- Email: [email protected]
Evaluating benefits and harm of therapies
Accepted Manuscript Evaluating benefits and harm of therapies Clovis Mariano Faggion, Jr. PII:
S1532-3382(16)30091-4
DOI:
10.1016/j.jebdp.2016.06.005
Reference:
YMED 1129
To appear in:
The Journal of Evidence-Based Dental Practice
Received Date: 25 June 2016 Accepted Date: 27 June 2016
Please cite this article as: Faggion Jr CM, Evaluating benefits and harm of therapies, The Journal of Evidence-Based Dental Practice (2016), doi: 10.1016/j.jebdp.2016.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Title: Evaluating benefits and harm of therapies
1
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Author: Clovis Mariano Faggion Jr1
Department of Periodontology and Operative Dentistry, Faculty of Dentistry, University of
M AN U
SC
Münster, Münster, Germany
Corresponding author: Clovis Mariano Faggion Jr, Faculty of Dentistry, University of Münster, Waldeyerstraße 30, 48149 Münster, Germany. Tel +49 (0)251 / 83-47061, Fax +49
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Number of words: 2496
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(0)251 / 83-47134, Email: [email protected]
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Key words: Treatment outcome; clinical effectiveness; patient harm
Running title: Benefits and harm of therapies
2
ACCEPTED MANUSCRIPT Abstract Objective This third article in a series of four aims to inform dental practitioners on the importance of weighing benefits and harm when making clinical treatment decisions.
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Methods
This article describes some examples of important consequences to patients’ health when potential side effects of interventions are not taken into consideration in the decision-making
SC
process. Some information to help dental practitioners search for data on negative effects of therapies is also presented, and the need to weigh benefits and harm of therapies is discussed.
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Results
Therapeutic interventions in dentistry may cause several side effects, such as nerve damage caused by dental implant placement. Adequate evaluation of potential side effects before performing a procedure and comprehensive communication with the patient about these side
Conclusions
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effects are sine qua non conditions for any clinical decision.
The information provided in this article may encourage dental practitioners to obtain more
EP
information regarding negative aspects of clinical interventions, to more comprehensively
AC C
inform patients and improve clinical decision making.
3
ACCEPTED MANUSCRIPT This third paper in a series of four addresses an important component of the decisionmaking process: the balance between harm and benefits of therapeutic approaches.1 Dental practitioners usually focus more on the effectiveness of therapies than on their potential side effects. This behavior is influenced by the way in which dental research is reported, with a
RI PT
greater focus on the positive results of therapies. The omission of reporting on non-significant results and negative effects of therapies (in the form of side effects) is a common situation in several medical disciplines, and it is considered to constitute publication bias, a form of
SC
reporting bias.2
Publication bias can be detected in several ways. One pragmatic form in which dental
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practitioners can assess publication bias is by the analysis of funnel plots.3 An asymmetric funnel may indicate publications bias. However, funnel asymmetry can be caused by factors other than publication bias, and the plot may not be sufficiently accurate when few studies are included in a meta-analysis.3 The lack of comprehensive reporting of research results may
TE D
generate important clinical consequences for patients. The main objective of this article is to provide an overview of how dental practitioners could address this topic, and how they should
Definitions
EP
share information on side effects with their patients to improve the decision-making process.
This article focuses on the effects of drugs or therapies that can be harmful to patients,
AC C
Slight differences exist in the meanings of terms used to define unexpected effects of drugs or interventions, defined as follows: Adverse effect/reaction. These terms refer to the possible causal relationship between a drug/intervention and an event. The terms “adverse effect” and “adverse event” are interchangeable. However, the former is related to the “effect” of the drug or intervention, and the latter is related to the “reaction” of the patient.4
4
ACCEPTED MANUSCRIPT Adverse event. An adverse event may occur during or after the use of a drug or other intervention, but is not necessarily caused by it. In other words, the event may be associated with the drug or intervention, but a cause-effect relationship may not exist. Side effect. A side effect is an unintended effect of an intervention, associated most
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commonly with the use of a pharmaceutical drug. Side effects do not necessarily have negative impacts on patients’ health.4
The effect of not reporting harm: two examples from the medical sciences
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The withdrawal of drugs from the market for reasons of safety is not unusual. For example, 19 drugs were withdrawn from the market in the European Union between 2002 and 2011.5
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Some of these drugs had been in the market for almost 50 years.5 Although many of these drugs may not cause relevant complications, some of them may create life-threatening conditions. This is the case for non-steroidal anti-inflammatory drugs, which may increase the risks of myocardial infarction, stroke, and cardiovascular death.6 For example, a well-known
TE D
case in the pharmaceutical industry was the withdrawal of rofecoxib (known commercially as Vioxx) from the market in 20046 due to its association with thrombotic events that could lead to heart attack and stroke, mainly when the drug was used long term in high doses.
