Australian Dental Journal

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1 Australian Dental Journal The official journal of the Australian Dental Association SCIENTIFIC ARTICLE Australian Dental Journal 2012; 57: doi: /j x Association between long-term aspirin use and periodontal attachment level in humans: a cross-sectional investigation M Faizuddin,*à F Tarannum,*à N Korla,* S Swamy *Department of Periodontics, MR Ambedkar Dental College and Hospital, Bangalore, Karnataka, India. Department of Periodontics, KLE Institute of Dental Sciences, Bangalore, Karnataka, India. àthe first and second author share the first authorship. ABSTRACT Background: Pharmaceutical inhibition of host response pathways may be an adjunctive or alternative strategy for treating periodontal diseases. In addition to inhibition of prostaglandin synthesis, aspirin is known to modify the action of cyclooxygenase, changing its activity to a lipoxygenase and leading to formation of lipoxins which have a proresolving effect. This study evaluated the periodontal attachment level of subjects on long-term low dose aspirin therapy. Methods: Oral hygiene index simplified, clinical attachment loss and bleeding index were recorded for 162 subjects who were on long-term (>6 months) low dose (75 mg and 150 mg) aspirin therapy (study group) and 146 subjects not taking the drug (control group). Results: Mean clinical attachment loss was 2.38 ± 0.49 mm in the control group and 2.01 ± 0.69 mm in the study group. The difference was statistically significant at p < Correlation analysis suggested that there was a negative correlation between clinical attachment loss and duration of aspirin intake but the clinical attachment loss was not significantly different in the two dosage groups. Conclusions: The results of this study suggest that low dose aspirin may reduce the risk of periodontal attachment loss. This hypothesis needs to be tested by larger sample sized prospective cohort studies. Keywords: Clinical attachment loss, low dose aspirin, lipoxins, periodontal disease. Abbreviations and acronyms: BI = bleeding index; BOP = bleeding on probing; CAL = clinical attachment loss; CHD = coronary heart disease; GCF = gingival crevicular fluid; OHI-S = oral hygiene index simplified; PGE 2 = prostaglandin-e 2. (Accepted for publication 6 June 2011.) INTRODUCTION Periodontitis is an inflammatory disease which results from complex interactions between plaque microorganisms and the host immune system. 1 Various inflammatory mediators like arachidonic acid metabolites and cytokines are released as host defence during periodontal infection to counteract the bacteria. But the recent concept of host bacterial interactions suggests more than destruction by bacterial virulence; it is an imbalance in the host response that causes local tissue destruction. 2 With this current understanding of the host response and periodontal disease pathogenesis, it is intuitive that pharmaceutical modulation of host response pathways may be an adjunctive or alternative strategy for treating periodontal diseases. According to a hypothesis by Vane and Botting, 3 the anti-inflammatory effects of aspirin lie in its ability to inhibit prostanoid synthesis. Prostaglandin-E 2 (PGE 2 )is an important prostanoid product implicated in the pathogenesis of destructive periodontal disease. 3 The powerful inhibitory effect of aspirin on cyclo-oxygenase metabolites, including PGE 2, has resulted in many studies on the effects of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on periodontal diseases. 4 6 It has been demonstrated that people taking aspirin at higher doses had reduced gingival indices, probing depth and attachment loss compared to controls. 7 In humans, systemic administration of NSAIDs has been demonstrated to reduce gingival inflammation in experimental gingivitis and halt the progression of periodontal bone loss in patients with periodontitis. 8 Originally, the anti-inflammatory effects of aspirin were attributed to its interruption of the enzyme activities of cyclo-oxygenase, which converts ª 2012 Australian Dental Association 45

2 M Faizuddin et al. arachidonic acid to PGE 2. 9 Recent studies showed that aspirin causes acetylation of cyclo-oxygenase-2, redirecting its catalytic activity from generating intermediates of PGE 2 to producing intermediates of 15-epi-lipoxin-A4 (also called aspirin triggered lipoxins). 10 These lipoxins are known to bind to distinct receptors on cells that alter cell functions to drive the lesion to resolution and healing. 11 Kim et al. studied the effect of aspirin on gingival crevicular fluid (GCF) levels of inflammatory and anti-inflammatory mediators in patients with gingivitis. They concluded that after administration of aspirin for seven days, GCF levels of 15-epi-lipoxin-A4 were 500-fold higher than the concentration of naturally occurring lipoxin A4. 12 Low dose aspirin irreversibly inhibits cyclo-oxygenase over the whole lifetime of platelets and therefore is widely used by middle-aged and elderly populations because of its benefits in preventing inflammation, coronary heart disease (CHD), stroke and peripheral vascular diseases. 