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Original Research |

Invasive Dental Treatment and Risk for Vascular Events: A Self-Controlled Case Series

Caroline Minassian, MSc; Francesco D'Aiuto, PhD; Aroon D. Hingorani, PhD; and Liam Smeeth, PhD
[+] Article and Author Information

From London School of Hygiene and Tropical Medicine, University College London Eastman Dental Institute, and University College London, London, United Kingdom.


Acknowledgment: The authors thank GlaxoSmithKline for supplying the Medicaid data and for their advice on using the database. The company had no role in the study design, analysis, interpretation of the findings, or preparation of this manuscript.

Grant Support: In part by a Wellcome Trust Senior Fellowship grant (Dr. Smeeth) and a senior fellowship from the British Heart Foundation (Dr. Hingorani). Dr. D'Aiuto holds a Clinical Senior Lectureship Award supported by the United Kingdom Clinical Research Collaboration. Drs. Hingorani and D'Aiuto work at University College London Hospital–University College London, who received a proportion of funding from the Department of Health's National Institute for Health Research Biomedical Research Centres funding scheme.

Potential Conflicts of Interest: Dr. Hingorani: Grants received/pending: British Heart Foundation and Medical Research Council Research Award on Biomarkers, with Pfizer as a co-funder. Employment: Editorial board member of the Drug and Therapeutics Bulletin, a BMJ Group publication. Other: Received honoraria for speaking at educational meetings and teaching a course on cardiovascular risk. Some of this money was donated to medical charities. Dr. Smeeth: Grants received/pending: Wellcome Trust Senior clinical fellowship. Other: GlaxoSmithKline provided access to the data but had no role in the study design, analysis, or interpretation of the manuscript. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M10-0574.

Reproducible Research Statement:Study protocol and statistical code: Available from Ms. Minassian (e-mail, caroline.minassian@lshtm.ac.uk). Data set: Not available.

Requests for Single Reprints: Liam Smeeth, PhD, Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom; e-mail, liam.smeeth@lshtm.ac.uk.

Current Author Addresses: Ms. Minassian and Dr. Smeeth: Department of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom.

Dr. D'Aiuto: Periodontology Unit, University College London Eastman Dental Institute, 256 Gray's Inn Road, London WC1X 8LD, United Kingdom.

Dr. Hingorani: Genetic Epidemiology Group, Department of Epidemiology and Public Health, University College London, 1-19 Torrington Place, London WC1E 6BT, United Kingdom.

Author Contributions: Conception and design: L. Smeeth, F. D'Aiuto.

Analysis and interpretation of the data: C. Minassian, L. Smeeth, A.D. Hingorani, F. D'Aiuto.

Drafting of the article: C. Minassian, L. Smeeth, A.D. Hingorani, F. D'Aiuto.

Critical revision of the article for important intellectual content: C. Minassian, L. Smeeth, A.D. Hingorani, F. D'Aiuto.

Final approval of the article: C. Minassian, L. Smeeth, A.D. Hingorani, F. D'Aiuto.

Statistical expertise: C. Minassian, L. Smeeth.

Obtaining of funding: L. Smeeth.

Administrative, technical, or logistic support: F. D'Aiuto.


Ann Intern Med. 2010;153(8):499-506. doi:10.7326/0003-4819-153-8-201010190-00006
Text Size: A A A

Background: Treatment of periodontal disease may reduce cardiovascular risk in the longer term, but studies have suggested a link among dental procedures, acute inflammation, and endothelial dysfunction. However, whether such acute inflammatory effects translate into a short-lived increased risk for vascular events is not known.

Objective: To investigate whether invasive dental treatment transiently increases the risk for vascular events.

Design: Self-controlled case series.

Setting: Data came from the U.S. Medicaid claims database.

Patients: All persons exposed to invasive dental treatment with a primary hospital discharge diagnosis of ischemic stroke (n = 650) or myocardial infarction (n = 525) from 2002 to 2006.

Measurements: The incidence of ischemic stroke and myocardial infarction in periods immediately after invasive dental treatment was compared with the incidence in all other observed time periods. Incidence ratios and 95% CIs were calculated.