EP
Interestingly, potential adverse effects of this drug were identified in 2000, but the authors of that study, which was supported by the company producing the drug, claimed that the
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adverse effect was not caused by rofecoxib.7 A cumulative meta-analysis of randomized controlled trials (RCTs)8 conducted several years earlier demonstrated that evidence was sufficient to withdraw rofecoxib. The authors of the meta-analysis stated at that time that “the reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified.”8 One potential explanation for this lack of monitoring is that the global sales of rofecoxib amounted to US$2.5 billion in 2003.9
5
ACCEPTED MANUSCRIPT Another drug that caused severe adverse reactions is thalidomide, which was prescribed as a sedative in the late 1950s.10 The drug was also prescribed for the treatment of nausea in pregnant women.10 The drug did not affect the mothers, but their babies were born with malformed limbs. It is estimated that thalidomide caused birth defects in thousands of
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children around the world.10 The drug was withdrawn several decades ago, although not uniformly across countries, which prolonged its devastating effects. The consequences of not reporting harm in dentistry
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Studies in dentistry are usually planned to detect the efficacy or effectiveness of therapies or products. “Efficacy” refers to the beneficial effect of a drug or intervention under ideal and
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well-controlled conditions. “Effectiveness” is related to the effect of a drug or intervention under ordinary or “real-life” conditions.11 Many clinical trials include reporting on the potential adverse effects or complications of therapies, but they are not usually primary study outcomes. Information on harm is usually presented only as a consequence of the therapies;
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the prospective identification of harm is not usually planned. Furthermore, a structured way of presenting data on harm in dental clinical trials appears to be lacking. For example, some evidence suggests that information on harm is not well reported in RCTs in periodontology.12
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It would be important that clinical trials reporting harm follow the guidelines proposed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network.13 These
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guidelines are an extension of the CONsolidated Standards Of Reporting Trials (CONSORT) statement for reporting of RCTs. The same group also produced guidelines for reporting of harm in systematic reviews.14 To make adequate clinical decisions, dental practitioners and patients need to have comprehensive information about the effects of therapies. Obviously, the “negative” impacts of therapies need to be taken into account when these decisions are made. Comprehensive information is also mandatory when dental practitioners legally need to inform patients about planned therapies. In legal informed consent, which is mandatory in
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ACCEPTED MANUSCRIPT most parts of the world, patients give permission to be treated after they have received information about their treatments. Transparent and comprehensive reporting of the benefits and harm of therapies is thus pivotal in obtaining more accurate and meaningful legal informed consent. Ethical concerns may arise when patients are not properly informed of the
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consequences of therapies. An imbalance in knowledge between dental practitioners and
patients regarding therapies may lead to biased decision making. One can consider that the party retaining the greater knowledge (dental practitioner) may influence the direction and
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content of the conversation and bias the decision-making process.15 Searching for evidence on harm
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Some evidence suggests that reporting of harm is less complete than reporting of benefits of therapies, and this might be true at the primary research (clinical studies) and secondary research (systematic reviews) levels.16 Thus, dental practitioners need to rely on evidencebased skills when searching for adequate literature that can give them a comprehensive view
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of all potential effects of a specific therapeutic intervention.
