Bodil Lund Margareta Hultin Sofia Tranæus Aron Naimi-Akbar €rn Klinge Bjo

Authors’ affiliations: Bodil Lund, Margareta Hultin, Sofia Tranæus, Aron Naimi-Akbar, Bj€ orn Klinge, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden Bodil Lund, Aron Naimi-Akbar, Department of Oral and Maxillofacial Surgery, Karolinska University Hospital, Huddinge, Sweden Sofia Tranæus, Swedish Council on Health Technology Assessment, Stockholm, Sweden Sofia Tranæus, Bj€ orn Klinge, Department of Periodontology, Faculty of Odontology, Malmo University, Malmo, Sweden Corresponding author: Bodil Lund, DDS Department of Oral and Maxillofacial Surgery, Karolinska University Hospital, S-141 86 Stockholm, Sweden Tel.: +46858583950 Fax: +46858583522 e-mail: [email protected]

Complex systematic review Perioperative antibiotics in conjunction with dental implant placement

Key words: antibiotic prophylaxis, complex systematic review, dental implant surgery,

knowledge gap, systematic review Abstract Objectives: The aim of this study was to revisit the available scientific literature regarding perioperative antibiotics in conjunction with implant placement by combining the recommended methods for systematic reviews and complex systematic reviews. Material and methods: A search of Medline (OVID), The Cochrane Library (Wiley), EMBASE, PubMed and Health technology assessment (HTA) organizations was performed, in addition to a complementary hand-search. Selected systematic reviews and primary studies were assessed using GRADE and AMSTAR, respectively. A meta-analysis was performed. Results: The literature search identified 846 papers of which 10 primary studies and seven systematic reviews were included. Quality assessment of the systematic reviews revealed two studies of moderate risk of bias and five with high risk of bias. The two systematic reviews of moderate risk of bias stated divergent numbers needed to treat (NNT) to prevent one patient from implant failure. Four of the primary studies comparing antibiotic prophylaxis with placebo were estimated to be of low, or moderate, risk of bias and subjected to meta-analysis. The NNT was 50 (pooled RR 0.39, 95% CI 0.18, 0.84; P = 0.02). None of these four studies individually show a statistical significant benefit of antibiotic prophylaxis. Furthermore, narrative analysis of the studies eligible for meta-analysis reveals clinical heterogeneity regarding intervention and smoking. Conclusion: Antibiotic prophylaxis in conjunction with implant placement reduced the risk for implant loss by 2%. However, the sub-analysis of the primary studies suggests that there is no benefit of antibiotic prophylaxis in uncomplicated implant surgery in healthy patient.

Insertion of dental implants is a widely used therapeutic option for patients with partially and totally edentulous jaws. Studies show high success rates, both in the short- and long-term perspectives (Albrektsson et al. 1988; Lekholm et al. 1999, 2006; Ekelund

et al. 2003; Pjetursson et al. 2004; Jemt & Johansson 2006; Roos-Jans aker et al. 2006a,b; Astrand et al. 2008; Kim et al. 2008). Original protocols for implant placement recommended dogmatic or consensus-based prescription of antibiotics prophylaxis and

Table 1. Issues of interest according to study population, intervention, control group and outcome measures (PICO) Parameters for eligible studies P I

C Date: Accepted 12 May 2015 To cite this article: Lund B, Hultin M, Tranæus S, Naimi-Akbar A, Klinge B. Perioperative antibiotics in conjunction with dental implant placement (EAO). Clin. Oral Impl. Res. 26 (Suppl. 11), 2015, 1–14 doi: 10.1111/clr.12637

O

Patients subjected to implant placement Antibiotics on day of surgery i.e. short-termed prophylaxis Antibiotics more than day of surgery i.e. “extended” prophylaxis Head-to-head comparison of different antibiotic compounds or regiments No antibiotic treatment Placebo Other non-antibiotic treatment e.g. such as antibacterial rinsing Other/comparing antibiotic treatment (alternative compound) Loss of implant Infection Pain Quality of life

P, population; I, intervention; C, control; O, outcome.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

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Table 2. Strategy and outcome of literature search conducted October 7, 2014

Database Medline (Ovid)

The Cochrane Library (Wiley)

