note.

Sibbing told heartwire that the point-of-care assay used for platelet-function testing in this study "is widely used and accepted." Other recent work by Sibbing's group has also demonstrated the ability of the same assay to predict the occurrence of stent thrombosis and other ischemic events following PCI in more than 1600 patients [2].

An editorial accompanying Sibbing et al's paper by Drs Victor Serebruany (Johns Hopkins University, Baltimore, MD) and Shinya Goto (Tokai University, Kanagawa, Japan) [3] calls the study a "timely, elegant, well-designed . . . important contribution to the field."

Drs Serebruany and Goto point out that PPIs are widely prescribed by physicians for symptomatic relief, rather than as therapy for a confirmed diagnosis of a range of gastrointestinal syndromes. Sibbing et al's study, on top of other recent studies, suggests that omeprazole, but not other PPIs, diminish the antiplatelet potency of clopidogrel--the upshot being that physicians could be putting patients at risk for little gain. "Use of [a] clopidogrel and PPI combination is difficult to justify since the gastrointestinal protection comes at the expense of reducing the vascular benefit of clopidogrel," they write. For now, they conclude, the combination "cannot be recommended until more randomized and mechanistic data become available."

That advice directly contradicts current guidelines, which recommend prescription of a PPI in all patients taking dual antiplatelet therapy. "Findings of the present study may have important clinical implications in terms of PPI selection in patients under dual antiplatelet treatment," Sibbing et al write.

Sibbing also agreed that the way omeprazole and clopidogrel interact requires further study. "Based on the clinical and platelet-function data available, it must be assumed that the adverse effects of omeprazole are, to a significant proportion, related to platelet effects," he said. "Other mechanisms, however, cannot be excluded and warrant further investigations."

They also offer the caveat that although their study showed similar results for both pantoprazole and esomeprazole, the study was only powered to consider pantoprazole treatment.

More answers are expected at the upcoming SCAI meeting in Las Vegas, where investigators for the Clopidogrel Medco Outcomes Study, addressing the effects of clopidogrel and individual PPIs, will be releasing new results.

Sibbing disclosed receiving speaker fees from Dynabyte (modest level), and fees for advisory-board activities from Eli Lilly (modest level). The study was funded by Dynabyte.

1. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101:714-719. Abstract
2. Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol 2009; 53:849-856. Abstract
3. Serebruany V, Goto S. Clopidogrel and proton pump inhibitors: Gastric protection at expense of vascular benefit? Thromb Haemost 2009; 101:607-609. Abstract

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Medscape Medical News 2009. © 2009 Medscape

April 15, 2009 — High serum cholesterol may contribute to the development of Alzheimer's disease (AD) and vascular dementia, but lowering cholesterol levels with statins does not prevent these problems, according to a new Cochrane review.

"The most important point is that we did not find any effect on dementia prevention from use of statins," lead author Bernadette McGuinness, MD, MRCP, from the Queen's University of Belfast, in the United Kingdom, told Medscape Psychiatry.

"Statins have a variety of uses and are very important in cardiovascular disease, but unfortunately they did not appear efficacious in preventing dementia. The studies included were very large, with approximately 26,000 participants in total, so if an effect were present one would have seen it. The patients were also at high vascular risk and so would have been at increased risk of developing dementia," she said.

Some researchers had hoped that statins would lower the risk for dementia because epidemiological studies have linked elevated cholesterol and Alzheimer's disease and because studies in animal models showed that reducing cholesterol decreased Alzheimer's-like symptoms.

The review, an update to an earlier review completed in 2001, comprised 26,340 participants in 2 major studies. One study, the Medical Research Council (MRC)/British Heart Foundation Heart Protection Study (HPS), looked at simvastatin use in 20,536 patients and followed them for 5 years. The other study, the PROSPER trial, looked at pravastatin use in 5804 patients, with an average follow-up of 3.2 years.

Both studies were double-blind, randomized, placebo-controlled trials of statin medications in individuals at risk for dementia and AD. Taken together, the studies included adults between the ages of 40 and 82 years.

Lack of Effect "Surprising"

“We were surprised at the lack of effect of statins in preventing dementia. Biologically, it seemed feasible they could, and the initial observational and cohort studies were very promising. There are problems with these types of studies (such as indication bias), which demonstrates why it is important to carry out randomized controlled trials," Dr. McGuinness said.

"The number of patients who developed dementia was very low in both studies, which was also surprising, given their age and vascular risk," Dr. McGuinness added. "This may relate to careful control of vascular risk factors, as was seen in previous vascular dementia trials, or may be that the screening used to detect dementia in the trials was not sensitive enough. This may be particularly important for the MRC/HPS trial, where just a telephone interview was used."

The researchers concluded that statins given in late life to individuals at risk for vascular disease do not protect against dementia. The review authors found no difference between patients receiving the medications and patients receiving placebo with respect to incidence of dementia, cognitive function, or performance on specific neuropsychological tests.