One approach would be to first search for evidence-based guidelines that primarily address side effects or complications of therapies. If such guidelines do not exist or current
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guidelines have low methodological quality, as evaluated with the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument,17 then dental practitioners need to search for
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other sources of evidence. For therapeutic interventions, scrutiny of systematic reviews of RCTs or robust RCTs with low risk of bias (ROB) for information about harm or complications would be the alternative choice. However, many side effects occur infrequently and cannot be “captured” in planned studies, such as RCTs. In many cases, side effects are identified in studies with low methodological quality, such as case series or even case reports, which were not designed specifically to identify complications or side effects of therapies. In other words, authors conduct retrospective analyses of dental charts to evaluate potential harm
7
ACCEPTED MANUSCRIPT or complications of therapies in many cases. One example is the case of retrospective assessment of complications of treatment with dental implants.18,19 Weighing benefits and harm
After selecting evidence on benefits and harm, dental practitioners must judge whether
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specific therapies are appropriate for their patients. Dental practitioners should carefully evaluate how research findings are reported. One easy approach would be to first evaluate what is reported regarding outcome measures in the Materials and Methods sections of
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articles. If the authors of a study report only outcome measures related to effectiveness, then the article is not very useful for dental practitioners seeking to gather comprehensive evidence
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for clinical decision making. This lack of reporting may mainly reflect authors’ omission of reporting on non-significant outcomes or negative findings.16,20,21 This practice may generate “selective outcome reporting” bias, as it is described in the ROB tool from the Cochrane Collaboration.22 Some authors, however, may not report information on harm or side effects
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of therapies in the Materials and Methods section, but directly in the Results section as a consequence of interventions.
Talking to your patient about harm of therapies
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Sharing information with patients about potential harm caused by the adverse effects of therapies is important. To provide only information on the “perfect scenario” after therapy is
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incorrect and may raise ethical concerns. The most accurate information possible should be provided to avoid biasing the patient´s decision. For example, reporting to a patient only that “the placement of a dental implant may cause nerve damage” may be overstatement. Similarly, reporting that “it is almost impossible to damage the nerve by placing a dental implant” is also not sufficiently detailed. Dental practitioners should search the literature for evidence on the prevalence of such cases, and report this information in a way that patients understand. In this example, the explanation should answer the following questions: “how many cases similar to mine are reported in the literature?,” “what is the level of evidence of
8
ACCEPTED MANUSCRIPT studies reporting these side effects?,” “what is the prevalence of adverse effects (in this case, nerve damage) in the existent literature?,” and “in case of nerve damage, what are the consequences?” Thus, the key to communication with a patient is the provision of comprehensive and accurate information on the balance between potential adverse effects and
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benefits of the proposed therapy. After a comprehensive explanation of potential side effects of therapies, some patients will likely prefer more conservative approaches due to
consideration of the risks. Other patients will prefer to take a “wait-and-see approach” and not
SC
immediately accept any intervention. Thus, one may consider that the provision of more
comprehensive and transparent information to patients might reduce the number of procedures
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performed in a dental practice and, consequently, the economic gain. However, more ethical behavior will increase patients´ trust in dental practitioners and improve long-term relationships between patients and professionals.
Importantly, information on side effects should be related not only to the preferred therapy,
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but also to alternate therapies in each clinical case. For example, in the case of dental implant placement in the mandibular premolar region, potential side effects of conventional prostheses or even non-interventional therapies should be discussed comprehensively with the patient
Clinical example
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before a definitive clinical decision is made.
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A patient comes to your dental office to solicit your opinion about the potential replacement of the mandibular left first molar, which was lost several years previously. The mandibular left first, second, and third molars are absent. In the left maxilla, the patient has a fixed bridge extending from the first pre-molar to the first molar. The patient does not complain of functional or aesthetic problems, but he wants a second opinion on the replacement of the mandibular left first molar. He was informed by another professional that the first molar should be replaced, and that a dental implant would be the best alternative. The patient is
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ACCEPTED MANUSCRIPT afraid that his condition (lack of posterior teeth) will cause him problems, but he is also concerned about potential risks/complications of dental implant placement. While the patient waits comfortably in the waiting room, you quickly check the Medline database (via PubMed) for potential complications of dental implant placement in this area.