Results: The rate of vascular events significantly increased in the first 4 weeks after invasive dental treatment (incidence ratio, 1.50 [95% CI, 1.09 to 2.06]) and gradually returned to the baseline rate within 6 months. The positive association remained after exclusion of persons with diabetes, hypertension, or coronary artery disease or persons with prescriptions for antiplatelet or salicylate drugs before treatment.

Limitations: Power to examine the effects of invasive dental treatment on stroke and myocardial infarction separately was limited because of the low frequency of invasive dental procedures. Lack of information about use of over-the-counter drugs limited the ability to assess confounding by possible withholding of antiplatelet or salicylate drugs before invasive dental treatment or by the use of nonsteroidal anti-inflammatory drugs after treatment.

Conclusion: Invasive dental treatment may be associated with a transient increase in the risk for vascular events. However, the absolute risks are minimal, and the long-term benefits on vascular health will probably outweigh the short-lived adverse effects.

Primary Funding Source: Wellcome Trust.

Figures

Grahic Jump Location
Figure.
Pictorial representation of the case series method.

Four possible scenarios for the timing of vascular events and invasive dental procedures (each representing a single participant) are shown. A. Participant is followed for the duration of the study period, has two 24-week risk periods (each after an invasive dental procedure), and has a vascular event during the second risk period. B. Participant is followed for part of the study period and has 1 dental procedure followed by a vascular event at baseline. C. Participant is followed from the start of the study period, has a vascular event at baseline before a dental procedure, and dies before the end of the study period. D. Participant is followed for most of the study period, has 2 dental procedures, and has a vascular event during the first risk period. All participants included in a particular analysis had at least 1 exposure and at least 1 vascular event. Each risk period began the day after a procedure, lasted 24 weeks (not drawn to scale relative to length of baseline periods), and was divided into the following intervals: 1 to 4, 5 to 8, 9 to 12, 13 to 16, and 17 to 24 weeks.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 1.
Study flow diagram.

MI = myocardial infarction.

* Individuals who had both an ischemic stroke and an MI during the study period.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 2.
Pictorial representation of the self-controlled case series method.

A single participant who had 2 exposures during the observation period is shown. The outcome event could occur at any time during the observation period.

Grahic Jump Location
Grahic Jump Location
Appendix Figure 3.
Pictorial representation of overlapping risk periods.
Grahic Jump Location

Tables

References

Letters

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Comments

Submit a Comment
Inflammation and Heart Disease. The Wisdom of listening to our Colleagues!
Posted on October 19, 2010
Richard M. Fleming
No Affiliation
Conflict of Interest: None Declared

We would like to congratulate the authors on their work recently published in the Annals of Internal Medicine regarding an increased risk of vascular disease following dental procedures. In 1995, following more than 20 years with the American Heart Association and multiple publications on the effect of diet, lifestyles and heart disease1-5, we began to question what we were missing. Following our efforts to review work from multiple disciplines and the work of not only American, but our European and Asian colleagues including those not in Cardiology but representing all scientific disciplines, including the Dental community, we began to uncover a series of risk factors which were "Inflammatory" in character and by 19996 we published our first chapter on the topic. While there have been several publications since, it is clear that we need to keep the communication between fields open if we are to uncover and fully treat "Inflammation" and "Heart" and "Vascular" diseases. Before we become too confident, it is important to understand that only 2/3rds7,8 of what produces this inflammation is currently known and while we independently pursue a better understanding of our work on "Inflammation and Heart Disease", we need to remember to continuing monitor and learn from our colleagues throughout the world. Congratulations to the authors and to Annals for publishing this important work.

References:

1. Fleming RM. The Fleming Unified Theory of Vascular Disease: A Link Between Atherosclerosis, Inflammation, and Bacterially Aggravated Atherosclerosis (BAA). Angiol 2000; 51: 87-89.

2. Fleming RM, Boyd L, Forster M. Reversing Heart Disease in the New Millennium - The Fleming Unified Theory, Angiology 2000;51(10):617-629.