Howard Fillit, MD, executive director of the Alzheimer's Drug Discovery Foundation, in New York, said that although there is little conclusive evidence that statins are useful in the treatment of dementia, some epidemiologic data suggest that they may be preventive.

"However, most patients with Alzheimer’s do not have 'pure' AD but have multiple comorbidities that may contribute to dementia, including vascular comorbidities that should be addressed if high cholesterol is present and treatment is indicated in any event to prevent cardiovascular disease and/or stroke," Dr. Fillit said.

Safety Concerns

Whether statins given in middle age for many years can protect against dementia in later life is unknown and perhaps unknowable. "Clinical studies in middle-aged patients followed for many years would be useful but may not be feasible. It may be that one needs to take a statin for many years before any benefit in prevention is seen. Clinical studies of statins in treatment of dementia are still largely unpublished and awaited. We are also carrying out a Cochrane review on that topic," Dr. McGuinness said.

Dr. Fillit would like to see a trial of statins in patients with high cholesterol who are at risk for stroke to see if such treatment prevents dementia — either vascular or AD.

Long-term use of statins to prevent dementia also raises some safety concerns. "Statins have a range of mechanisms that could help or hurt cognition," said Beatrice Golomb, MD, PhD, from the University of California, San Diego. "Regarding statins as preventive medicines, there are a number of individual cases in case reports and case series where cognition is clearly and reproducibly adversely affected by statins."

Dr. Golomb also said that some randomized trials have shown that the net effect of statin medications was significantly adverse and others that have shown it was neutral but that none has shown statin use to be favorable for cognition.

Study coauthor Peter Passmore, also from the Queen's University of Belfast, discloses that he was an investigator in the Leade study and received grants from Pfizer, Merck Sharp & Dohme, Bristol-Myers Squibb, and Novartis and honoraria from Pfizer, Merck Sharp & Dohme, Novartis, and AstraZeneca.

Cochrane Database Syst Rev. 2009;1:CD007514.

Introduction

Best Evidence Reference

Humphrey LL, Fu R, Buckley DI, Freeman M, Helfand M. Periodontal disease and coronary heart disease incidence: a systematic review and meta-analysis. J Gen Intern Med. 2008;23:2079-2086.

Abstract

This study was selected from Medscape Best Evidence, which uses the McMaster Online Rating of Evidence System. Of a possible top score of 7, this study was ranked as 5 for newsworthiness and 7 for relevance by clinicians who used this system.

Brief Summary

Previous research has found that periodontal disease can increase the risk for cardiovascular risk factors. The current systematic review and meta-analysis examine the association between periodontal disease and coronary heart disease (CHD). A summary of its findings as well as recommendations in regard to how physicians may promote better oral and cardiovascular health are described below.

Background

Dental and periodontal disease is very common, but this significant public health problem receives little attention from physicians. Using data from the 1999-2002 National Health and Nutrition Examination Survey (NHANES), researchers demonstrated that approximately 90% of adults had caries in their adult teeth.^[1] The average number of retained natural teeth was 24 (of a possible 28) among adults, and 8% of adults were edentulous. The rate of edentulism grew by 6% among older adults between the 1988-1994 and 1999-2002 study periods. Another study described the risk factors for edentulism, and older age was the most prominent.^[2] Tooth loss was not related to biological sex, and rates of tooth loss were lowest among Mexican Americans and highest among black, non-Hispanic adults. Poverty is also associated with a disproportionate burden of periodontal disease. Adults with low income and less than a high school education are approximately twice as likely to have periodontal disease compared with more affluent adults with higher educational attainment.^[3]

Physicians should be concerned about the high rates of caries, tooth loss, and periodontal disease because these oral conditions are associated with significant negative health outcomes. In one analysis that adjusted for traditional risk factors, the prevalence of the metabolic syndrome was 2.31 times higher among patients with severe periodontal disease compared with adults without periodontal disease.^[4] Moreover, the prevalence of metabolic syndrome increased gradually with the severity of periodontal disease, with a 12% increase in the risk for metabolic syndrome per 10% increase in the measurement of gingival bleeding.

One of the significant ways that periodontal disease may promote metabolic syndrome and subsequent cardiovascular disease is an increase in the degree of intravascular inflammation. Periodontal disease has been associated with increases in the levels of inflammatory markers, including an increase in serum C-reactive protein (CRP) levels of over 40% and an increase in plasma fibrinogen levels.^[5] However, this same study failed to demonstrate a significant relationship between periodontal disease and serum lipid values.

