An introduction to evidence-based practice and the effectiveness of antibiotic prophylaxis MARCO ESPOSITO Senior Lecturer Lect rer in Oral and Maxillofacial Ma illofacial Surgery S rger Director of the Postgraduate Courses in Dental Implantology Editor of the Cochrane Oral Health Group The University of Manchester, UK Assoc Prof in Biomaterials, Gรถteborg University, Sweden Editor-in-Chief or the European Journal of Oral Implantology (EJOI) Editor of the Rivista Italiana di Stomatologia (RIS)
Conflict of interests - consultant for: Apollonia e Fama Implants srl Biomax srl Biomet o e 3i 3 Bioteck srl Bone System y srl Br책nemark Integration AB CMS Dental Dentsply-Friadent AG Geistlich Pharma AG Geass srl MegaGen g Implant p Co
Nano Bridging Molecules SA Nobel Biocare Ricerfarma ce a a srl s Saint Jude Medical Inc Southern Implants S p Tecnoss Dental srl Thommen Medical AG Tutogen Medical GmbH Zimmer Dental Z-System AG
Why we do clinical research? 1. To get an academic promotion? 2. To show colleagues how good we are? 3. To show how good is the product I wish to sell? 4. To save money y for national health services? 5 To solve clinical problems for helping patients? 5.
Why reliable clinical research is needed? Evidence-based clinical research should help people to take the right clinical decisions: - Which is the best implant surface? - May I load the implants immediately? - Is GBR needed to cover an implant fenestration?
What is evidence-based practice ( (EBP)? ) The integration of best clinical research evidence with individual clinical expertise and patient ti t values l
How does the process of EBP work? • Formulate a clinical question • Find the evidence • Critically appraise the evidence • Act on the evidence
Why EBP is needed? Clinical Cli i l decisions d ii should h ld be b based b d on updated and reliable evidence and not on p personal opinions p (opinion-biased practice)
YOU CANNOT MAKE AN INFORMED DECISION WITHOUT INFORMATION BUT NOT ALL INFORMATION IS CREATED EQUAL
Wh t iis the What th clinical li i l question? ti ? • Diagnosis • Prognosis • Treatment • Risk / Benefit • Cost effectiveness
How do we discriminate between reliable and p poor clinical research?
CRITICAL APPRAISAL The process of assessing and interpreting evidence through the systematic consideration off its i (internal) (i l) validity lidi andd relevance l
INTERNAL VALIDITY Th degree The d to t which hi h th the results lt off a study t d are likelyy to approximate pp to the ‘truth’ How well the studyy is conducted
EXTERNAL VALIDITY The degree to which the results of a trial hold true in another setting
IS CRITICAL APPRAISAL NECESSARY? is ABSOLUTELY necessary to limit BIAS since there are so many poor quality studies whose claims should be discounted
Critical appraisal is a very difficult process since there are no “absolute rules” p
BIAS A systematic error or deviation in the results occurring in a study determining a difference between the obtained results and the results we should have obtained in absence of bias
TYPES OF BIAS • Publication bias: bias towards positive results • Selection bias: systematic differences in groups that are compared p • Performance bias: exposures to other factors apart from the intervention of interest • Attrition bias: withdrawals or exclusion of subjects j entered into a study • Detection bias: how outcomes are measured • Commercial bias: the tendency y for the sponsored p intervention to be more effective than what actually is
Different studyy designs g answer different q questions QUESTION
IDEAL STUDY DESIGN
Therapy
Randomised controlled trial (RCT)
S Screening i
Cross-sectional C ti l survey (prevalence) ( l ) RCT to assess efficacy
Diagnosis
Cohort study (incidence) RCT to assess efficacy
Prognosis g
Cohort studyy
Causation
Cohort study (in the case of very rare conditions diti useful f l information i f ti may be b derived d i d from case control studies and case reports)
The most common clinical study designs are - Case report/case series - Cross-sectional Cross sectional surveys - Case-control studies - Cohort studies - Randomized controlled clinical trials (RCTs)
Case reports/case series describes the medical history of a single patient (case report) or a series of patients (case series) with i h a particular i l condition di i Appropriate for describing rare adverse events: - 2 newborn babies do not have limbs (p (phocomelia)) and both mothers took a new drug (talidomide)
Inappropriate for describing treatment efficacy: - A technique q to rebuild the interdental p papilla p works
Cross sectional surveys Synonyms: y y p prevalence study, y, disease frequency q y survey A representative samples of subjects is examined t answer a specific to ifi clinical li i l question ti (i.e. (i prevalence of a disease at a particular time) - How many implants are affected by peri-implantitis 5 years after their placement?