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You know that the inferior alveolar nerve, an important anatomic structure, is close to the area. Thus, you search the database using keywords and Boolean operators: "dental implant" AND “complication” AND “nerve.” The system retrieves 11 potentially relevant documents
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(as searched on 11 March 2016), and you use the PubMed filter to select documents based on systematic reviews. You find two potentially relevant systematic reviews on this topic,23,24
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and one of these reviews23 is related directly to your concern. You focus on this systematic review and find that several cases of nerve damage, some with permanent loss of sensation, were reported in the primary studies included. To answer the patient’s question, you also quickly search the Medline database for information on the concept of the shortened dental
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arch using the keyword “shortened dental arch” and the “systematic review” filter. The system retrieves six documents (as searched on 11 March 2016), and you select the two most recent systematic reviews related directly to the question.25,26 Both reviews suggest that the
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creation of a shortened dental arch is a reasonable treatment approach that provides patients with good masticatory function. Furthermore, potential long-term complications, such as peri-
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implantitis,27 related to dental implant therapy make you less confident that dental implantation in this area is the best option for this patient. Finally, although your literature search did not yield accurate information about the prevalence of nerve damage after dental implant placement in this area, you realize that a substantial number of cases (n = 157) included in the systematic review involved nerve injury. After carefully weighing the benefits and harm of dental implant surgery, you return to the patient and inform him about the potential adverse effects. The patient is averse to risk, and his final decision is to take a noninterventional (wait-and-see) approach.
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ACCEPTED MANUSCRIPT Bounded edentulous space (BES) is another clinical situation in which a posterior tooth has been lost and the edentulous space is limited by adjacent teeth. Some evidence suggests that this condition can be stable in the long term in some cases, and that the replacement of the lost tooth is not a sine qua non condition.28 Four main options are available as acceptable
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therapeutic interventions for the management of a BES case. Figure 1 shows a potential
decision pathway for BES management from the perspective of consideration of the therapies’ benefits and harm. When the benefits of one therapy clearly outweigh the potential harm in
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comparison with other alternatives, then the clinical decision is relatively easy. In the case of balance among therapies regarding benefits and harm, the decision will also be based on the
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patient’s profile. “Risk takers” will likely choose therapies with greater risks of side effects, but with some advantages (even those that are not very prominent), over alternatives. Conclusions
This article intended to provide dental practitioners with basic information on how to
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address potential side effects of clinical interventions. Decision making on therapies that takes only information on effectiveness into account may place patients at risk, sometimes with lifelong consequences. Comprehensive information about the potential harm and benefits of
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therapies should be discussed thoroughly with patients before therapeutic decisions are made.
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ACCEPTED MANUSCRIPT References 1. Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55.
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2. Higgins JP, Altman D. Assessing the risk of bias in included studies. J. Higgins, S. Green (Eds.), Cochrane handbook for systematic reviews of interventions 5.0.1, John Wiley & Sons, Chichester, UK (2008).
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3. Sterne, J. A., Egger, M. and Moher, D. (2008) Addressing Reporting Biases, in Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series (eds J. P. Higgins and S. Green), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470712184.ch10
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4. Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000 Oct 7;356(9237):1255-9. 5. McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014 Jan 15;4(1):e004221.
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6. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342:c7086. doi: 10.1136/bmj.c7086.
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7. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528.
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8. Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004 Dec 410;364(9450):2021-9. 9. Singh D. Merck withdraws arthritis drug worldwide. BMJ. 2004 Oct 9;329(7470):816. 10. Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. 11. Gartlehner G, Hansen RA, Nissman D, Lohr KN, Carey TS. Criteria for Distinguishing Effectiveness From Efficacy Trials in Systematic Reviews. Technical Review 12 (Prepared by the RTI-International–University of North Carolina Evidence-based Practice Center under Contract No. 290-02-0016.) AHRQ Publication No. 06-0046. Rockville, MD: Agency for Healthcare Research and Quality. April 2006
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ACCEPTED MANUSCRIPT 12. Faggion CM Jr, Tu YK, Giannakopoulos NN. Reporting adverse events in randomized controlled trials in periodontology: a systematic review. J Clin Periodontol. 2013 Sep;40(9):889-95. 13. Ioannidis JP, Evans SJ, Gøtzsche PC, O'Neill RT, Altman DG, Schulz K, Moher D; CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004 Nov 16;141(10):781-8.
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14. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, Moher D, Vohra S; PRISMA harms group. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.
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15. Faggion CM Jr. Informing the patient: the "forgotten" link. J Clin Epidemiology. In press.
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16. Saini P, Loke YK, Gamble C, Altman DG, Williamson PR, Kirkham JJ. Selective reporting bias of harm outcomes within studies: findings from a cohort of systematic reviews. BMJ. 2014 Nov 21;349:g6501. 17. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna S, Littlejohns P, Makarski J, Zitzelsberger L for the AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J. 2010. Dec 2010; 182:E839-842.
