Levels of clinical significance

levels of clinical significance in periodontics

1. LEVELS OF CLINICAL SIGNIFICANCE Presented by: d.Hema Pg -ii

2. Introduction Terminologies Clinical significance Statistical significance How to make “clinically significant more relevant to the clinician???” Tangible vs Intangible benefits Size of the treatment effect Levels of clinical significance Periodontal applications Conclusion Contents

3. Introduction In one study of periodontal tissue regeneration , investigators reported that treatment that resulted in a gain of 1.2 mm in clinical attachment level and a reduction of 1 mm in probing pocket depth “ may not have a great clinical impact .” ( Esposito et al. 2003 ) In another study of a local antimicrobial , the investigators reported that a treatment that resulted in a gain of 0.0 mm in clinical attachment level and a reduction of 0.2 mm in probing depth had such clinical significance that it should “be used universally . ” ( Williams et al. 2001 ) American Dental Association defined a substantial effect as a mean change in CAL greater than 0.6 mm ( smiley et al. 2015 ). These examples illustrate that different individuals will reach different decisions regarding what is meant by the term clinical significance As a result, the term clinically significant has become more useful to marketers than to clinicians .

4. Terminologies Tangible benefits are treatment outcomes that reflect how a patient feels , functions, or survives. Intangible benefits cannot be realized or perceived by the patient's mind .

5. Endpoints: A periodontal endpoint is any measurement that is thought to be related to the periodontal disease process and that is used to assess periodontal treatment efficacy. 2 types of endpoints can be distinguished: “True " endpoints: reflect unequivocal evidence of tangible benefit to the patient “Surrogate " endpoints: usually a measure of disease process . Hujoei PP, De Rouen TA: A survey of endpoint characteristics in periodontal clinical trials published 1988-1992, and implications for future studies. J Clin Periodontol 1995; 22: 397-407. © Munksgaard , 1995.

6. True endpoints are tangible to the patient. They include subjective oral health-related quality-of-life measurements, Tooth loss, painful periodontal abscesses or simple self-reported symptoms such as bleeding after brushing . True endpoints are sometimes referred to as clinically relevant endpoints, clinically meaningful endpoints, terminal endpoints, or ultimate endpoints . Surrogate endpoints are intangible to the patient’s mind. Changes in probing attachment level or gingival crevicular fluid markers are examples of changes the mind cannot identify or realize; hence they are intangible. Typical surrogate endpoints in periodontal research include anatomic measures (e.g. probing depth), measures of inflammation, microbiological measures, and immunologic measures Surrogate endpoints are sometimes referred to as intermediate endpoints, biological markers, or biomarkers.

7. A ‘ subjective’ evaluation of significance by the clinician . Before a finding can be clinically significant it must have achieved statistical significance or else it could be a chance-happening . - Killoy , 2002 . Hujoel and colleagues: suggested a working definition for clinical significance as “ statistically significant difference in a clinically important outcome identified in a definitive or phase III clinical trial .” definition of clinical significance varies depending on the specific clinical field being addressed , size of the effect, measurement used to evaluate a therapy and clinical importance of the findings. Clinical Significance: Lindgren BR, Wielinskyi CL, Finkelstein SM, Warwick WJ. Contrasting clinical and statistical significance within the research setting. Pediatr Pulmonol 1993;16:336-40.

8. Statistical Significance: Greenstein G. Clinical versus statistical significance as they relate to the efficacy of periodontal therapy. JADA; 2003 Vol. 134, May. Also known as hypothesis testing. denotes that the associations between tested variables did not occur by chance. “ statistically significant at an α level of .05 ” means that The null hypothesis [there is no relationship regarding specific variables between test and control groups] is rejected & the chances of the association occurring by chance was small.

9. How to make “clinically significant more relevant to the clinician???” The term clinically significant could be made more relevant by recognizing the nature of the benefits (tangible/intangible) the size of the treatment effect (large/small).

10. Nature of benefits Controversies remain as to whether outcomes tested in clinical trials designed for drug approval are tangible to the patient. Some will argue that the clinical significance of a treatment should depend exclusively on whether the benefits identified are tangible or intangible to the patient who undergoes the procedure.