Search strategy 1. exp Dental Implants/ 2. exp Dental Implantation/or dental implantation.mp. 3. exp Dental Prosthesis, Implant-Supported/ 4. ((osseointegratedadj implant$) and (dental or oral)).mp. 5. dental implant$.mp. 6. (implant$ adj5 dent$).mp. 7. (((overdenture$ or crown$ or bridge$ or prosthesis or restoration$) adj5 (Dental or oral)) and implant$).mp. 8. “implant supported dental prosthesis”.mp. 9. (“blade implant$” and (dental or oral)).mp. 10. ((endosseous adj5 implant$) and (dental or oral)).mp 11. ((dental or oral) adj5 implant$).mp. 12. or/1–11 13. antibiotics.mp. or exp Anti-Bacterial Agents/ 14. penicillin.mp. or exp Penicillins/ 15. antibiotic prophylaxis.mp. or exp Antibiotic Prophylaxis/ 16. chemoprevention.mp. or exp Chemoprevention/ 17. Lincosamides.mp. or exp Lincosamides/ 18. Postoperative Complications/dt, pc, su [Drug Therapy, Prevention & Control, Surgery] 19. or/13–18 20. 12 and 19 #1 DENTAL IMPLANTS explode all trees (MeSH) #2 DENTAL IMPLANTATION explode all trees (MeSH) #3 DENTAL PROSTHESIS IMPLANT-SUPPORTED single term (MeSH) #4 ((osseointegrat* near implant*) and (dental* or oral*)) #5 (dental next implant*) #6 (implant* near dent*) #7 dental-implant* #8 ((overdenture* near dental*) and implant*) #9 ((overdenture* near oral*) and implant*) #10 ((crown* near dental*) and implant*) #11 ((crown* near oral*) and implant*) #12 ((bridge* near dental*) and implant*) #13 ((bridge* near oral*) and implant*) #14 ((prosthesis near dental*) and implant*) #15 ((prosthesis near oral*) and implant*) #16 ((prostheses near dental*) and implant*) #17 ((prostheses near oral*) and implant*) #18 ((restoration* near dental*) and implant*) #19 ((restoration* near oral*) and implant*) #20 (implant next supported next dental next prosthesis) #21 (blade next implant*) #22 ((endosseous near implant*) and dental) #23 ((endosseous near implant*) and oral*) #24 ((dental* near implant*) or (oral* near implant*)) #25 (#1 or #2 or #3 or #4 or #5 or #6 or #7 or #8 or #9 or #10 or #11 or #12 or #13 or #14 or #15 or #16 or #17 or #18 or #19 or #20 or #21 or #22 or #23 or #24) #26 MeSH descriptor: [Anti-Bacterial Agents] explode all trees #27 MeSH descriptor: [Antibiotic Prophylaxis] explode all trees #28 MeSH descriptor: [Chemoprevention] explode all trees #29 MeSH descriptor: [Penicillins] explode all trees #30 MeSH descriptor: [Lincosamides] explode all trees #31 MeSH descriptor: [Postoperative Complications] explode all trees and with qualifier(s): [Drug therapy – DT, Prevention & control – PC, Surgery – SU] #32 antibiotic* or penicillin* or “antibiotic prophylaxis” or chemoprevention* or Lincosamid* or “Postoperative Complication*” #33 #26 or #27 or #28 or #29 or #30 or #31 or #32 #34 #25 and #33

extension of antibiotic treatment during the postoperative period (Adell et al. 1981). However, this tradition was early suggested to be redundant by some surgeons (Gynther et al.

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No of references retrieved

Clin. Oral Impl. Res. 26 (Suppl. 11), 2015 / 1–14

572

201

1998). Reports show that, in some regions, the number of dental implant surgeons who chose to omit antibiotic prophylaxis from their surgical protocol is increasing (Khalil

et al. 2014). Over the years the benefits of antibiotic prophylaxis during implant placement has remained a controversial subject (Schwartz & Larson 2007; Ahmad 2012; Esposito & Worthington 2013). The Swedish Council on Health Technology Assessment (SBU) conducted a literature review, published in 2010, regarding antibiotic prophylaxis in surgery. The report, written by experts assembled from all fields of surgery, included over 600 references, could not find any high- or moderate-quality studies supporting antibiotic prescription beyond the day of surgery, to prevent postoperative infections (SBU). Antibiotic Prophylaxis for Surgical Procedures. In Swedish: Antibiotikaprofylax vid kirurgiska ingrepp. En systematisk litteratur€ oversikt. Stockholm: Statens beredning f€ or medicinsk utv€ardering (SBU); 2010. SBU-rapport nr 200. ISBN 97891-85413-36-2). This was also valid for surgery performed in clean contaminated regions, such as the oral cavity, head and neck oncology, and colorectal surgery (Brand et al. 1982; Johnson et al. 1984; Righi et al. 1996; Song & Glenny 1998; Hopkins & Smaill 2012; Carroll et al. 2003; Andersen et al. 2005; Liu et al. 2008; Kang et al. 2009; Oomens et al. 2014). The overall conclusion was that there was no further benefit to the patient by prolonging the antibiotic course beyond the day of surgery, in any field of surgery, including oral and maxillofacial surgery. The review thereby disqualifies any uncertainty regarding safety aspects concerning the relinquishing of “extended prophylaxis”. Today antibiotic resistance is the largest threat to modern health care where many treatment options require access of effective antibiotics (Davies et al. 2013). Some parts of the world have already entered the post-antibiotic era where the efficacy of antibiotics can no longer be taken for granted (http:// www.who.int). Important measures to counteract this development involve applying restrictive antibiotic policies and meticulous hygienic routines to prevent further nosocomial dissemination of these resistant bacterial strains. Characteristics for countries with low levels of antibiotic resistance are rational antibiotic consumption supported by health care authorities, governmental prescription policies, high educational standards, and available regulating guidelines and recommendations (Tomson & Vlad 2014). The correlation between increasing rates of antibiotic resistance and antibiotic utilization is undisputed and supported by numerous studies (Hughes & Datta 1983; Bronzwaer et al. 2002; Livermore 2005; Foucault & Brouqui 2007). A

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Lund et al  Perioperative antibiotics in dental implant placement

Table 2. (continued) No of references retrieved

Database

Search strategy

EMBASE (www.embase.com)