13,14 There is only one published report available on the effect of low dose aspirin on periodontal attachment loss. 15 Hence, in light of the above facts, the present preliminary study was conducted to investigate the association between low dose aspirin intake and periodontal attachment level with the intention of exploring the possibility of using low dose aspirin as a therapeutic modality for chronic periodontal diseases. MATERIALS AND METHODS Selection of study population This was a cross-sectional study comprising 162 subjects in the study group and 146 subjects in the control group. The study sample population was selected from the Department of Cardiology, Sri Sathya Sai Institute of Higher Medical Sciences, Bangalore, India between November 2008 to April Ethical clearance was obtained from the Institutional Review Board of Sri Sathya Sai Institute of Higher Medical Sciences. Ethical clearance was given for the examination of patients with Class I and Class II functional capacity only. 16 These patients had not undergone any surgical intervention; they were patients on regular follow-up in an out-patient department and on preventive measures. Patients were screened after granting informed consent. A total of 431 patients were screened for inclusion in the study of which 225 patients were on aspirin therapy for more than six months and 206 patients were not on aspirin. While 192 patients on aspirin agreed to participate in the study, only 162 satisfied the criteria. Of the 162 patients, 75 were on 75 mg aspirin and 87 were on 150 mg aspirin. A total of 180 patients not on aspirin Patients on aspirin (N = 225) 150 mg (N = 87) Case group (N = 192) Analysed (N = 162) 75 mg (N = 75) Assessed for eligibility (N = 431) SCREENING AND ALLOCATION Agreed to participate Satisfy criteria and confirmed eligible Fig 1. Selection of study population. Patients not on aspirin (N = 206) Control group (N = 180) Analysed (N = 146) agreed to participate and of these 146 satisfied the criteria. The flow chart in Fig. 1 depicts the selection and allocation of the study population. Inclusion and exclusion criteria To be included in the study, patients had to be over 40 years of age and with 20 teeth, excluding the third molars. Exclusion criteria included: (1) patients on any systemic antibiotics or other NSAIDs; (2) patients who smoked or used any other form of tobacco; (3) female patients who were pregnant or lactating; (4) patients who were diabetics (self reporting and laboratory assessment); (5) patients on statins; (6) patients on hormone replacement therapy; and (7) patients with prosthodontic replacements of missing teeth. Subject information Subjects completed an information sheet, signed a consent form and completed a questionnaire on demographic factors, medical and dental history (including aspirin use; dosage and duration) and smoking history. All patients included in this study were instructed to follow a fat-free diet and were regularly evaluated for lipid profile (HDL, LDL and triglycerides). Patients with changes in lipid profile that predisposed them to cardiovascular risks were strictly reminded and regulated about diet protocol. Information about aspirin use was taken from the patient s hospital out-patient 46 ª 2012 Australian Dental Association

3 Aspirin use and periodontal attachment level records and prescriptions. Patients with previous and current use were only included in the study group. The control group did not include patients with previous use of aspirin. Periodontal parameters During the oral clinical examination, the following parameters on all erupted teeth in each subject were recorded: (1) number of missing teeth excluding the third molars; (2) oral hygiene status 17 was evaluated using the oral hygiene index simplified (OHI-S); (3) bleeding on probing (BOP) was evaluated on all teeth using the dichotomous bleeding index (BI); 18 and (4) clinical attachment loss (CAL) was measured from the cemento-enamel junction to the base of the pocket at six sites per tooth (mesiobuccal, midbuccal, distobuccal, mesiolingual, midlingual and distolingual) using an UNC-15 probe. Percentage of sites with presence of BOP and mean CAL were calculated per patient. All the parameters were recorded by two experienced periodontists and the examiners were blinded about the two groups to prevent examination bias. Statistical methods Descriptive statistical analysis was carried out in the present study. Results on continuous measurements are presented as mean ± SD and results on categorical measurements are presented in number (%). Significance was assessed at the 5% level of significance. Student s t test (two tailed, independent) was used to find the significance of study parameters on a continuous scale between the two groups. Intergroup analysis and Mann Whitney U test was used to find the significance of BI (%) between the control group and the study group. Pearson s correlation was used to find the relationship between duration and study parameters. Student s t test (two tailed, independent) was