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18. Anavi Y, Allon DM, Avishai G, Calderon S. Complications of maxillary sinus augmentations in a selective series of patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 Jul;106(1):34-8.
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19. Kolgeci L, Mericske E, Worni A, Walker P, Katsoulis J, Mericske-Stern R. Technical complications and failures of zirconia-based prostheses supported by implants followed up to 7 years: a case series. Int J Prosthodont. 2014 Nov-Dec;27(6):544-52.
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20. Elangovan S, Prakasam S, Gajendrareddy P, Allareddy V. A Risk of Bias Assessment of Randomized Controlled Trials (RCTs) on Periodontal Regeneration Published in 2013. J Evid Based Dent Pract. 2016 Mar;16(1):30-40. 21. Pandis N, Fleming PS, Worthington H, Dwan K, Salanti G. Discrepancies in Outcome Reporting Exist Between Protocols and Published Oral Health Cochrane Systematic Reviews. PLoS One. 2015 Sep 14;10(9):e0137667. 22. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. BMJ. 2011 Oct 18;343:d5928. 23. Shavit I, Juodzbalys G. Inferior alveolar nerve injuries following implant placement importance of early diagnosis and treatment: a systematic review. J Oral Maxillofac Res. 2014 Dec 29;5(4):e2.
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ACCEPTED MANUSCRIPT 24. Wanner L, Manegold-Brauer G, Brauer HU. Review of unusual intraoperative and postoperative complications associated with endosseous implant placement. Quintessence Int. 2013 Nov-Dec;44(10):773-81. 25. Faggion CM Jr. The shortened dental arch revisited: from evidence to recommendations by the use of the GRADE approach. J Oral Rehabil. 2011 Dec;38(12):940-9.
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26. Khan S, Musekiwa A, Chikte UM, Omar R. Differences in functional outcomes for adult patients with prosthodontically-treated and -untreated shortened dental arches: a systematic review. PLoS One. 2014 Jul 3;9(7):e101143.
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27. Atieh MA, Alsabeeha NH, Faggion CM Jr, Duncan WJ. The frequency of peri-implant diseases: a systematic review and meta-analysis. J Periodontol. 2013 Nov;84(11):1586-98.
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28. Faggion CM Jr, Giannakopoulos NN, Listl S. How strong is the evidence for the need to restore posterior bounded edentulous spaces in adults? Grading the quality of evidence and the strength of recommendations. J Dent. 2011 Feb;39(2):108-16.
14
ACCEPTED MANUSCRIPT Figure 1. Decision path for managing a bounded edentulous space (BES) with focus on benefits and harm of therapies. BES 46
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Check benefits and harm (short- and long-term)
„Wait and see“
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Removable prosthesis
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Fixed bridge 45-47
Implant + crown
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Benefits clearly outweighs harm
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Analyze patient´s profile (risk-taking or risk-averse)
Select the best therapy
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Balanced benefits and harm
Risktaker
Select the therapy with „greatest“ effectiveness
Riskaverse
Select the therapy with least risk
15
ACCEPTED MANUSCRIPT Appendix Table 1. Methodological tools reported in this article
AGREE II17
Checklist consisted of the original PRISMA checklist for systematic reviews plus four reporting elements directly related to harm reporting Instrument with 23-items, distributed in six domains. Items are rated using a seven-point response scale The instrument cover six domains of bias with the assessment of ROB performed in two parts: firstly, assessors generate the support for judgement; secondly, assessors assign a judgement of ROB, based on the information provided in the first part
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Cochrane ROB22
Rationale Checklist with 10 recommendations about reporting harm-related issues
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PRISMA harms* 14
Objective To evaluate the report of harm in randomized trials To improve to improve harm reporting in systematic reviews To assess the quality and reporting of practice guidelines To asses risk of bias in randomized trials
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Tool CONSORT harms*13
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* Authors of these tools use the term “harms”. In the present article the term used was harm (singular)
16
ACCEPTED MANUSCRIPT Table 2. List of acronyms
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RCT: randomized controlled trial EQUATOR: Enhancing the QUAlity and Transparency Of health Research CONSORT: CONsolidated Standards Of Reporting Trials ROB: risk of bias BES: bounded edentulous space AGREE: Appraisal of Guidelines for Research & Evaluation
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• • • • • •
S1532-3382(16)30091-4
DOI:
10.1016/j.jebdp.2016.06.005
Reference:
YMED 1129
To appear in:
The Journal of Evidence-Based Dental Practice
Received Date: 25 June 2016 Accepted Date: 27 June 2016