#14 #12 AND #13 #13 #1 OR #2 OR #3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 #12 #10 OR #11 #11 antibiotic*:ab,ti OR penicillin*:ab,ti #10 ‘antibiotic prophylaxis’/exp #9 ((‘dental implant’ OR ‘dental implants’ OR ‘dental implantation’ OR implant*) NEAR/3 (dent* OR oral OR tooth OR teeth)):ab,ti #8 ((dental OR oral OR tooth OR teeth) NEXT/1 implant*):ab, ti #7 (endosseous NEAR/3 implant*):ab,ti AND (dental:ab,ti OR oral:ab,ti OR tooth:ab,ti OR teeth:ab,ti) #6 ‘blade implant’ OR ‘blade implants’ AND (dental OR oral OR tooth OR teeth) #5 ‘implant supported dental prosthesis’ #4 ((overdenture* OR crown* OR bridge* OR prosthesis OR prostheses OR restoration*) NEAR/5 (dental OR oral)):ab,ti AND implant*:ab,ti #3 (osseointegrated NEAR/5 implant*):ab,ti AND (dental:ab,ti OR oral:ab,ti) #2 ‘implant-supported’:ab,ti OR (implant* NEAR/3 support): ab,ti #1 ‘tooth implantation’/exp OR ‘tooth implantation’:ab,ti (((Dental*[tiab] AND implant*[tiab]) OR (Dental*[tiab] prosthes*[tiab]) OR ((osseointegrat*[tiab] AND implant*[tiab]) AND (oral[tiab] OR dental[tiab])) OR ((overdentur*[tiab] OR crown*[tiab] OR bridge*[tiab] OR restoration*[tiab]) AND (dental[tiab] OR oral[tiab]) AND implant*[tiab]) OR “implant supported dental prosthesis”[tiab] OR ((blade[tiab] AND implant*[tiab]) AND (dental[tiab] OR oral[tiab])) OR ((endosseous[tiab] AND implant*[tiab]) and (dental[tiab] OR oral[tiab])) OR ((dental[tiab] OR oral[tiab]) AND implant* [tiab])) AND (antibiotic*[tiab] OR (Anti-Bacterial[tiab] AND Agent*[tiab]) OR penicillin*[tiab] OR lincosamid*[tiab])) NOT (medline[sb]) AND (“2014/01/01”[PDAT]: “2014/12/31”[PDAT])

PubMed*

331

37

*Recent publications.

restrictive approach to antibiotic usage is an equally important counteracting action in health care environments with comparatively prudent antibiotic consumption and low levels of resistance (Aldrin et al. 2013). It has been shown that also short-term antibiotic treatments may select for resistance (Chardin et al. 2009). This highlights the importance of revisiting antibiotic prophylaxis prescribing policies. Epidemiologic data show increasing rates of antibiotic resistance in viridans streptococci of the oral cavity against antibiotics commonly used in dentistry (Doem & Burnham 2010). It has also been shown that resistant viridans streptococci of the oral microflora may serve as a reservoir of resistance genes that can be transferred to more pathogenic bacteria (Dowson et al. 1990; J€ onsson & Swedberg 2006). Previous policies to prescribe antibiotics until it is proven safe to refrain from its use, is

because of the emerging antibiotic resistance, an outdated and consumed option in otherwise healthy patients. Currently, the potential risk must always be weighed against possible benefits for each indication and patient. An acknowledged risk with antibiotic treatment is, besides the risk of side-effects, allergic reactions and interactions with other medications, ecological disturbances of the normal microflora in the oral cavity and gastrointestinal tract. An important function of the normal microflora is colonization resistance, defined as the protection provided by the resident microbiota against exogenous or endogenously colonizing potentially pathogenic bacteria (Van der Waaij 1983). When the ecology of the resident microbial community is disturbed it reduces the infection dose, that is the number of pathogens required to cause infection, and increases the host’s risk of becoming colonized or infected by antibiotic

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

resistant bacterial strains. In a patient already colonized by resistant strains at the time of antibiotic treatment, these bacteria will increase in number potentiating the risk of causing infection. This rising numbers of resistant strains may also lead to an augmented shedding of these bacteria from the host, increasing the risk of transmission to other individuals. It has recently been suggested that for broad spectrum compounds, like clindamycin, ecological disturbances may remain for long periods, in the magnitude of 12 months or more (Jernberg et al. 2010). Furthermore, it cannot be excluded that dogmatic routine utilization of antibiotic prophylaxis may reduce vigilance regarding importance of strict aseptic surgical working conditions. The risks with antibiotic prophylaxis must always be weighed against patient safety. An overly pronounced restrictive approach may harm the patient and jeopardize patient safety. Consequently, rational antibiotic usage must be as close as possible to this cut-off but without passing it. Calculations of number needed to treat (NNT) are an important guidance and should be interpreted in relation to the severity of the studied event. Review of the scientific literature is an acknowledged important means to summarize state of evidence for particular clinical interventions and may as such constitute the base for clinical treatment protocols, recommendations, guidelines and health care policies. Currently, numerous scientific studies are being published yearly, in various fields of medicine and odontology, rendering the busy clinician with the hopeless mission of keeping updated with the latest findings. In this context, systematic reviews are important tools for implementing knowledge in a more digestible form. In recent years the number of published systematic reviews has increased significantly and it has been suggested that this trend is likely to continue (Straus & Moher 2009; Booth et al. 2011). However, a poorly performed review with shortcomings, such as insufficient literature search, lack of independent analyses or misuse of statistical tools may be hazardous giving the erroneous illusion of solid conclusions. It is therefore of utmost importance that systematic reviews are performed according to high standards and likewise, the independent quality control of systematic reviews should consequently be equally important as an assessment of original research (Liberati et al. 2009; Moher et al. 2009). For methodological evaluation of systematic reviews, AMSTAR is regarded a validated and reliable tool that is increasingly being adopted for quality assessment of such

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Table 3. Criteria of low, moderate and high risk of bias according to AMSTAR assessment (Shea et al. 2007a,b) Level of bias

Criteria

Low

Predetermined research question and inclusion criteria established A minimum of two independent data extractors and consensus procedure reported At least the database MEDLINE/PubMed used. Reproducible search strategy reported The publication type used as an inclusion/exclusion criteria Included and excluded studies reported* Relevant characteristics of included studies stated Scientific quality assessed and reported for each included study Alignment between scientific quality of included studies and formulating conclusions Rational and methods for pooling results reported Publication bias estimated. Can be omitted if publication bias was unlikely and not reported Conflict of interest stated. This item can be omitted if conflicts of interest were unlikely A yes-answer to question 1–3 and 5–8 required A no-answer to any of the questions listed under moderate risk of bias

Moderate High

Q 1 2 3 4 5 6 7 8 9 10 11

Q, AMSTAR question. *List of included studies mandatory. Lacking report of excluded studies is accepted.