Cause effect relationships cannot be established Cause-effect
Case control studies Case-control Patients with a particular disease (or other outcome variables) of interest are “matched� with suitable controls without the disease despite having or not the suspected risk factors of the disease Concerned with the aetiology of a disease (what cause the disease and not how to treat it) Less reliable than cohort studies but are the only option for rare conditions diti Retrospective by definition since it starts after the onset of the disease and looks back to the postulated casual factors
E Example l off a case-control t l study t d Can talidomide cause limb malformations (phocomelia) in newborns? Select a group of phocomelic babies and match it with a group of healthy babies calculating the proportion of mothers who took talidomide during pregnancy for both groups
Cohort studies Synonyms: y y concurrent,, follow-up, p, incidence,, longitudinal, prospective studies 2 or more groups of people are selected on the basis of differences in their exposure to a particular agent and followed up to see how many in i each h group develop d l a particular ti l disease or other outcome Large number of patients followed up for long periods (years)
Cohort studies - Ideal study design to determine the prognosis of a disease (i.e. what is likely to happen to someone who has it) and “cause-effect” relationships - In the 1950, 40.000 doctors were divided into 4 cohorts (non-smokers, light, moderate and heavy smokers) smokers), a “dose-response” dose-response relation was found (i.e. the more you smoke, the greater are the chances to get lung cancer)
Randomised controlled clinical trials - Is a controlled trial in which participants are allocated at random to receive one of the several clinical interventions - Ideal study design to assess treatment efficacy since randomisation is the only way to control for confounding factors which are not known or measured, thus minimizing bias
Why not using other types of study t d d design i tto assess efficacy? ffi ? - More uncertainty with non non-RCTs RCTs - Non-RCTs are much more difficult to assess
Types of RCTs - Explanatory RCT: aimed to understand how things happen (efficacy of a bone substitute to form more bone in a sinus) - usually single centre - strict inclusion criteria - complex surrogate outcomes: quantification of subtle tissue volume changes, histomorphometry, bacteriological evaluation
- Pragmatic RCT: aimed to evaluate how things go in clinical practice (effectiveness of antibiotic prophylaxis) - Usually large multicentre trials including many patients - broad inclusion criteria - using few primary outcomes: prosthesis and implant failures, p complications
HIERARCHY OF EVIDENCE FOR THERAPEUTIC EFFICACY STRONG Randomized controlled clinical trials - Systematic review of IPD RCTs - Systematic review of RCTs - multiple confirmatory RCTs - single RCT multicenter-monocenter
WEAK
Controlled clinical trials Controlled observational studies Observational studies without controls C Case reports, expert opinions, i i consensus
The choice of a correct study design is not a synonymous of study quality Within a particular Withi ti l study t d design d i there th iis a huge h variability between studies with regard to their execution It is the task of the reader to evaluate the quality of the study and to identify flaws
Essential questions to evaluate RCTs - Was the sample size calculated?
- Were the treatments randomly allocated ( ll (allocation i concealment?) l ?) - Were outcomes assessed blind? - Were all the patients accounted for?