Please cite this article as: Faggion Jr CM, Evaluating benefits and harm of therapies, The Journal of Evidence-Based Dental Practice (2016), doi: 10.1016/j.jebdp.2016.06.005. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
ACCEPTED MANUSCRIPT Title: Evaluating benefits and harm of therapies
1
RI PT
Author: Clovis Mariano Faggion Jr1
Department of Periodontology and Operative Dentistry, Faculty of Dentistry, University of
M AN U
SC
Münster, Münster, Germany
Corresponding author: Clovis Mariano Faggion Jr, Faculty of Dentistry, University of Münster, Waldeyerstraße 30, 48149 Münster, Germany. Tel +49 (0)251 / 83-47061, Fax +49
EP
Number of words: 2496
TE D
(0)251 / 83-47134, Email: [email protected]
AC C
Key words: Treatment outcome; clinical effectiveness; patient harm
Running title: Benefits and harm of therapies
2
ACCEPTED MANUSCRIPT Abstract Objective This third article in a series of four aims to inform dental practitioners on the importance of weighing benefits and harm when making clinical treatment decisions.
RI PT
Methods
This article describes some examples of important consequences to patients’ health when potential side effects of interventions are not taken into consideration in the decision-making
SC
process. Some information to help dental practitioners search for data on negative effects of therapies is also presented, and the need to weigh benefits and harm of therapies is discussed.
M AN U
Results
Therapeutic interventions in dentistry may cause several side effects, such as nerve damage caused by dental implant placement. Adequate evaluation of potential side effects before performing a procedure and comprehensive communication with the patient about these side
Conclusions
TE D
effects are sine qua non conditions for any clinical decision.
The information provided in this article may encourage dental practitioners to obtain more
EP
information regarding negative aspects of clinical interventions, to more comprehensively
AC C
inform patients and improve clinical decision making.
3
ACCEPTED MANUSCRIPT This third paper in a series of four addresses an important component of the decisionmaking process: the balance between harm and benefits of therapeutic approaches.1 Dental practitioners usually focus more on the effectiveness of therapies than on their potential side effects. This behavior is influenced by the way in which dental research is reported, with a
RI PT
greater focus on the positive results of therapies. The omission of reporting on non-significant results and negative effects of therapies (in the form of side effects) is a common situation in several medical disciplines, and it is considered to constitute publication bias, a form of
SC
reporting bias.2
Publication bias can be detected in several ways. One pragmatic form in which dental
M AN U
practitioners can assess publication bias is by the analysis of funnel plots.3 An asymmetric funnel may indicate publications bias. However, funnel asymmetry can be caused by factors other than publication bias, and the plot may not be sufficiently accurate when few studies are included in a meta-analysis.3 The lack of comprehensive reporting of research results may
TE D
generate important clinical consequences for patients. The main objective of this article is to provide an overview of how dental practitioners could address this topic, and how they should
Definitions
EP
share information on side effects with their patients to improve the decision-making process.
This article focuses on the effects of drugs or therapies that can be harmful to patients,
AC C
Slight differences exist in the meanings of terms used to define unexpected effects of drugs or interventions, defined as follows: Adverse effect/reaction. These terms refer to the possible causal relationship between a drug/intervention and an event. The terms “adverse effect” and “adverse event” are interchangeable. However, the former is related to the “effect” of the drug or intervention, and the latter is related to the “reaction” of the patient.4
4
ACCEPTED MANUSCRIPT Adverse event. An adverse event may occur during or after the use of a drug or other intervention, but is not necessarily caused by it. In other words, the event may be associated with the drug or intervention, but a cause-effect relationship may not exist. Side effect. A side effect is an unintended effect of an intervention, associated most
RI PT
commonly with the use of a pharmaceutical drug. Side effects do not necessarily have negative impacts on patients’ health.4
The effect of not reporting harm: two examples from the medical sciences
SC
The withdrawal of drugs from the market for reasons of safety is not unusual. For example, 19 drugs were withdrawn from the market in the European Union between 2002 and 2011.5
M AN U
Some of these drugs had been in the market for almost 50 years.5 Although many of these drugs may not cause relevant complications, some of them may create life-threatening conditions. This is the case for non-steroidal anti-inflammatory drugs, which may increase the risks of myocardial infarction, stroke, and cardiovascular death.6 For example, a well-known
TE D
case in the pharmaceutical industry was the withdrawal of rofecoxib (known commercially as Vioxx) from the market in 20046 due to its association with thrombotic events that could lead to heart attack and stroke, mainly when the drug was used long term in high doses.