Table 4. Grading quality of evidence according to GRADE (Atkins et al. 2004; Guyatt et al. 2011) Levels of quality grading of scientific evidence Strong Moderate Limited

Insufficient

Definition Based on studies with high quality without weakening factors. Further research is very unlikely to change the estimated effect Based on studies with high quality with occurrence of single weakening factors. Further research is likely to have an important impact on the estimated effect Based on studies of high to moderate quality with weakening factor. Further research is very likely to have an important impact on the estimated effect and will probably change the estimate Scientific evidence is lacking. Available studies are of low quality or shows contradictory results. Any estimated effect is very uncertain

publications (Shea et al. 2007a,b, 2009). By definition, the systematic review is based on a reproducible literature search of relevant proportions. Several studies show that a mere search in only one database is insufficient and will fail the complete identification of relevant studies (Lefebvre et al. 2011). A supplementary hand-search is regarded mandatory and may, besides identifying complementary studies, serve as an adequate control of the database search strategy. However, the importance of grey literature is debated since their inclusion may reduce publication bias but simultaneously such literature often hampers from insufficient methodological descriptions rendering quality assessment precarious (Dundar et al. 2006). Decisions regarding inclusion of literature and quality assessment of allocated studies should be performed by at least two independent researchers. Transparency is regarded as essential. Researchers, commissioned to review the literature within a particular field, are frequently faced with the

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problem of how to handle pre-existing reviews. It has been suggested, that if a stringent and transparent methodology is adopted, incorporation of systematic reviews into a complex systematic review may contribute significantly to the composite result (Whitlock et al. 2008). This process involves strict inclusion and exclusion criteria, according to a predefined population, intervention, control and outcome/observation (PICO), utilization of established quality rating instruments, assessment by independent reviewers and exclusive inclusion of high-quality reviews. As part of the process, primary research data included in the systematic reviews should also be revisited. This is especially important when facing discordant reviews (Whitlock et al. 2008). Also the influence of conflict of interest cannot be underestimated since studies unambiguously show that industrial sponsorship leads to an overestimation of effects (Lexchin et al. 2003; Bell et al. 2006; J€ orgensen et al. 2008). For quality assessment of

randomized controlled trials (RCT), such an evaluation preferentially estimates alignment with or deviation from, international agreements regarding study design and account for results, such as the CONSORT statement (Schulz et al. 2010). A problem for the reader is the frequently occurring inconsistencies in grading quality evidence, which obstructs interpretation of the scientific value of the conclusions and therefore limits the usefulness of the systematic review as a foundation for recommendations (Atkins et al. 2004). The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was developed for rating quality of evidence and strength of recommendations. The GRADE system composes an explicit and comprehensive tool and is rapidly being introduced worldwide as the quality evaluation system of choice (Guyatt et al. 2008, 2011). In addition to summarizing contemporary state of knowledge, the methodological systematic review of scientific literature has the hugely significant role in identifying knowledge-gaps within different subject fields. This in turn highlights areas of interest for future research and as such, signals to authorities the urgent priority to allocate the necessary financial resources. Furthermore, in the absence of solid recommendations, the systematic literature review may serve as a starting-point for consensus statements which may, despite its lack of scientific foundation, facilitate decision making for everyday clinical practice and stream-line health care processes while awaiting sound facts. The aim of the current study was to approach the discordant opinions regarding the value of antibiotic prophylaxis in conjunction with dental implant placement by revisiting the available scientific literature through a two stage approach where the first stage consisted of quality assessment of existing systematic reviews and a second stage involving assessment and meta-analysis of primary studies within the field.

Material and methods Objective

The objective of the study was to assess the effect of antibiotic prophylaxis on implant survival in conjunction with dental implant placement. Criteria for considering studies (PICO)

Studies considered for inclusion in this literature review were systematic reviews, metaanalyses and randomized controlled trials

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Table 5. Included and excluded systematic reviews Author (year)

I

Ata-Ali et al. (2014) Ahmad (2012) Bowen Antolin & Nasimi (2007) Chrcanovic et al. (2014) Coulthard et al. (2003) Esposito & Worthington (2013) Esposito et al. (2010)* Esposito et al. (2010)* Esposito et al. (2008)* Esposito et al. (2008)* Esposito et al. (2003) Esposito et al. (1998) Garg (2004) Garg (2001) Garg (1992) Greenstein et al. (2008) Heitz-Mayfield et al. (2014) Lawler & Goss (2005) Pjetursson et al. (2012) Pye et al. (2009) Rizzo et al. (2010) Schwartz & Larson (2007) Sennerby (1998) Sharaf & Dodson (2011) Sharaf et al. (2011) Trieger (1999) Zablotsky (1993)

X X

E

Reason for exclusion

x

Not a systematic review

x

Not a systematic review

x x x x x x x x x x x x x x

More recent publication More recent publication More recent publication More recent publication More recent publication Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Out of topic Not a systematic review

x

Not a systematic review

x x x

Not a systematic review Not a systematic review Not a systematic review

X X by by by by by

same same same same same

author author author author author

found found found found found

X X X

Year, year of publication; I, inclusion; E, exclusion. *Publications in reference list with same first author and year, denoted with year and either a, b or c.

No of articles identified by search according to Table 2 n = 846 Exclusion of irrelevant articles based on title n = 761 Retrieved abstracts n =85 Exclusion after examining abstracts n = 58 Retrieved fulltext n = 27 Hand-search n=0 Exclusion based on fulltext n = 20 Included systematic reviews n=7 Fig. 1. Flow chart illustrating the screening process of systematic reviews.

