Effect of Intensive Periodontal Therapy on Vascular Function
Condition: Periodontitis
MeSH terms: Periodontitis
Study type: Interventional
Phase: Phase 3

Summary: 
      The hypothesis of the existence of a causal association between the systemic
      infectious/inflammatory burden represented by periodontitis and endothelial function assessed
      by flow mediated dilatation of the brachial artery (FMD) is the subject of the proposed
      investigation.

      The objective of this randomized controlled clinical trial is to evaluate the effects of
      periodontal therapy on endothelial function assessed by Flow mediated dilatation (FMD).

      The rationale for this project is twofold:

        -  Establish the extent of acute systemic inflammation and endothelial dysfunction
           associated with the delivery of subgingival instrumentation for the treatment of chronic
           periodontitis

        -  Establish whether or not improved control of chronic periodontal infections results in
           improved endothelial function and thus the existence of a causal association between
           periodontitis and endothelial dysfunction.
    

Detailed description: 
      In the last decade considerable evidence has supported the hypothesis that chronic low-grade
      infections, periodontitis included, and the inflammatory responses associated with them may
      play a significant role in the onset of atherosclerosis. An inflammatory alteration of the
      normal endothelial activity is thought to be one of the mechanisms that may link infection
      with atherosclerosis. It consists of loss of the normal vasodilation, antiplatelet and
      antithrombotic properties of the vascular walls and it is frequently called endothelial
      dysfunction. Impaired endothelium-dependent dilatation, an early functional marker of
      endothelial dysfunction has been demonstrated in young populations with family history of
      cardiovascular diseases. In the past 15 years a new non invasive and reproducible technique
      called Flow mediated dilatation (FMD) has been used to assess endothelial function.

      Periodontitis is a chronic infection of the tooth supporting apparatus caused primarily by
      anaerobic gram negative bacteria organised in a biofilm (commonly known as sub-gingival
      dental plaque); it leads to inflammatory destruction of the periodontal ligament and alveolar
      bone and eventually to tooth exfoliation. Periodontitis is highly prevalent in both
      industrialised and developing countries with 10-15% of the adult population being affected by
      severe forms of this disease. Recognized risk factors include genetic polymorphisms in
      inflammatory genes, environmental exposures such as cigarette smoking, and systemic diseases
      such as diabetes. Local periodontal production of prostaglandins and pro-inflammatory
      cytokines has been associated with activation of matrix metalloproteinases and eventually to
      destruction of the periodontal ligament and alveolar bone. It is the primary cause of tooth
      loss in adult populations and as such leads to long term disability and increased treatment
      needs.

      Local periodontal infections have been associated with a systemic response characterized by
      increased serum levels of C-reactive protein (CRP), hyper-fibrinogenemia, moderate
      leukocytosis, as well as increased serum levels of IL-1 and IL-6 when compared with
      unaffected control populations.

      Several epidemiological studies have associated increased levels of acute phase markers with
      higher risk for cardiovascular atherosclerotic events. Among these markers, C-reactive
      protein is considered to be one of the most sensitive and probably to be an independent risk
      factor of atherosclerosis. It is produced by the liver presumably for adaptive or defensive
      reasons in response to a variety of inflammatory stimuli, including chronic low grade
      infections.

      In a recently completed pilot trial we have been able to establish that treatment of
      periodontal infections resulted in a significant decrease in serum CRP. In that study,
      treatment of periodontal infections led to a significant decrease in serum CRP (0.5 mg/L, 95%
      CI 0.4 to 0.7 mg/L) and IL6 in otherwise healthy individuals affected with severe,
      generalized periodontitis and indicated that periodontitis contributed to the systemic
      inflammatory responses.

      The treatment associated decrease in systemic inflammatory markers observed in this study
      supports the hypothesis that periodontal infections, along with chronic low grade infections
      in other body districts, contribute to the inflammatory burden of an individual and may play
      a contributory etiologic role in atherosclerosis. It remains to be established whether or not
      the observed improvements in serum CRP have an impact on functional vascular parameters and
      endothelial function/dysfunction.

      The relationship between periodontal treatment and changes in serum CRP is likely to be
      bimodal: an increase associated with the delivery of the standard subgingival instrumentation
      and the associated bacteremia and tissue damage is expected shortly after treatment is
      delivered.

      Preliminary trials from our group aimed at the establishment of the pattern of CRP changes in
      the first days following delivery of periodontal therapy. The data indicate that serum CRP
      levels sharply increase after treatment but that values tend to return to baseline levels by
      one week. This bimodal pattern of changes in serum CRP levels is important since previous
      investigations have established links between functional vascular parameters such as flow
      mediated dilatation (FMD) and serum markers of systemic inflammation such as CRP.

      Periodontal therapy therefore may lead to an initial improve FMD parameters in subject were
      periodontitis contributes to systemic inflammation and atherosclerosis. The hypothesis of the
      existence of a causal association between the systemic infectious/inflammatory burden
      represented by periodontitis and endothelial function assessed by FMD is the subject of the
      proposed investigation.

      Compare the effects of an intensive periodontal treatment regimen with a community based
      periodontal care approach in terms of changes in:

        -  Flow mediated dilatation of the brachial artery (primary outcome)

        -  Acute phase response in serum (CRP, IL-6,fibrinogen)

        -  Clinical periodontal parameters: PI, BoP, PPD (CAL)

        -  Presence of periodontal pathogens in the periodontal pockets before and after treatment

        -  Patient perception and adverse events associated with the treatment experience This will
           be a randomized controlled clinical trial. Its design will be parallel arm, single
           blind; outcomes will be evaluated over a 6 months period and will include approximately
           120 subjects. Two interventions will be compared: test treatment will be an intensive
           regimen of periodontal therapy consisting of oral hygiene instructions and subgingival
           debridement delivered at two appointments over a 24 hour period; control treatment will
           consist of a community based periodontal care approach consisting of supragingival
           removal of deposits delivered at two appointments over a 24 hour period. The control
           group will receive the intensive regimen upon completion of the study or upon evidence
           that periodontitis is progressing. Subjects with moderate to severe periodontitis will
           be recruited among those referred for care to the Periodontal Clinic of the Eastman
           Dental Hospital. The primary outcome measure of this study will be changes in Flow
           Mediated Dilatation (FMD) of the brachial artery. Secondary outcomes will include
           changes in serum CRP and plasma fibrinogen. Periodontal, microbiological and subjective
           outcomes will be evaluated as control outcomes. The primary and the secondary outcome
           variables will be evaluated before treatment and at 1 day, 7 days, 2 months and 6 months
           following completion of treatment. Subjects will be randomized to treatment stratifying
           for smoking status by a study registrar. Treatment allocation will be concealed to study
           personnel by using opaque envelopes and to the examiner by making treatment records
           unavailable. All laboratory and FMD analyses will be performed by unrelated study
           personnel blind with respect to treatment allocation or stage of progression of the
           trial. Intent to treat analyses will be performed by a statistician blind with respect
           to treatment allocation.
    

Intervention name(s): Intensive periodontal therapy; Community based periodontal therapy
Intervention type(s): Procedure; Procedure
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double
Primary purpose: Treatment
Keywords: Inflammation; Periodontitis; Endothelial function; Atherosclerosis; Controlled trial