EP
Interestingly, potential adverse effects of this drug were identified in 2000, but the authors of that study, which was supported by the company producing the drug, claimed that the
AC C
adverse effect was not caused by rofecoxib.7 A cumulative meta-analysis of randomized controlled trials (RCTs)8 conducted several years earlier demonstrated that evidence was sufficient to withdraw rofecoxib. The authors of the meta-analysis stated at that time that “the reasons why manufacturer and drug licensing authorities did not continuously monitor and summarize the accumulating evidence need to be clarified.”8 One potential explanation for this lack of monitoring is that the global sales of rofecoxib amounted to US$2.5 billion in 2003.9
5
ACCEPTED MANUSCRIPT Another drug that caused severe adverse reactions is thalidomide, which was prescribed as a sedative in the late 1950s.10 The drug was also prescribed for the treatment of nausea in pregnant women.10 The drug did not affect the mothers, but their babies were born with malformed limbs. It is estimated that thalidomide caused birth defects in thousands of
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children around the world.10 The drug was withdrawn several decades ago, although not uniformly across countries, which prolonged its devastating effects. The consequences of not reporting harm in dentistry
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Studies in dentistry are usually planned to detect the efficacy or effectiveness of therapies or products. “Efficacy” refers to the beneficial effect of a drug or intervention under ideal and
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well-controlled conditions. “Effectiveness” is related to the effect of a drug or intervention under ordinary or “real-life” conditions.11 Many clinical trials include reporting on the potential adverse effects or complications of therapies, but they are not usually primary study outcomes. Information on harm is usually presented only as a consequence of the therapies;
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the prospective identification of harm is not usually planned. Furthermore, a structured way of presenting data on harm in dental clinical trials appears to be lacking. For example, some evidence suggests that information on harm is not well reported in RCTs in periodontology.12
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It would be important that clinical trials reporting harm follow the guidelines proposed by the Enhancing the QUAlity and Transparency Of health Research (EQUATOR) Network.13 These
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guidelines are an extension of the CONsolidated Standards Of Reporting Trials (CONSORT) statement for reporting of RCTs. The same group also produced guidelines for reporting of harm in systematic reviews.14 To make adequate clinical decisions, dental practitioners and patients need to have comprehensive information about the effects of therapies. Obviously, the “negative” impacts of therapies need to be taken into account when these decisions are made. Comprehensive information is also mandatory when dental practitioners legally need to inform patients about planned therapies. In legal informed consent, which is mandatory in
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ACCEPTED MANUSCRIPT most parts of the world, patients give permission to be treated after they have received information about their treatments. Transparent and comprehensive reporting of the benefits and harm of therapies is thus pivotal in obtaining more accurate and meaningful legal informed consent. Ethical concerns may arise when patients are not properly informed of the
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consequences of therapies. An imbalance in knowledge between dental practitioners and
patients regarding therapies may lead to biased decision making. One can consider that the party retaining the greater knowledge (dental practitioner) may influence the direction and
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content of the conversation and bias the decision-making process.15 Searching for evidence on harm
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Some evidence suggests that reporting of harm is less complete than reporting of benefits of therapies, and this might be true at the primary research (clinical studies) and secondary research (systematic reviews) levels.16 Thus, dental practitioners need to rely on evidencebased skills when searching for adequate literature that can give them a comprehensive view
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of all potential effects of a specific therapeutic intervention.