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

(RCT) regarding the effect of perioperative prophylactic antibiotics vs. no treatment or placebo on outcome of dental implant placement. Studies comparing two different antibiotic protocols or antibiotics compared with alternative treatments, such as antibacterial rinsing, were also accepted. The predefined study population, intervention, comparing therapies and outcome parameters for the eligible studies are summarized in Table 1. Search strategies

One of the authors (BL) and two information specialists performed the literature search. The following databases were searched until October 7 2014: Medline (OVID), The Cochrane Library (Wiley) and EMBASE. For detection of recent publications a complementary search was performed in PubMed on October 7 2014. The search terms used for the various databases are summarized in Table 2. Health technology assessment (HTA) organizations were searched regarding dental implants and antibiotic prophylaxis until October 30 2014: NICE, http://www.nice.org.uk/; CADTH, http://www. cadth.ca/; CRD database (contains reviews from INAHTA, Cochrane, CRD and NIHR), http://www.crd.york.ac.uk/CRDWeb/; Kunnskapssenteret, http://www.kunnskapssenteret. no/home?language=english; ASERNIP-S http:// www.surgeons.org/for-health-professionals/aud its-and-surgical-research/asernip-s/publications/. The reference lists of all the eligible studies were hand-searched for potential complementary trials. There was no restriction of the search by language. However, retrieved papers in language other than English, German, French or Swedish, were excluded. Study selection

Eligible studies were included according to inclusion/exclusion criteria. The retrieved list of publications was subjected, by BL (first author), for a crude exclusion of irrelevant publications based on title. In case of uncertainty, a study remained included until the next selection step, which consisted of an examination of abstracts. The abstracts were divided in two groups, which were read independently in duplicate by two reviewers, either BL and BK or MH and AN. Full-text versions of all studies that remained after abstract examination were retrieved and read in duplicate and independently by two reviewers each. Any disagreement during the screening process were resolved by discussion between the two reviewers or, if necessary, by a third party (ST). Studies excluded at this stage, and

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Table 6. Systematic reviews with moderate risk of bias

Author (year)

Objectives

Main results*

Esposito & Worthington (2013)

(1) Assess beneficial or harmful effects of systemic antibiotic prophylaxis at implant placement. (2) If antibiotics are beneficial, to determine type, dosage and duration of treatment To investigate the effects of prophylactic antibiotics during implant placement on implant failure and postoperative infections in healthy patients

Meta-analyses displayed significantly higher number of implant failures in patients not receiving antibiotics. Antibiotic prophylaxis had no effect on postoperative infection rates. n=6 NNT = 25 The use of prophylactic antibiotics significantly reduced the number of implant failures. Antibiotic prophylaxis had no effect on postoperative infection rates. n = 13 (implant failure) n = 8 (postop infect) NNT = 50

Chrcanovic et al. (2014)

Estimated level of evidence*

Knowledge/Knowledge gaps*

Level of risk of bias Comments

(1) Moderate quality. (2) Evidence is lacking

Antibiotics are beneficial for reducing implant failures. Unknown if postoperative antibiotics are beneficial and which is the most effective compound

Moderate Studies with high risk of bias included in the meta-analyses

High risk of bias: seven studies. Moderate risk of bias: one study. Low risk of bias: six studies

Evidence suggesting that antibiotic prophylaxis significantly reduces implant failures under ordinary conditions

Moderate Studies with high risk of bias included in meta-analyses

*According to authors. n, number of studies included in meta-analyses, NNT, numbers needed to treat to prevent one implant failure; RCT, randomized controlled trials.

Table 7. Systematic reviews with high risk of bias according to the criteria listed in Table 5 A no answer to critical questions (no 1,2, 5–8) Comments

Author (year)

Objectives

Ahmad (2012)

Review whether or not antibiotics are beneficial to implants and when pre- and/or postoperative antibiotics should be prescribed Assess if the use of antibiotics in patients receiving implants reduces the frequency of implant failures and postoperative infections Retrospective observational study and review of literature regarding effect of antibiotic prophylaxis during implant placement* To assess if administration of prophylactic antibiotics reduces early implant failure To assess evidence regarding the use of preoperative antibiotic prophylaxis in children and adults undergoing dental extractions or implant placement†

Ata-Ali et al. (2014)

Rizzo et al. (2010)

Sharaf & Dodson (2011), Sharaf et al. (2011) Schwartz & Larson (2007)

2, 5–8

3, 6, 8

Stage I: Assessment of existing meta-analyses and systematic reviews Inclusion criteria for systematic reviews



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Data were extracted from the systematic reviews regarding objectives, main results, authors’ estimated level of evidence, and knowledge-gaps according to authors.

2, 3, 5–8

2, 6–8

Stage II: Assessment of primary studies 6–8

Inclusion criteria for primary studies

• • • •

systematic antibiotic treatment in comparison to control treatment or placebo Systematic review or meta-analysis

Exclusion criteria for systematic reviews

• • • • • •

The level of bias for systematic reviews were assessed using AMSTAR (Shea et al. 2007a,b, 2009). The reviews were classified as low, moderate or high risk of bias according to the criteria shown in Table 3. Data extraction

*Only the review part of the study was considered for AMSTAR classification. † Only the review part regarding implant placement considered in AMSTAR classification.

reason for exclusion, were recorded. At the stage of full-text examination the studies were divided into systematic reviews and meta-analyses or primary studies for further analyses in the below described two-staged approach.

Quality assessment

More recent systematic review available by same author Non-systematic review Guidelines Letter Position paper Consensus statements

Patient subjected to dental implant placement Systemic antibiotic treatment in conjunction with dental implant placement Control group included in study RCT

Exclusion criteria for primary studies

• • •

Animal studies In vitro studies Any study type except RCT

Quality assessment The included primary studies were assessed using a protocol for assessment of randomized studies. The scientific quality of the evidence in the primary studies was graded according to GRADE and set as strong, moderate, limited or insufficient (Guyatt et al.