BLINDING Used to keep the study subjects, therapy providers, g about outcome assessors and statisticians ignorant the interventions participants received (PLACEBO) Not always possible to blind those providing/receiving care (surgical interventions) i d independent d t assessors should h ld b be used d iinstead t d
PRIMARY AND SECONDARY OUTCOMES PRIMARY or TRUE OUTCOMES: those having a tangible influence on the patient’s life (function of the prosthesis, h i absence b off pain, i aesthetics, h i etc)) SECONDARY or SURROGATE OUTCOMES: those yp predict the p primary y outcomes (p (plaque, q , which may bleeding, pocket depths, marginal bone levels, etc) Be careful since they can induce to wrong conclusions
What implications for your practice? - How big was the effect? - Was the effect clinically important? - Is the paper of good quality? - Are the findings likely to be true? - Is your patient similar to those evaluated in the trial? - The conditions in which the study was carried out resemble the circumstances of your practice?
Where to find the best evidence? •A Ask k someone with ith more ““experience”? i ”? usually “opinion opinion biased practice” practice • Consult a textbook? not peer reviewed • Search an electronic database for articles - PubMed, P bM d Embase, E b The Th Cochrane C h Library Lib
Where to easily access scientific evidence? U d d review Updated i off the h li literature Unfortunately the quality of many narrative reviews is not optimal, since often - not structured in a systematic way - do not follow the scientific principles of objectivity in data collection and interpretation
Systematic reviews and meta-analyses meta analyses • Systematic reviews (SRs) employ explicit and rigorous methods to identify, critically appraise and synthesize relevant research for limiting bias t reach to h evidence-based id b d conclusions l i • A meta-analysis is a statistical technique for combining quantitative data to estimate a common pooled effect with increased precision used in a systematic review
When systematic reviews are particularly useful? - Results from several studies disagree regarding magnitude or direction of effect - Individual sample sizes are too small to detect a statistical significance
How should be a systematic review? • If dealing with therapies/prevention, it must
be b b based d on RCT RCTs, since i th they offer ff th the hi highest h t provide more reliable information chance to p • Non N RCT RCTs tend t d tto overstimate ti t intervention i t ti effects
Who makes systematic reviews? The COCHRANE COLLABORATION (www cochrane org): an international (www.cochrane.org): collaboration aimed to help people making well informed decisions by preparing and maintaining SRs on risks/benefits of healthcare interventions
MAIN QUESTIONS ANSWERED BY A META META-ANALYSIS ANALYSIS 1) In which direction goes the treatment effect? 2) How big is the treatment effect? 3) Is I th the ttreatment t t effect ff t consistent i t t among studies? t di ?
SUMMARY 1 • Evaluate the appropriateness of the study design to answer your question • When evaluating the effectiveness of an intervention look for SYSTEMATIC REVIEWS of RCTs or RCTs • If SR/RCTs are not available then consider the next best level of “inferior” inferior evidence (cohort studies) with extreme caution! • Whichever level of evidence you consider, the validity and the clinical utility of the study have to be critically evaluated
SUMMARY 2 • Identify the main flaws which may actually alter significantly the results • Decide whether the results are transferable to your population of interest • Use your head, read all the paper carefully, do not trust what is written in the conclusions alone
Wh t iis needed? What d d? - Better research
- Balanced information (benefits/harms) “We need less research, better research, and research done for the right reasons� Altman DG 1994
SUGGESTED READING 1) The pocket guide to clinical appraisal. Crombie IK. B iti h Medical British M di l Journal J l Publishing P bli hi Group, G L d London, 1996 2) Cochrane Handbook for Systematic Reviews of interventions. Higgins JPT, Green S, editors. WileyBlackwell, Chichester, 2008 http://www.cochrane.org/resources/handbook/hbo ok htm ok.htm 3) ….. and especially for clinicians seeking for evidence-based answers to clinical questions……
Reliable clinical articles related to the practice of oral implantology and related disciplines Updated evidence-based information to help clinicians take th b the bestt d decisions ii ffor th their i patients Systematic reviews, RCTs, cohort and case-control studies http://quintessenz.de/ejoi h // i d / j i
Clinical question Are antibiotics effective in reducing complications li ti and d implant i l t failures? f il ?