3. Fleming RM. Coronary Artery Disease is More than Just Coronary Lumen Disease. Amer J Card 2001;88:599-600.

4. Fleming RM. Angina and coronary Ischemia are the result of coronary regional Blood Flow Differences. J Amer Coll Angiol 2003;1:127- 42.

5. Fleming RM. Using C-Reactive Protein as a Marker of Bacteriallly Aggravated Atherosclerosis in Acute Coronary Syndromes. J Amer Coll Angiol 2003;1:165-71.

6. Fleming RM.: Chapter 64. The Pathogenesis of Vascular Disease. Textbook of Angiology. John C. Chang Editor, Springer-Verlag New York, NY. 1999, pp. 787-798.

7. Nielson C, Fleming RM. Blood glucose and cerebrovascular disease in non-diabetic patients. Angiology 2007;58(5):625-9.

Conflict of Interest:

None declared

Possible intra-individual confounding
Posted on November 5, 2010
Sok-Ja Janket
Henry M. Goldman School of Dental Medicine, Boston University
Conflict of Interest: None Declared

Editor, This letter is in response to the article titled "Invasive dental treatment and risk for vascular events: a self-controlled case series" by Minassian C, et al, published in the October issue of the Annals.(1) The use of a self-controlled case series to prove a causal relationship and the oversight of some important intra-person confounding factors has forced us to challenge their conclusion.

Self-controlled case series can be interspersed with intra-person biases, as demonstrated by Minassian and colleagues.(1) In addition, case- series is only useful for hypothesis generation and not for demonstrating causal relationships.(2) Here, we list a few time-varying within-person confounding ignored in this study: acute upper respiratory infections that were reported to increase cardiovascular (CV) risk(3) ; illicit drug use that can cause severe arrhythmia, thrombosis, and cardiac arrest (3); menopause that can engender increased level of plasminogen activator Inhibitor-1 (PAI-1) and decreased stress-coping ability that may contribute to a surge in endogenous catecholamines and can lead to arrhythmia and subsequent CV events.(4) Thus, considering the fact that nearly 2/3 of the events occurred in women and their age, confounding by thrombotic tendency and adrenergic dysregulation due to menopause might be directly responsible for some of the findings seen in this study.

Furthermore, if we look at the most prevalent dental procedures cited as invasive in this article (appendix Table 1)(1), all suggest past oral infections and indicate potential dental neglect. Root remnants, which are the vestige of serious past dental infection contributed very strongly to the Asymptotic Dental Score which was associated with coronary artery disease in our data.(5) Cardiovascular disease is a chronic multifactorial process although the manifestations appear to be acute and sudden. Without knowing the molecular changes in cardiovascular pathology associated with Minassian and colleague's study, we are reluctant to accept their results as unbiased or causal. Unfortunately, this study, with its bias and inadequacy, might still provoke unsubstantiated fears in the general public and elicit further avoidance of needed dental treatments.

Additionally, bias-ridden results of this study could become a platform for baseless litigations or inappropriate health policy inclusions. The take home message to the public is "it is better to prevent serious surgical procedures by taking care of dental disease when incipient and easily manageable". Thus, the need for health policy that includes routine dental care as a part of over all health is evident.

Sok-Ja Janket, DMD, MPH Research Associate Professor Henry M. Goldman School of Dental Medicine Boston University

Kamal, Jethwani, MD, MPH Research Fellow Massachusetts General Hospital Harvard Medical School

Jukka H. Meurman, MD, PhD, DDS Chief, Oral Maxillofacial Disease Helsinki University Central Hospital University of Helsinki

References:

1. Minassian C, D'Aiuto F, Hingorani AD, Smeeth L. Invasive dental treatment and risk for vascular events: a self-controlled case series. Ann Intern Med. 2010;153(8):499-506.

2. Hennekens CH, Buring JE. Epidemiology in Medicine Hagerstown, MD. 21740: Lippincott Williams & Wilkins; 1987.

3. Goldstein LB, Adams R, Alberts MJ, et al. Primary prevention of ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council: cosponsored by the Atherosclerotic Peripheral Vascular Disease Interdisciplinary Working Group; Cardiovascular Nursing Council; Clinical Cardiology Council; Nutrition, Physical Activity, and 3 Metabolism Council; and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation. 2006;113(24):e873-923.