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Lund et al  Perioperative antibiotics in dental implant placement

Table 8. Included and excluded primary studies Author (year)

I

Abu-Ta’a et al. (2008) Anitua et al. (2009) Binahmed & Peterson (2005) Caiazzo et al. (2011) Dent et al. (1997) El-Kholey (2014) Esposito et al. (2010)* Esposito et al. (2008)* Hosseini et al. (2014) Karaky et al. (2011) Laskin et al. (2000) Morris et al. (2004) Nolan et al. (2014) Tan et al. (2014) Givens et al. (2013)

x x

E

Reason for exclusion

x

Non randomized

x

Non randomized

x x x

Non randomized Non randomized Non randomized

x x x x x

x x x

Thompson 2002). A P-value of 50% were interpreted as significant heterogeneity (Deeks et al. 2011). A meta-analysis was performed using the random effect model. Risk ratio and risk difference were calculated using Review Manager 5.3, Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014.

Results Literature search

Year, year of publication; I, inclusion; E, exclusion. *One out of three (denoted year and either a, b or c) publications in reference list with same first author and year.

No of articles identified by search according to Table 2 n = 846

The search strategy resulted in 1141 articles of which 846 remained after deduplication (Wichor’s method 1–10). Number of retrieved studies for each database search is shown in Table 2. The search of HTA organizations did not yield any further studies. One further primary study was retrieved through the hand-search. Stage I: Existing meta-analyses and systematic reviews

Exclusion of irrelevant articles based on title n = 761

Study selection

Retrieved abstracts n = 85 Exclusion after examining abstracts n = 71 Retrieved fulltext n = 14 Hand-search n=1

Quality assessment and data extraction

Exclusion based on fulltext n=6 Included primary studies n=9 Fig. 2. Flow chart illustrating the process of selection of eligible primary studies.

2008, 2011). The criteria for the quality levels are defined in Table 4. Data extraction Data were extracted from the primary studies regarding number of included patients, age, gender distribution, number of implants inserted, length of follow-up, type of control intervention, complications, pain and quality of life.

Abstract screening yielded 27 potential systematic reviews allocated for full-text inspection, which resulted in the inclusion of seven systematic reviews, see Table 5. The most common reason for exclusion was that the study was not considered a systematic review (n = 14) followed by a more recent publication by the same author (n = 5). The screening process of systematic reviews and meta-analyses is shown in Fig. 1.

Assessment of publication bias and heterogeneity The data were plotted in a funnel plot for assessment of publication bias and visualization of heterogeneity. The primary studies were examined regarding study population, intervention and outcomes for assessment of clinical heterogeneity. Statistical heterogeneity was estimated using Chi-square (Q value) and I2 analyses (Higgins &

© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Quality assessment of systematic reviews of included trials resulted in two studies estimated as moderate risk of bias (Esposito & Worthington 2013; Chrcanovic et al. 2014). The main objective for classification as moderate risk of bias was the inclusion of high risk of bias primary studies in the metaanalyses (Esposito & Worthington 2013; Chrcanovic et al. 2014) and pooling of RCT and observational studies in the meta-analyses (Chrcanovic et al. 2014), see Table 6. The remaining included systematic reviews (n = 5), were classified as high risk of bias (Schwartz & Larson 2007; Rizzo et al. 2010; Sharaf & Dodson 2011; Sharaf et al. 2011; Ahmad 2012; Ata-Ali et al. 2014). The most frequently occurring short-comings were lack of alignment between scientific quality of included studies, formulation of conclusions and insufficient reporting of relevant characteristics of included studies (n = 5). Another frequently occurring problem was inadequate

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Table 5. Included and excluded systematic reviews Author (year)

I

Ata-Ali et al. (2014) Ahmad (2012) Bowen Antolin & Nasimi (2007) Chrcanovic et al. (2014) Coulthard et al. (2003) Esposito & Worthington (2013) Esposito et al. (2010)* Esposito et al. (2010)* Esposito et al. (2008)* Esposito et al. (2008)* Esposito et al. (2003) Esposito et al. (1998) Garg (2004) Garg (2001) Garg (1992) Greenstein et al. (2008) Heitz-Mayfield et al. (2014) Lawler & Goss (2005) Pjetursson et al. (2012) Pye et al. (2009) Rizzo et al. (2010) Schwartz & Larson (2007) Sennerby (1998) Sharaf & Dodson (2011) Sharaf et al. (2011) Trieger (1999) Zablotsky (1993)

X X

E

Reason for exclusion

x

Not a systematic review

x

Not a systematic review

x x x x x x x x x x x x x x

More recent publication More recent publication More recent publication More recent publication More recent publication Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Not a systematic review Out of topic Not a systematic review

x

Not a systematic review

x x x

Not a systematic review Not a systematic review Not a systematic review

X X by by by by by

same same same same same

author author author author author

found found found found found

X X X

Year, year of publication; I, inclusion; E, exclusion. *Publications in reference list with same first author and year, denoted with year and either a, b or c.

No of articles identified by search according to Table 2 n = 846 Exclusion of irrelevant articles based on title n = 761 Retrieved abstracts n =85 Exclusion after examining abstracts n = 58 Retrieved fulltext n = 27 Hand-search n=0 Exclusion based on fulltext n = 20 Included systematic reviews n=7 Fig. 1. Flow chart illustrating the screening process of systematic reviews.