used to test the homogeneity of samples based on age (or continuous parameters) and chi-square test to test the homogeneity of samples based on parameters on a categorical scale between the two groups. Multiple regression analysis was conducted with CAL as the dependent factor. The statistical significance was considered at p < RESULTS A total of 308 patients participated in this crosssectional study. Table 1 shows the mean age, CHD status and gender distribution. Mean age in the study and control group was ± 6.23 years and ± 6.70 years respectively. There was no significant difference in the mean age between the study and Table 1. Mean age and gender distribution in the study and control group Age (years) (Mean ± SD) Control group Study group P value ± ± 6.23 p = CHD status No. % No. % Class I p = Class II Gender No. % No. % Male p = 0.019* Female Total There is no statistically significant difference in age among study group and control group. There is no statistically significant difference in severity of heart disease among study group and control group. Table 2. Comparison of missing teeth, OHI-S, BI and CAL between controls and study group Mean ± SD (range) Control group Study group Significance OHI-S 2.83 ± ± 0.67 p = BI (%) ± ± p < 0.001* CAL 2.35 ± 0.47 ( ) 1.86 ± 0.60 ( ) p < 0.001* control group. Heart disease severity was not significantly different between the study and control group at p = Periodontal parameters that were compared between the two groups were OHI-S, BI and CAL. Table 2 shows a comparison of the periodontal parameters between the study and control group. Mean OHI-S was 2.83 ± 0.59 in the control group and 2.69 ± 0.67 in the study group. It was not significantly different between the two groups. Mean BI was ± in the control group and ± in the study group. Mean BI was significantly higher in the study group at p < Mean CAL was 2.35 ± 0.47 in the control group and 1.86 ± 0.60 in the study group. Mean CAL was significantly higher in the control group at p < Information was collected regarding the dose and duration of aspirin therapy for patients in the study group. There were 75 patients on 75 mg and 87 patients on 150 mg of aspirin. The periodontal parameters were compared among the two different dosage groups. Table 3 shows the mean values and significance in periodontal parameters among subjects taking 75 mg and subjects taking 150 mg of aspirin. There was no significant difference for all the periodontal parameters among the two groups. ª 2012 Australian Dental Association 47

4 M Faizuddin et al. Table 3. Comparison of OHI-S, BI and CAL between 75 mg and 150 mg dosage groups Mean ± SD Table 4. Correlation between duration of aspirin intake and study parameters Pair r value p value Duration vs. BI * Duration vs. CAL ) * Pearson s correlation coefficient was used to find the relationship between duration and study parameters. Table 4 shows the Pearson s coefficient for the correlation between the duration of aspirin intake and the periodontal parameters. As BI was measured as a percentage, Spearman s correlation was evaluated for this association. There was a positive correlation between duration and BI. This means that greater values of duration are associated with greater values of BI. But there was a negative correlation between CAL and duration of aspirin intake and this correlation was statistically significant. Table 5 shows regression analysis to evaluate the effect of aspirin s duration and dosage on CAL in the study group. We observed that both duration and dose were not significant predictors of CAL (p > 0.05). Both parameters were found to have a very low R 2 value, almost equivalent to zero, but there was a negative effect on CAL. Table 6 shows multiple regression analysis to evaluate the effect of aspirin s duration and dosage, OHI-S, Table 5. Effect of duration and dose on CAL (regression) Parameter Constant b R 2 p-value Duration ) Dose ) Table 6. Multiple regression analysis (CAL as dependent variable) Parameter b p-value Constant R 2 (adj) Age Duration ) Dose ) OHI-S * BI Dose 75 mg (n = 75) Dose 150 mg (n = 87) Significance OHI-S 2.58 ± ± * BI (%) ± ± CAL (mm) 1.82 ± ± BI and age on CAL in the study group. Among the different parameters chosen for predicting CAL, OHI-S was found to be a significant predictor for CAL (p < 0.05). For every unit increase in OHI-S, there was an increase of units in CAL. We observed that duration (greater than six months) and dosage (75 mg and 150 mg) of aspirin did not have a significant influence on CAL. DISCUSSION Periodontal disease is an inflammatory disease that is characterized by the destruction of connective tissue and alveolar bone. Introduction of an exogenous infection in the form of plaque bacteria triggers a cascade of responses in the host. Once the host response is able to contain these causative pathogens, disease is limited to gingivitis and if not, the pathogens penetrate the host tissues, stimulating the release of various inflammatory mediators which cause local tissue destruction. 