Background Osseointegrated dental implants used since 1965 Various antibiotic prophylactic types/regimens have been recommended ranging from: 2 g of penicillin-V 1 hour preop + 2 g twice a day for 10 days to
no antibiotics
B k Background d There could be adverse events associated with antibiotics ranging from: di h diarrhoea, erythema h multiforme, l if urticaria, i i etc to life-threatening allergic reactions risk of selecting antibiotic-resistant bacteria
WHERE TO FIND THE EVIDENCE? Esposito, Cannizzaro, Bozzoli, Checchi, Ferri Landriani Ferri, Landriani, Leone, Leone Todisco, Todisco Torchio, Torchio Testori, Galli, Felice Effectiveness of prophylactic antibiotics at placement of dental implants: a pragmatic multicentre placebo-controlled randomised clinical trial 2010; 3: 101-110 Conflict of Interest: self-funded study Antibiotics & placebo kindly donated by Merk Generics Italia
Aim Ai To evaluate the effectiveness of a single dose 2 g amoxicillin administered orally 1 hour before implant p p placement STUDY DESIGN Pragmatic multicenter placebo-controlled placebo controlled randomised clinical trial
Inclusion/exclusion criteria Any patient undergoing implant placement Apr 2008 – Nov 2009 Excluded if: 1) at risk of bacterial endocarditis (as decided by the cardiologist) 2) having implanted biomaterials (hip or knee prostheses, etc.) 3) immunosuppressed or immunocompromised 4) affected by controlled or not diabetes 5)) radiotherapy py in the head and neck area 6) need of augmentation procedure at implant placement 7) allergic to penicillin 8) chronic/acute infections at implant sites 9) already under antibiotic treatment 10) treated or under treatment with intravenous amino amino-bisphosphonates bisphosphonates 11) pregnant and lactating g an informed consent 12)) less than 18 yyear old or not able to sign 13) already included once in the present study
Outcome measures 1) Prosthesis failure 2) Implant failure: - implant mobility - any infection dictating implant removal Implant stability was tested at 4 months by tightening the abutment with a 20 20-30 30 Ncm torque 3) Any complication 4) Any adverse event Outcomes recorded at 1, 2 weeks and 4 months All assessments made by treating dentists who remained unaware of group allocation for the entire study duration
Methodological aspects • Computer generated randomisation lists with equal number b off participants ti i t • Randomised codes enclosed in envelopes p opened p 1h prior to implant placement (concealed allocation) • Triple blind: – Patient – operator/outcome assessor – statistician
• S Sample l size i for f detecting d i a difference diff in i implant i l failure f il from 1 to 5%: 333 patients per group
Clinical procedures • Patients recruited in experienced Italian private clinics • All p patients underwent at least 1 session of oral hygiene • 1 h prior to implant placement patients were randomised to receive amoxicillin (2 1g tablets) or 2 identical placebo tablets • All patients rinsed for 1 min prior to implant placement l t with ith chlorhexidine hl h idi 0.2% 0 2% • Operators p were allowed to p place and restore the implants according to their routine procedures
Results • 13 centres agreed g to p participate p • Each centre had to recruit 50 patients: 25 per group f a total for t t l off 650 patients ti t • 1 centre withdrew from the study y • 1 centre did not deliver any data • 1 centre t gave all ll th the study t d material t i l to t another th centre that therefore recruited 100 patients • 2 centres recruited only 34 and 25 patients