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(RCT) regarding the effect of perioperative prophylactic antibiotics vs. no treatment or placebo on outcome of dental implant placement. Studies comparing two different antibiotic protocols or antibiotics compared with alternative treatments, such as antibacterial rinsing, were also accepted. The predefined study population, intervention, comparing therapies and outcome parameters for the eligible studies are summarized in Table 1. Search strategies

One of the authors (BL) and two information specialists performed the literature search. The following databases were searched until October 7 2014: Medline (OVID), The Cochrane Library (Wiley) and EMBASE. For detection of recent publications a complementary search was performed in PubMed on October 7 2014. The search terms used for the various databases are summarized in Table 2. Health technology assessment (HTA) organizations were searched regarding dental implants and antibiotic prophylaxis until October 30 2014: NICE, http://www.nice.org.uk/; CADTH, http://www. cadth.ca/; CRD database (contains reviews from INAHTA, Cochrane, CRD and NIHR), http://www.crd.york.ac.uk/CRDWeb/; Kunnskapssenteret, http://www.kunnskapssenteret. no/home?language=english; ASERNIP-S http:// www.surgeons.org/for-health-professionals/aud its-and-surgical-research/asernip-s/publications/. The reference lists of all the eligible studies were hand-searched for potential complementary trials. There was no restriction of the search by language. However, retrieved papers in language other than English, German, French or Swedish, were excluded. Study selection

Eligible studies were included according to inclusion/exclusion criteria. The retrieved list of publications was subjected, by BL (first author), for a crude exclusion of irrelevant publications based on title. In case of uncertainty, a study remained included until the next selection step, which consisted of an examination of abstracts. The abstracts were divided in two groups, which were read independently in duplicate by two reviewers, either BL and BK or MH and AN. Full-text versions of all studies that remained after abstract examination were retrieved and read in duplicate and independently by two reviewers each. Any disagreement during the screening process were resolved by discussion between the two reviewers or, if necessary, by a third party (ST). Studies excluded at this stage, and

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Table 11. Comments regarding studies with high risk of bias Author (year) Country

Risk of bias Comments

Abu-Ta’a et al. (2008) Belgium

Unclear randomization process and allocation concealment No placebo, no blinding of study subjects Poor presentation of baseline data Unclear blinding of care givers and assessors Unclear definition of outcome measures No published study protocol Unclear randomization process and allocation concealment No placebo, no blinding of study subjects Poor presentation of baseline data Unclear blinding of care givers and assessors Unclear definition of outcome measures No published study protocol Poor randomization process, differences between groups No allocation concealment Poor presentation of baseline data Unclear blinding of care givers and assessors Poor definition of outcome measure No published study protocol Unclear randomization process Blinding of subjects not clear Poor presentation of baseline data Poor definition of outcome measure Poor presentation of follow-up period No published study protocol Method used to produce allocation sequence not presented No presentation of number of implants placed in treatment groups Poor definition of outcome measure Very high loss to follow-up high, 28 patients (35%) excluded after randomization No published study protocol

Caiazzo et al. (2011) Italy

Givens et al. (2013) USA

Hosseini et al. (2014) USA

Nolan et al. (2014) Ireland

Study

Selection bias

Performance bias

Detection Attrition Reporting Conflict Summary bias bias bias of interest

Anitua et al. 2009 El-Kholey el al. 2014

Quality assessment and data extraction

Assessment of quality of primary studies rendered an estimated low risk of bias for three studies (Esposito et al. 2008a 2010a; Tan et al. 2014), moderate risk of bias for two studies (Anitua et al. 2009; El-Kholey 2014) and high risk of bias for five studies (AbuTa’a et al. 2008; Caiazzo et al. 2011; Givens et al. 2013; Hosseini et al. 2014; Nolan et al. 2014). Type of intervention and study population characteristics for studies classified as being of low or moderate risk of bias are shown in Table 9. Four of these studies compared antibiotic prophylaxis using amoxicillin with placebo (Esposito et al. 2008a 2010a; Anitua et al. 2009; Tan et al. 2014) and one compared two different types of amoxicillin regimes (El-Kholey 2014). The outcome of the studies with low or moderate risk of bias are shown in Table 10. The judgements regarding each bias item for the studies with low and moderate risk of bias are summarized in Fig. 3. In Table 11, the primary studies classified as high risk of bias are listed, as well as the motivations for this scoring. Of the studies classified as low or moderate risk of bias, only one registered patient reported outcome measures such as pain (Tan et al. 2014), while none the included primary studies measured quality of life, thus ruling out meta-analysis of these outcomes. Publication bias and heterogeneity

Esposito et al. 2008 Esposito et al. 2010 Tan et al. 2013 Low risk

were excluded, yielding 10 primary studies included for further analyses. Table 8 shows the eligible primary studies and, when applicable, the reason for exclusion. Flow-chart of the screening process for primary studies is described in Fig. 2.

Medium risk

High risk

Fig. 3. Summary of methodological assessment of included primary studies estimated as low or moderate risk of bias.

account of scientific quality assessment for the included studies (n = 4). Systematic reviews estimated to be of high risk of bias are summarized in Table 7. No studies were found to be of low risk of bias.

Stage II: Primary studies Study selection

A total of 15 primary studies were read in full-text. At this stage another five studies

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The study by El-Kholey (2014) compared two different antibiotic regimes and was therefore not included in the meta-analyses. The funnel plot of the primary studies with low risk of bias indicated low risk for publication bias (Fig. 4). Preoperative antibiotic prophylaxis reduced the risk for implant loss (pooled RR 0.39, 95% CI 0.18, 0.84; P = 0.02) (pooled RD 0.02, 95% CI 0.04, 0.00; P = 0.02), see Figs 5 and 6, respectively. A risk difference of 2% yielded NNT of 50 to prevent one patient from implant loss. The statistical heterogeneity between the studies was low (Chi2 = 1.93, df = 3 (P = 0.59); I2 = 0%), Fig. 5. The narrative analyses of studies with low or moderate risk of bias revealed considerable heterogeneity regarding smoking and type of implant therapy, where two studies (Anitua et al. 2009; Tan et al. 2014) had considerable less smokers in the study population and only

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Fig. 4. Funnel plot of primary studies with low risk of bias comparing antibiotic prophylaxis with placebo (Esposito et al. 2008a, 2010a; Anitua et al. 2009; Tan et al. 2014).

included patients subjected to single implant placements (Table 9). Excluding these studies from the meta-analyses resulted in a NNT of 33 (pooled RR 0.36, 95% CI 0.15, 0.84; P = 0.02) (pooled RD 0.03, 95% CI 0.06, 0.01; P = 0.01). However, a separate metaanalyses of the two studies with less smokers and merely single implants showed that there is no benefit of antibiotic prophylaxis in these straight forward cases of implant placement (pooled RR 0.48, 95% CI 0.06, 3.85; P = 0.49), Fig. 7, (pooled RD 0.01, 95% CI 0.04, 0.02; P = 0.45), Fig. 8.