4. Sclarovsky S, Nikus KC. The role of oestrogen in the pathophysiologic process of the Tako- Tsubo cardiomyopathy. Eur Heart J. 2010;31(3):377; author reply 377-8.

5. Janket SJ, Qvarnstrom M, Meurman JH, Baird AE, Nuutinen P, Jones JA. Asymptotic dental score and prevalent coronary heart disease. [see comment]. Circulation. 2004;109(9):1095-100.

Conflict of Interest:

Dr. Janket is supported by a grant from the American Heart Association # 0635351N. Dr. Meurman is supported by grants from the Helsinki University Central Hospital, and the Finnish Medical Society, Helsinki, Finland.

Observational bias
Posted on November 7, 2010
Joseph D. Matthews
University of New Mexico School of Medicine, Department of Dental Servces
Conflict of Interest: None Declared

The study by Minassian et al. highlights the difficulty of applying results from retrospective studies of claims data to clinical practice. The most important confounder which was not discussed by the authors is the proximity of extraction to an odontogenic infection or other acute condition necessitating invasive dental treatment. Since the analysis was restricted to dental extractions it would be important to ascertain the reason for the extraction in each case. Rarely are extractions an elective procedure and in fact are often delayed until an acute condition makes successful alternatives unlikely. One recent study found that over 80% of tooth extractions were due to dental caries and it's sequelae or periodontal disease (1). It seems far more likely that patients in this study who suffered vascular events were experiencing sequelae from the disease itself rather than treatment of the disease.

References

1. Aida J, Morita M, Akhter R, Aoyama H, Masui M, Ando Y 2009 Relationships between patient characteristics and reasons for tooth extraction in Japan. Community Dental Health; 26(2):104-9.

Conflict of Interest:

None declared

Reply from study authors
Posted on December 15, 2010
Caroline Minassian
London School of Hygiene and Tropical Medicine
Conflict of Interest: None Declared

We are pleased that our study on the risk of vascular events following invasive dental treatment has generated interest. However, it is clear that the study was poorly understood by some readers, and we would like to address some of the points raised.

Dr Janket, Dr Jethwani and Dr Meurman may have misinterpreted the self-controlled case series method we used as a collection of case reports with no comparison group. We agree such case-series could be prone to confounding and are not suitable for investigating casual relationships. This must not be confused with the self-controlled case series (SCCS) method used in our study. The SCSS provides an alternative to the more established cohort method for estimating the relative incidence of an event. Derived from a Poisson cohort model, it makes within-person comparisons, thus each individual serves as his or her own control. We used this method to assess the risk for vascular events after invasive dental treatment by deriving incidence ratios of events occurring during exposed versus unexposed periods. The method has been extensively used in epidemiology to assess causal associations, in a variety of different settings (1-3). The technical appendix to our paper explains the approach and its advantages in detail.

We chose to use the SCCS design because it avoids much of the problem of confounding to which other observational study designs are prone. This is achieved by all comparisons being within-person; thus fixed covariates are implicitly controlled for. The only scope for confounding is by intra- person risk factors for vascular events that change with time and which are also associated with the timing of invasive dental treatment. Dr Janket et al appear not to have considered that all analyses were adjusted for the time-varying effect of age, thus any possible confounding by age- related factors are controlled for implicitly. Since the other factors they mention (acute upper respiratory infections and illicit drug use) are unlikely to be associated with the timing of dental treatment, they will not be confounders. Dr Janket et al rightly stated that many of the procedures studied might suggest past oral infections and dental neglect. However, such infections and/or neglect could not confound the association observed unless their onset coincided with the timing of dental treatment.