Results 781 patients screened for eligibility 183 patients did not meet the inclusion criteria 89 patients did not want to join the trial 509 patients randomised and treated at the 10 centres but 3 patients had to be excluded because: – 1 included twice in the study (only data of the 1st intervention evaluated) – In 1 patient was not possible to place the implant – Data D off 1 patient i was llost by b the h treating i centre
506 patients evaluated: 252 antibiotic - 254 placebo
PROTOCOL DEVIATIONS A i i i group (3): Antibiotic (3) 2p patients received p post-op p antibiotics ((1 was augmented) g ) 1 insulin-dependent diabetic was included
Placebo group (9): 5 patients received post-op antibiotics (1 was augmented) 4 non insulin dependent diabetics were included non-insulin A single centre accounted for 67% exclusions & 50% deviations
Results • All patients treated according to the allocated interventions, none dropped out • No apparent baseline imbalances between the 2 groups • Implants used: Zimmer Dental, Dentsply, Friadent, Nobel Biocare, Intra-Lock, Intra Lock, Camlog, Dyna, Biomet 3i, Endopore, Z-system, PF Tecom, Ghimas, Silpo, MegaGen Geass MegaGen,
Patient/intervention characteristics Amoxicillin n = 252
Placebo n = 254
Females
138 (54.8%)
132 (52.0%)
Mean age at implant insertion (range)
49 1 (18 49.1 (18-85) 85)
47 6 (18 47.6 (18-86) 86)
Non-smokers
171 (67.9 %)
166 (65.4%)
Smoking up to 10 cigarettes/day
55 (21 (21.8%) 8%)
60 (23 (23.6%) 6%)
Smoking more than 10 cigarettes/day
26 (10.3%)
28 (11.0 %)
Duration of the intervention in min (range)
32 (4-190) (4 190)
31 (5-180) (5 180)
Total number of inserted implants
489
483
Implants in fresh extraction sockets
60
76
Took post-op antibiotics
2 (0.8%)
5 (2.0%)
Intra-op complications
8 (3.2%)
7 (2.8%)
Di t ib ti off ffailures Distribution il and d complications li ti Amoxicillin n = 252
Placebo n = 254
P values
Patients who had a prosthesis failure
4 (1.6%)
10 (3.9%)
0.11
Patients who had implant failures
5 (2.0%)
12 (4.7%)
0.09
Patients who had adverse events at 1 week
0 (0%)
0 (0%)
1.00
Patients who had complications at 1 week
6 (2.4%)
7 (2.8%)
1.00
Patients who had complications at 2 weeks
2 (0.8%)
4 (1.6%)
0.69
Patients who had complications at 4 months
3 (1.2%)
2 (0.8%)
0.69
No significant difference for any outcome – no adverse events
R lt Results â&#x20AC;˘ No centre effect â&#x20AC;˘ Immediate post-extractive implants were more likely to fail (9% versus 2%, P<0.001) post-hoc analysis â&#x20AC;˘ Antibiotics did not help to reduce failures in the 99 patients ti t receiving i i immediate i di t implants i l t (P=0.48) (P 0 48)
Conclusions • N No statistically t ti ti ll significant i ifi t differences, diff however h more than the double of patients (12 versus 5) experienced early l implant i l t losses l in i the th placebo l b group • No reported p adverse events • This trial may be underpowered, therefore a metaanalysis of similar RCTs or further trials are needed to provide the definitive answer • Immediate post-extractive post extractive implants were more likely to fail • Please, keep in mind the big pictures…
WHERE TO FIND ADDITIONAL EVIDENCE? Esposito Grusovin, Esposito, Grusovin Loli, Loli Coulthard, Coulthard Worthington Interventions for replacing missing teeth: antibiotics at dental implant placement to avoid complications The Cochrane Library 2010, issue 7 Last literature search: January 2010
2010; 3: 101-110