19 Excessive release of the inflammatory mediators is potentially deleterious. The inhibition of inflammatory mediators represents a new equilibrium in periodontal disease intervention. 9 Attempts to inhibit an exuberant inflammatory response in tissues have traditionally involved the use of various pharmacological agents, such as non-steroidal anti-inflammatory drugs, which antagonize pro-inflammatory pathways and signalling. 1 A well-known anti-inflammatory action of aspirin is inhibition of prostaglandins, which are a major group of pro-inflammatory mediators produced via the cyclooxygenase pathway. Research in recent years has suggested that aspirin also directly modifies the action of COX-2, changing its activity towards the lipoxygenase pathway, resulting in the formation of aspirin triggered lipoxins. Lipoxins are known to inhibit neutrophils chemotaxis, superoxide generation and secretion of proinflammatory cytokines and proteolytic molecules including prostaglandins. 11 Aspirin has a well-established anti-inflammatory action at higher doses such as 600 mg to 1000 mg day. There are studies published in the literature where high doses of aspirin have been administered experimentally to evaluate the effects on periodontal inflammation. A study has demonstrated that people taking aspirin had reduced gingival inflammation, PD and CAL compared with controls. 7 However, high doses of aspirin have many side effects (gastrointestinal, bleeding disorders and hypersensitivity) and its long-term use has not been advocated since the risks outweigh the benefits. 20 Aspirin, because of its antithrombolytic effect, is widely used among patients with cardiovascular disorders for long periods at different doses ranging from 75 mg to 325 mg. 21 As stated, aspirin has proresolving properties due to the formation of 15-epi-lipoxin A4 48 ª 2012 Australian Dental Association

5 Aspirin use and periodontal attachment level which is more stable, bioactive and possesses more proresolving properties. 1 Hence, the aim of this study was to evaluate the effect of low dose, long-term aspirin intake on periodontal attachment levels. This was a cross-sectional study conducted on patients suffering from cardiovascular diseases. Periodontal and cardiovascular disease patients share common risk factors, hence CVD patients were selected for both the case and control groups to avoid any selection bias. 22,23 Patients suffering from systemic diseases are known to exhibit diminished manual dexterity and are negligent to oral hygiene practices due to their medical condition. 8 Patients who are systemically healthy are more cautious about their oral hygiene compared to systemically compromised patients. Subjects over 40 years of age were recruited as chronic periodontitis is more prevalent in this age group as are cardiovascular diseases. Since smoking is an established risk factor for both CHD and periodontal disease, current and former smokers were excluded from the study. CHD status was similar in the study and control group, hence it was less likely to be a confounding factor in our study. There was no significant difference in oral hygiene status between the study and control group. Drouganis and Hirsch also suggested that there was no significant association of aspirin intake with plaque scores. The OHI-S did not differ among the 75 mg and 150 mg group in our study. 15 Our results are similar to those reported by Royzman et al. 24 where it was stated that subjects in different aspirin dosage groups did not demonstrate a significant difference in plaque index. Percentage of bleeding sites was significantly higher in the study group compared to the control group. This difference in bleeding tendency can be attributed to the well-established antithrombolytic effect of aspirin. Our finding is in accordance with a previous study 24 which stated that patients on aspirin therapy exhibited more BOP as compared to the non-aspirin takers. In the abovementioned short-term experimental study, placebo had no significant effect on BOP relative to baseline while both 81 mg and 325 mg did have an effect on BOP. Our results are also in accordance with Schrodi et al. 25 who investigated the antithrombolytic effects of aspirin on BOP in patients with healthy periodontium. Their results demonstrated that 81 mg (low dose) or 325 mg (regular dose) aspirin did not have an effect on BOP in healthy individuals. The results of another study showed that the effect of aspirin on BOP is dose dependant with a 10.93% increase in patients on 325 mg and a 1.62% increase in patients on 81 mg compared to the placebo. 12 Our results suggest that dosage has no significant difference on BOP. There was also positive correlation between the BI and duration of aspirin intake. The longer the duration, the greater the BOP. To the best of our knowledge, there are no published reports in the literature evaluating the effect of long-term aspirin intake on BOP for us to compare our results. Our findings lend credence to the notion that BOP may be related to an inadequate function of platelets in patients taking aspirin. A failure to take into account aspirin use in patients undergoing periodontal treatment could lead to false positive results, which in turn would lead to an improper diagnosis, treatment choice, and assessment of disease activity and disease progression. 