11. Treatment outcomes that reflect how a patient feels , functions, or survives. Examples: improved oral health–related quality of life, decrease in self-reported symptoms (e.g ., bleeding ) after brushing, prevention of tooth loss, elimination of a painful periodontal abscess. These can be precisely identified or realized by the patient's mind — i.e , they are tangible. Also be referred to as “ clinically relevant” or “clinically meaningful” benefits. Tangible Benefits

12. cannot be realized or perceived by the patient's mind. Examples: Changes in probing attachment level as a result of scaling , Changes in bone fill, depth etc after regeneration Changes in enamel mineralization level as a result of fluoride application , Changes in the size of a periapical radiolucency as a result of root canal treatment. Intangible treatment benefits can often be measured objectively by the clinician or by laboratory methods . Intangible benefits

13. First and most important step in assessing the clinical significance of a treatment is to determine whether the documented treatment benefits are tangible or intangible. This distinction is important because intangible benefits often do not translate into tangible benefits. A treatment that increases bone density  an intangible benefit can increase fracture risk  a tangible harm . A treatment that provides extensive periodontal bone regeneration  an intangible benefit may lead to tooth loss  a tangible harm .

14. A treatment showing tangible benefits has a higher level of clinical significance than a treatment for which only evidence of intangible benefits exists. The finding that implant-supported dentures improve quality of life (tangible) has a higher level of clinical significance than the finding that scaling increases probing attachment levels (intangible).

15. Size of the Treatment Effect A second important criterion for assessing clinical significance It is a comparison of the success rates of the experimental treatment and the control treatment. This comparison can be a subtraction of the success rates , division of the success rates, or some other mathematical operation. Regardless of how it is calculated, larger the size of the treatment effect, higher is the level of clinical significance

16. N umber needed to treat (NNT ) may be a good measure to separate large and small treatment effects. A large benefit is defined as one that can reliably be identified using epidemiologic methodology. If the treatment effect is large : it is easy determining the effectiveness of these treatments and sufficient to convince an audience. Ex : general anesthesia effectiveness. A small benefit is defined as one that requires randomized controlled trials for reliable identification. If the treatment effect is small: large randomized controlled trials are required to provide reliable evidence as to whether small benefits indeed are associated with treatment. Ex: effect of local antibiotics in the treatment of periodontitis.

17. Defining Four Levels of Clinical Significance

18. Clinical Significance Level 1 Treatments of clinical significance level 1 are the “magic bullets” or “miracle cures,” in which the treatment provides a tangible benefit and a large treatment effect. Examples: use of vitamin C to treat scurvy, bone marrow transplantation to treat leukemi a, very-low-carbohydrate diet to prevent all forms of dental decay . Understanding the biologic mechanisms of a treatment is not required to establish that the treatment has clinical significance level 1. Lemon juice was identified as an effective method to prevent scurvy in 1601, but it was not until the beginning of the 20th century that vitamin C was isolated. Treatments of clinical significance level 1 are not always immediately accepted or widely used. Although it is easy to determine clinical significance level 1 in retrospect , it may be difficult to recognize at the time of discovery .

19. Clinical Significance Level 2 Treatments that have demonstrated a tangible benefit but for which the likelihood of obtaining the benefit from treatment is small . Randomized controlled trials ( RCTs ), large in size and rigorous in execution and analysis , are required to provide unequivocal evidence that the treatment provides tangible patient benefits. Examples: advantage of tissue plasminogen activator ( t-PA ) over streptokinase [GUSTO investigators, 1993] benefits of penciclovir in the treatment of herpetic lesions . [ Raborn et al. 2002 ] Determining the clinical relevance of treatments of clinical significance level 2 is an individual choice in which issues such as cost and side effects often play a more important role. For example, administering antibiotics to 25 individuals could prevent 1 person from experiencing early implant loss. [Esposito et al. 2013 ] Is a 4% increased survival probability of dental implants worth the potential side effects of antibiotics? Different individuals, different governments, and different health insurance companies may decide differently on this important question .

20. An all-or-none situation is defined as one of the following two scenarios in evidence-based medicine: either when all patients experienced an adverse tangible outcome before the treatment became available but some do not experience this adverse outcome , or when some patients experienced the tangible adverse outcome before the treatment became available but none now experience it. All-or-none situations reflect the highest level of evidence. [Phillips et al. 2009 ] Clinical Correlation: It is easy to overlook all-or-none situations in dentistry. For instance, root caries in periodontal patients can be prevented with a very-low-carbohydrate diet. Such a conclusion can be made because carbohydrates and dental caries reflect an all-or-none situation.