I l i criteria Inclusion it i Any RCT with a follow-up follow up of at least 3 months including patients receiving or not antibiotic prophylaxis at implant placement
O t Outcome measures • • • •
Prosthesis success Implant success Infections Adverse events
Literature search strategy gy Electronic databases: 1) The Cochrane Oral Health Group Register 2) The Cochrane Central Register of Controlled Trials 3) MEDLINE 4) EMBASE
++ + ++ +
Handsearching: g Br J Oral Maxillofac Surg, Clin Implant Dent Rel Res, COIR, EJOI, Implant Dent, IJOMI, Int J Oral Maxillofac Surg, Int J Periodont Rest Dent, Int J Prosthod, J Clin Periodontol, J Dent Res, J Oral Implantology, J Oral Maxillofac Surg, J Periodontol, J Prosthet Dent ++
Strategies g for the identification of unpublished or ongoing RCTs - Checked reference lists of RCTs - Checked reference lists of SRs - Personal contacts - Contacted all authors of RCTs - Contacted C t t d more th than 55 manufacturers f t - Contacted a discussion group on internet - No language restriction
+ + ++ ++ +
Study selection, quality assessment, data extraction In duplicate In case of disagreement g a 3rd reviewer consulted All RCT authors contacted Statistical unit the patient and not the implant
QUESTIONS Is antibiotic prophylaxis effective? Which is the most effective antibiotic? Which is the most effective dose? When should antibiotic administered? For how long should be administered?
4 RCTs 0 0 0 0
4 included incl ded RCTs with ith 1007 patients: • Esposito E i 2008 (EJOI) (EJOI): 2 g amoxicillin i illi vs placebo l b 1 h prior i to placement in 316 patients • Abu-Ta’a 2008 (JCP): 1 g amoxicillin preoperatively + 500 mg x 4 times a day for 2 days vs no antibiotics in 80 patients • Anitua 2009 (EJOI): 2 g amoxicillin vs placebo 1 h prior to placement in 105 p p patients ((only y single g implants p in bone of medium hardness) • Esposito 2010 (EJOI): 2 g amoxicillin vs placebo 1 h prior to placement in 506 patients
Adequatte seque ence gene eration? Allocatio on conce ealment? Blinding? Incomplete outco ome data a addresssed? Free of sselective e reportin ng? Free of o other bia as?
Risk of bias Abu-Ta'a 2008 + ? â&#x20AC;&#x201C; + + +
A i Anitua 2009 + + + + + +
Esposito 2008a + + + + + +
Esposito 2010 + + + + + +
RESULTS • Prosthesis failures = no statistically significant difference y significant g difference • Infections = no statistically • Adverse events = no statistically significant difference only 2 minor adverse events events, 1 in the placebo group
RESULTS: IMPLANT FAILURES Study or Subgroup Abu-Ta'a 2008 Anitua 2009 Esposito 2008a Esposito 2010 Total (95% CI)
Antibiotics No antibiotics Events Total Events Total Weight 0 2 2 5
40 52 158 252 502
3 2 8 12
40 53 158 254
Risk Ratio M-H, Random, 95% CI
6.6% 15.4% 24.2% 53.8%
0.14 [0.01, 2.68] 1.02 [0.15, 6.97] 0.25 [0.05, 1.16] 0.42 [0.15, 1.17]
505 100.0% 100 0%
0 40 [0 0.40 [0.19, 19 00.84] 84]
Total events 9 25 Heterogeneity: Tau² = 0.00; Chi² = 1.77, df = 3 (P = 0.62); I² = 0% Test for overall effect: Z = 2.41 (P = 0.02)
Risk Ratio M-H, Random, 95% CI
0.001
0.1 1 10 Favours antibiotics Favours no antibioti
• •Significantly more implant failures in the placebo/no antibiotic group • NNT = by giving antibiotics to 33 patients we avoid 1 patient experiencing early implant losses • Absence of relevant adverse events • It might i ht b be advisable d i bl tto routinely ti l use prophylactic h l ti antibiotics tibi ti
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