Discussion This study, combining the recommended methods for systematic reviews and complex systematic reviews, shows that utilization of antibiotic prophylaxis during implant placement gives a modest, but significant, reduction of patients losing implants compared to placebo. The analyses suggest that 50 patients need to be subjected to antibiotic prophylaxis to prevent one patient from implant failure. However, the confidence interval (CI) for this calculation shows a wide

range indicating an uncertainty regarding this figure. Furthermore, none of the primary studies included in the meta-analysis shows a statistically significant beneficial effect of antibiotic prophylaxis on their own suggesting that any effect seen in the meta-analysis should be interpreted with caution. Previous systematic reviews within the field, with moderate risk of bias, state NNT of 25 (Esposito & Worthington 2013) or 50 (Chrcanovic et al. 2014), thus well within the range of the current study. The main objection to previous systematic reviews is the inclusion of studies with high risk of bias in the metaanalyses. Another fact to consider in systematic reviews is the heterogeneity of the included studies, which if extensive, may preclude meta-analyses. In accordance with this it is questionable whether the study by Anitua et al. (2009) and Tan et al. (2014) should be included in the current analyses since solely single implant placements were included and the number of smokers were considerably less compared to the other two primary studies included in the meta-analysis (Esposito et al. 2008a 2010a). Although the statistical heterogeneity was low, these two clinical differences concerns factors likely to

affect the outcome of the studies. Therefore the sub-analyses, separating studies of clinical heterogeneity, is important to obtain a nuanced and more accurate view of the effect of antibiotic prophylaxis during implant placement. Only five primary studies fulfilling the inclusion criteria were estimated to be of low or moderate risk of bias (Esposito et al. 2008a 2010a; Anitua et al. 2009; El-Kholey 2014; Tan et al. 2014). Common problems with primary studies estimated as high risk of bias are unclear randomization process and allocation concealment, insufficient and poorly described blinding as well as unclear outcome measures. It cannot be over emphasized that designing and performing RCT should be in accordance of international agreements such as the CONSORT statement for proper conclusions to be drawn (Schulz et al. 2010). A systematic review based on poor quality research may be deceptive in a hazardous manner if not critically assessed by the reader. Especially since reviews are commonly used by clinicians to get a time-effective survey of a particular field of interest. The increasing numbers of systematic reviews necessitates the methodology of complex systematic review (Whitlock et al. 2008; Liberati et al. 2009; Moher et al. 2009). The core of the systematic review will always be the quality grading system of the included primary studies. Since a large validity diverseness of such grading system exists the assessment of previous reviews should embrace an audit of the included primary studies as performed in the current study (Whitlock et al. 2008). Due to the emerging problems with antibiotic resistance all aspects of antibiotic usage should be evaluated even in low resistance environments and regarding short duration prescriptions (Chardin et al. 2009; Aldrin et al. 2013). The cost and risks of using antibiotics must always be weighed against the

Fig. 5. Forest plot(risk ratio) of comparison between amoxicillin prophylaxis vs. placebo using the outcome: patients with implant loss.

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Lund et al  Perioperative antibiotics in dental implant placement

Fig. 6. Forest plot (risk difference) of comparison between amoxicillin prophylaxis vs. placebo, for the outcome: patients with implant loss.

Fig. 7. Forest plot (risk ratio) of comparison between amoxicillin prophylaxis vs. placebo, based on studies investigating single implant placement using the outcome: patients with implant loss.

Fig. 8. Forest plot (risk difference) of comparison between amoxicillin prophylaxis vs. placebo, based on studies investigating single implant placement using the outcome: patients with implant loss.

severity of the condition to be prevented or treated. Therefore, the result that preoperative antibiotic prophylaxis significantly reduces implant losses does not necessarily give the conclusion that this should be an adopted protocol. This is especially true considering the wide CI. The value of this risk reduction must be put in the context of the emerging problems with antibiotic resistance before solid guidelines regarding the use of antibiotic prophylaxis in implant surgery can be formulated.

Conclusion The scientific evidence for antibiotic prophylaxis during dental implant placement is limited. The current systematic review suggests that antibiotic prophylaxis in conjunction with implant placement gives a modest

reduction by 2% of the risk for implant loss. However, the assessment of the included primary studies reveals a high clinical heterogeneity. A sub-analysis suggests that there is no benefit of antibiotic prophylaxis in uncomplicated implant surgery in healthy patients while a beneficial effect in complicated cases cannot be excluded. Upon formulating recommendations for antibiotic prophylaxis, the calculated risk reduction at the patient level should be put in relation to the risk of adverse reactions, side-effects and the emerging problems with antibiotic resistance.

Acknowledgements: The authors would like to acknowledge the library at Karolinska Institutet for skilful assistance and Ene Leipalu for providing administrative resources.

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Ethical approval Not required.

Conflict of interest The authors have no conflicts of interest to declare.

Source of funding This study was supported by a special grant from the Swedish Research Council (Dnr 2012-55) in support of National Clinical Research Schools regarding research on infection and antibiotics and to facilitate networking in this area.

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© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Complex systematic review - Perioperative antibiotics in conjunction with dental implant placement.

The aim of this study was to revisit the available scientific literature regarding perioperative antibiotics in conjunction with implant placement by ...
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