21. Clinical Significance Level 3 the magic bullets or miracle cures in the surrogate world, in which the beneficial but intangible effects are so convincing that the need for RCTs may appear unethical. Examples: Highly active antiretroviral therapy ( HAART) in patients with acquired immunodeficiency syndrome ( AIDS ), complete restoration of periodontal attachment and bone around teeth that had extensive destruction of the periodontal apparatus, and reconstruction of voluminous amounts of bone on an atrophic mandible for the purpose of placing dental implants . With a treatment that has the label “clinical significance level 3,” there is always uncertainty as to whether the intangible benefits translate into real, tangible patient benefits . For instance, bone marrow transplantation to the periodontal defect indeed resulted in regenerating prodigious amounts of bone, but about 50% of the teeth were lost due to root resorption . [ Hujoel , 2004] Nonetheless, the larger the effect size observed on the surrogate, the more likely the surrogate benefit translates into a real, tangible patient benefit. [Fleming et al. 1994 ]

22. Clinical Significance Level 4 Treatments that have reliable evidence on small, intangible treatment benefits. Epidemiologic studies are incapable of identifying treatments of clinical significance level 4. Rigorously conducted RCTs are necessary to reliably identify a small surrogate benefit. Examples : treatments that cause a small decrease in lipid level , a small drop in blood pressure, or a small decrease in pocket depth. A large leap of faith is often required to jump from the observation that small changes in surrogate endpoints translate into real, tangible benefits . Treatment of clinical significance level 4 may cause more harm than good . [ Psaty et al. 1999] This observation has significant consequences in periodontics, because approved periodontal therapies are commonly of clinical significance level 4 and information on their long-term safety and lack of harm is minimal .

23. PERIODONTAL APPLICATIONS

24. Periodontal treatments are intended to provide tangible benefits to the patient such as: increased chewing comfort , Relief from pain Improved esthetics , improved digestion. decreased tooth loss (Barrington 1981 , AAP 1989a, b). Barrington. E, P, (1981) An overview of periodontal surgical procedures. Journal of Periodomology 52. 518-28,

25. Endpoints in perio

26. Endpoints in perio True endpoints oral health-related quality-of-life measurements, Tooth loss, painful periodontal abscesses or simple self-reported symptoms such as bleeding after brushing Sensitivity Esthetic treatments Surrogate endpoints PPD CAL Recession depth and width bone fill GCF markers measures of inflammation, microbiological measures, and immunologic measures

27. Endpoints in perio are classified as: Anatomic landmarks using non-invasive techniques : attachment level, pocket depth, recession, furcation, radiographic changes in alveolar bone dimensions, width of k.t Anatomic landmarks using invasive techniques : histologic measurements on extracted teeth and surgical re-entry Inflammation, plaque and others : bleeding, suppuration, plaque indices, mobility and gcf flow Microbiology and miscellaneous : dark field microscope, culture and bacteriological markers hujoei and rouen , 1995 Hujoei PP, De Rouen TA: A survey of endpoint characteristics in periodontal clinical trials published 1988-1992, and implications for future studies. J Clin Periodontol 1995; 22: 397-407. © Munksgaard , 1995.

28. Hujoei PP, De Rouen TA: A survey of endpoint characteristics in periodontal clinical trials published 1988-1992, and implications for future studies. J Clin Periodontol 1995; 22: 397-407. © Munksgaard , 1995.

29. Endpoint of subgingival debridement Immediate end point Theoretically, the immediate end point of subgingival debridement is disruption and/or removal of biofilm so that a root surface is obtained that is biologically acceptable for the (re)attachment of periodontal tissues. the clinical end point of debridement is achieved by removing all detectable biofilm from the root surfaces. SRP endpoint can be measured based on the smoothness of the root surface. Although reattachment, after scaling and root planing, on subgingival calculus and any remaining biofilm has been described in the literature, removal of all subgingival calculus and leaving a smooth root surface is still the clinical end point for SRP .

30. Clinical Significance In Perio

31. Clinical significance of local chemotherapies Killoy WJ: The clinical significance of local chemotherapies. J Clin Periodontol 2002; 29 ( Suppl 2): 22–29. # Blackwell Munksgaard , 2002. LDD as adjunct to SRP Clinical significance CHX chip, Doxy gel, Mino spheres Improvement of 2mm PD Same with CAL (Doxy gel) Doxycycline gel & Minocycline spheres Non-significant worsening of >/= 2mm of PD Same with CAL (Doxy gel) Doxy gel in PD 5-6mm Improved to 5 mm in 69% of sites at 3 months 60% C.S than SRP Doxy gel in > 5mm PD Improved to 5 mm in 58% of sites at 3 months 50% C.S than SRP Mino spheres in > 6mm PD Reduction in PD to < 5mm at 9 months in 65% of sites 35% C.S than SRP

32. Morbidity for all systems: low and similar to SRP . Time taken to treat: less  Chlorhexidine chip, doxycycline gel and minocycline microspheres. Combined use of doxycycline gel and debridement significantly reduced total treatment time compared with SRP (1 h and 11 min). Cost: of adding chlorhexidine chip to treatment regimens is partially offset by reduced surgical costs.

33. Tools to assess true endpoints Visual Analog Scale (VAS) Self-reported questionnaires Oral health related quality of life assessment

34. Summary