We believe that Dr Janket et al's assertion that our study results are "bias-ridden" reveals a misunderstanding of the study design, which was carefully chosen over all the available alternatives to minimize bias. We strongly disagree with their suggestion that our study might "provoke unsubstantiated fears in the general public and elicit further avoidance of needed dental treatments." We recognize the long-term benefits of such treatment, which is why we interpreted our findings with due caution. We suggest another look at the conclusion to our paper:

"Although the mechanisms are uncertain, we conclude that invasive dental treatment may be associated with a transient increase in the risk for stroke and myocardial infarction in adults. The short-lived adverse effects are nevertheless likely to be outweighed by long-term benefits of invasive dental treatment to vascular health."

Dr Mathews raises an interesting question about possible confounding by odontogenic infection or other acute condition necessitating dental extraction. Unfortunately we did not have details of the reason for each dental extraction. While in the case of extractions following an acute condition we cannot disentangle the effects of the condition from those of the dental treatment, we believe it is highly unlikely that the entire association between invasive dental treatment and vascular events is due to such acute conditions. The invasive dental procedures included in our main analysis were those which could feasibly result in bacteremia and induce an inflammatory response: they were not in fact confined to extractions, nor did they necessarily follow acute infections. Even if the effect we observe is in part attributed to acute infection at the time of dental treatment, this would actually support an inflammatory mechanism for the association between dental treatment and vascular events.

References

1. Smeeth L, Cook C, Thomas S, Hall AJ, Hubbard R and Vallance P. Risk of deep vein thrombosis and pulmonary embolism after acute infection in a community setting. Lancet 2006; 367:1075-1079.

2. Taylor B, Miller E, Farrington CP, Petropoulos M-C, Favot-Mayaud I, Li J, Waight PA. Autism and measles, mumps and rubella vaccine: no epidemiological evidence for a causal association. Lancet 1999; 353:2026- 2029.

3. Hubbard R, Farrington P, Smith C, Smeeth L and Tattersfield A. Exposure to tricyclic and selective serotonin reuptake inhibitor antidepressants and the risk of hip fracture. Am J Epidemiol 2003; 158:77- 84.

Conflict of Interest:

We are the authors of the paper

Re: Reply from study authors
Posted on January 19, 2011
Sok-Ja Janket
Boston University School of Dental Medicine
Conflict of Interest: None Declared

We understand the self-as-control study design and its advantage of balanced inter-individual confounding. However, 24 weeks (approximately 6 months) or even the riskiest category, 1-4 weeks are overly wide windows of opportunity for other acute events such as upper respiratory infections and illicit drug use. Additionally, if a person is compromised in managing stress, then "is it the influence of the stress or is it the invasive dental treatment that contributed to the events?"

Minassian et al. believed they estimated the risk of acute effects of invasive dental treatment but this acute effects that were apparent one day after the treatment had disappeared after one week.(1) In our view, unless they can provide a molecular basis, this study generates nothing but fear.

Most journal editors and reviewers like studies with large sample sizes: but the truth is that large sample sizes are prohibitive regarding the precision of risk assessment. For example, consider the cost of assaying PAI-1 among 20,369 persons. Thus, epidemiologists opt for a proxy and the end results are imprecise large sample that can generate biased conclusions with significant p-value (N.B: p-value is largely the function of sample size).

Although we recognize the hard work Minassian et al. put into this study, it has only heuristic value. Nevertheless, scientifically inexperienced legal professionals would not hesitate to use this study for their cause. Even before Minassian et al.'s study, we were bombarded with recruitment commercials on TV for class-action lawsuits by some lawyers citing research results. We as researchers have to be cognizant of these facts in what we publish.

Reference:

1. Tonetti MS, D'Aiuto F, Nibali L, et al. Treatment of periodontitis and endothelial function. New England Journal of Medicine. 2007;356(9):911 -20.

Conflict of Interest:

None declared

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Summary for Patients

Invasive Dental Treatment and Risk for Vascular Events

The summary below is from the full report titled “Invasive Dental Treatment and Risk for Vascular Events. A Self-Controlled Case Series.” It is in the 19 October 2010 issue of Annals of Internal Medicine (volume 153, pages 499-506). The authors are C. Minassian, F. D'Aiuto, A.D. Hingorani, and L. Smeeth.

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