Summary of Current Trial

These associations between periodontal disease and cardiovascular risk factors are not as critical as whether periodontal disease contributes to outcomes important to patients themselves, particularly heart attack. The current systematic review and meta-analysis describe the relationship between periodontal disease and CHD. Researchers examined the MEDLINE database between 1966 and March 2008, as well as other review materials, to find pertinent research related to periodontal disease and the risk for CHD. Included research was prospective and focused on patients without a prior history of CHD. Studies that focused on the broader outcome of cardiovascular disease could also be included.

Of 143 abstracts, 7 studies with a total of 345,000 subjects were included in the final review. The duration of follow-up ranged between 5 years and 21 years. The quality of the included research was good in 3 studies and fair in the other 4.

The definition and ascertainment of periodontal disease differed between studies but generally used accepted criteria. In 2 studies, patient self-report was used to define periodontal disease, but these participants had to either cite a specific history of periodontal disease or quantify tooth loss.

Six studies examined the association between periodontitis and CHD, and half of these studies demonstrated a significant increase in the risk for CHD associated with periodontitis. When the results of these studies were combined in a meta-analysis, periodontal disease increased the risk for incident CHD by a risk ratio of 1.24.

Tooth loss was also associated with an increased risk for CHD. Compared with participants having 25-32 teeth, subjects with 0-10 teeth experienced a risk ratio of 1.34 for all CHD and cardiovascular events.

There was significant heterogeneity in the included research. The studies that used dental examination to define periodontal disease and had a longer follow-up period demonstrated a stronger relationship between periodontal disease and the risk for CHD. Women experienced a slightly higher risk for CHD associated with periodontal disease compared with men, but this difference was not statistically significant.

The collective research was limited by a lack of uniformity in the definition for periodontal disease, but any such bias would be more likely to result in underreporting the relationship between oral disease and CHD. Not all research accounted for other cardiovascular risk factors as confounders in the outcome of CHD. However, some higher-quality research did perform appropriate analyses, and this research consistently demonstrated that periodontal disease was an independent risk factor for CHD.

Commentary

The current review and meta-analysis are consistent with previous summaries of the cardiovascular risk associated with periodontal disease. A meta-analysis of 8 prospective and 1 retrospective study found a summary relative risk of 1.19 for cardiovascular events associated with periodontal disease.^[6] The negative effect of periodontal diagnosis on cardiovascular outcomes was most pronounced among adults at age 65 or younger (relative risk, 1.44). Although periodontal disease was independently linked with a higher risk for fatal cardiac events, it was even more strongly associated with a higher risk for stroke.

A prospective cohort study of 9760 subjects published in BMJ also demonstrated a 25% increase in the risk for CHD associated with periodontal disease.^[7] Moreover, even poor oral hygiene without periodontal disease, which was defined by the degree of dental debris and calculus, also increased the risk for CHD, and both periodontal disease and poor oral hygiene increased the risk for overall mortality. These findings suggest a possible continuum between the degree of poor oral health and the risk for cardiovascular disease.

The collective scientific evidence offers a clear mandate to physicians: The rate of poor oral health is high, and this problem results in severe consequences for patients. Physicians should save time during office visits to remind patients of good oral health habits and regular follow-up with dentists. This alone may help prevent cardiovascular outcomes in a significant number of patients.

Antibiotics, Periodontal Disease, and Cardiovascular Disease. However, could physicians do even more to ameliorate the risk for cardiovascular disease among patients with periodontal disease? One of the principal mechanisms by which periodontal disease may promote cardiovascular disease is transient bacteremia, which, in turn, increases intravascular inflammation and atherosclerosis. Antibiotics may be able to curb this process.

However, antibiotics have a poor track record in the prevention of cardiovascular disease. Most of the research into this subject has involved secondary prevention among patients with known CHD, and this group is at inherently higher risk compared with adults without CHD. In one trial of 4372 patients with heart disease randomized to receive clarithromycin or placebo for 2 weeks, the antibiotic actually increased the risk for mortality by 27% at 2.6 years.^[8] A recent update of this study cohort found that the hazard ratio for death continued to be higher in the clarithromycin group at 6 years (hazard ratio, 1.21).^[9] This research included a meta-analysis of all research into the use of antibiotics for patients with CHD. In a total of 17 trials involving 25,271 patients, the relative risk for death for those taking antibiotics compared with placebo was 1.10, which was statistically significant. Another systematic review suggested that whereas antibiotics appeared to be effective in smaller trials in the secondary prevention of cardiovascular disease, larger trials of a variety of antibiotics failed to confirm these results.^[10] Overall, there is no evidence to recommend the routine use of antibiotics to prevent cardiovascular disease.

The overall failure of antibiotics to prevent cardiovascular events, and the possibility that they might actually increase the risk for mortality, directs physicians back to the concept of primary prevention of periodontal disease. However, they are certainly not alone in this effort. Dental health professionals should champion this cause and educate patients with regard to the consequences of poor oral health. In addition, given the disproportionate burden of periodontal disease among the poor, health policy planners should prioritize dental hygiene programs for these communities.

Clinical Pearls