24 The results of our study show that mean CAL was significantly higher in the control group compared to the study group. Drouganis and Hirsch 15 assessed the effect of aspirin (300 mg or less per day for at least two years) on CAL and reported results similar to our study. They stated that in aspirin takers, there was significantly less CAL than non-aspirin takers. 23 Our study also evaluated the association between duration of aspirin intake and CAL. We found a negative correlation between CAL and duration of aspirin intake but the magnitude of this correlation was very small (r = )0.088), although it was statistically significant (p = 0.032). Contradictory to our results, Drouganis and Hirsch 15 did not find any association between the duration of aspirin intake and CAL. Our study also evaluated the effect of different dosages (75 mg and 150 mg) of aspirin intake on CAL, but we did not observe any significant difference in CAL. To our knowledge, there is no published data on the effect of variations in dosage of aspirin on CAL. The only other study which dealt with the effect of aspirin on periodontal status was by Kim et al. 12 They assessed probing pocket depth in healthy volunteers on aspirin (81 mg and 325 mg day) for a period of seven days. Though our results cannot be directly compared to theirs, in their study there was a resolution of inflammation which resulted in reduction of probing pocket depth. CAL is a more effective measure of periodontal destruction rather than probing pocket depth, 26 hence we evaluated the effect of aspirin use at different doses and duration on CAL. The results of this study should be interpreted cautiously in light of its limitations as indicating that aspirin may have a role in reducing the rate of attachment loss could be used as a therapeutic modality to treat periodontal disease. This was a cross-sectional study with parameters recorded at one point of time, whereas a cohort study design with follow-up would have been preferable. The number of missing teeth excluding the third molars in each individual were recorded, but the reasons for their loss was not recorded and tooth loss could mirror periodontal disease severity. The selected subjects were on a strict fat-free diet according to the regulations for CHD prevention and monitored regularly for hyperlipidaemia. Although the ª 2012 Australian Dental Association 49

6 M Faizuddin et al. patients lipid profiles were regularly evaluated, we did not record the data for statistical analysis and interpretation. It is possible that variations in lipid intake could have influenced the results. There is now a considerable amount of evidence which implicates the products of arachidonic acid metabolism in the pathogenesis of periodontal disease and pharmaceutical inhibition of these host response pathways may be used as an adjunctive or alternative strategy for treating periodontal diseases. 18 Aspirin, one of the most commonly used drugs, is a preventive for several chronic diseases with inflammatory aetiologies. Although periodontitis is a common inflammatory oral disease, the effect of aspirin on periodontitis is poorly understood. The present study is a preliminary investigation addressing the association between aspirin use and periodontal attachment level. Though the results of our data indicate that periodontal status measured as CAL is significantly better among regular long-term aspirin users compared to non-aspirin users, it may be premature to conclude that use of aspirin as a therapeutic modality for the treatment of periodontal diseases is beneficial. This hypothesis needs to be further confirmed by large sampled well-designed multicentre prospective cohort studies. ACKNOWLEDGEMENTS The authors thank Dr Hemalata M, Principal, MR Ambedkar Dental College and Hospital, for her cooperation during the study. The authors acknowledge the clinical facilities provided by Sri Sathya Sai Institute of Higher Medical Sciences, Bangalore, Karnataka, India. Statistical assistance was provided by Mr Thejasvi from Bangalore, Karnataka, India. REFERENCES 1. Van Dyke TE. The management of inflammation in periodontal disease. J Periodontol 2008;79(Suppl 8): Kantarci A, Van Dyke TE. Resolution of inflammation in periodontitis. 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Crit Rev Oral Biol Med 2004;15: Royzman D, Recio L, Badovinac RL, et al. The effect of aspirin intake on bleeding on probing in patients with gingivitis. J Periodontol 2004;75: Schrodi J, Recio L, Fiorellini J, Howell H, Goodson M, Karimbux NY. The effect of aspirin on periodontal parameter bleeding on probing. J Periodontol 2002;73: Page RC, Eke PI. Case definitions for use in population-based surveillance of periodontitis. J Periodontol 2007;78: Address for correspondence: Dr Fouzia Tarannum 79 13, 5th Cross Pillanna Garden, 1st stage Bangalore India dr_fouzta@indiatimes.com 50 ª 2012 Australian Dental Association