One approach would be to first search for evidence-based guidelines that primarily address side effects or complications of therapies. If such guidelines do not exist or current
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guidelines have low methodological quality, as evaluated with the Appraisal of Guidelines for Research & Evaluation (AGREE II) instrument,17 then dental practitioners need to search for
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other sources of evidence. For therapeutic interventions, scrutiny of systematic reviews of RCTs or robust RCTs with low risk of bias (ROB) for information about harm or complications would be the alternative choice. However, many side effects occur infrequently and cannot be “captured” in planned studies, such as RCTs. In many cases, side effects are identified in studies with low methodological quality, such as case series or even case reports, which were not designed specifically to identify complications or side effects of therapies. In other words, authors conduct retrospective analyses of dental charts to evaluate potential harm
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ACCEPTED MANUSCRIPT or complications of therapies in many cases. One example is the case of retrospective assessment of complications of treatment with dental implants.18,19 Weighing benefits and harm
After selecting evidence on benefits and harm, dental practitioners must judge whether
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specific therapies are appropriate for their patients. Dental practitioners should carefully evaluate how research findings are reported. One easy approach would be to first evaluate what is reported regarding outcome measures in the Materials and Methods sections of
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articles. If the authors of a study report only outcome measures related to effectiveness, then the article is not very useful for dental practitioners seeking to gather comprehensive evidence
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for clinical decision making. This lack of reporting may mainly reflect authors’ omission of reporting on non-significant outcomes or negative findings.16,20,21 This practice may generate “selective outcome reporting” bias, as it is described in the ROB tool from the Cochrane Collaboration.22 Some authors, however, may not report information on harm or side effects
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of therapies in the Materials and Methods section, but directly in the Results section as a consequence of interventions.
Talking to your patient about harm of therapies
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Sharing information with patients about potential harm caused by the adverse effects of therapies is important. To provide only information on the “perfect scenario” after therapy is
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incorrect and may raise ethical concerns. The most accurate information possible should be provided to avoid biasing the patient´s decision. For example, reporting to a patient only that “the placement of a dental implant may cause nerve damage” may be overstatement. Similarly, reporting that “it is almost impossible to damage the nerve by placing a dental implant” is also not sufficiently detailed. Dental practitioners should search the literature for evidence on the prevalence of such cases, and report this information in a way that patients understand. In this example, the explanation should answer the following questions: “how many cases similar to mine are reported in the literature?,” “what is the level of evidence of
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ACCEPTED MANUSCRIPT studies reporting these side effects?,” “what is the prevalence of adverse effects (in this case, nerve damage) in the existent literature?,” and “in case of nerve damage, what are the consequences?” Thus, the key to communication with a patient is the provision of comprehensive and accurate information on the balance between potential adverse effects and
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benefits of the proposed therapy. After a comprehensive explanation of potential side effects of therapies, some patients will likely prefer more conservative approaches due to
consideration of the risks. Other patients will prefer to take a “wait-and-see approach” and not
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immediately accept any intervention. Thus, one may consider that the provision of more
comprehensive and transparent information to patients might reduce the number of procedures
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performed in a dental practice and, consequently, the economic gain. However, more ethical behavior will increase patients´ trust in dental practitioners and improve long-term relationships between patients and professionals.
Importantly, information on side effects should be related not only to the preferred therapy,
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but also to alternate therapies in each clinical case. For example, in the case of dental implant placement in the mandibular premolar region, potential side effects of conventional prostheses or even non-interventional therapies should be discussed comprehensively with the patient
Clinical example
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before a definitive clinical decision is made.
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A patient comes to your dental office to solicit your opinion about the potential replacement of the mandibular left first molar, which was lost several years previously. The mandibular left first, second, and third molars are absent. In the left maxilla, the patient has a fixed bridge extending from the first pre-molar to the first molar. The patient does not complain of functional or aesthetic problems, but he wants a second opinion on the replacement of the mandibular left first molar. He was informed by another professional that the first molar should be replaced, and that a dental implant would be the best alternative. The patient is
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ACCEPTED MANUSCRIPT afraid that his condition (lack of posterior teeth) will cause him problems, but he is also concerned about potential risks/complications of dental implant placement. While the patient waits comfortably in the waiting room, you quickly check the Medline database (via PubMed) for potential complications of dental implant placement in this area.
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You know that the inferior alveolar nerve, an important anatomic structure, is close to the area. Thus, you search the database using keywords and Boolean operators: "dental implant" AND “complication” AND “nerve.” The system retrieves 11 potentially relevant documents
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(as searched on 11 March 2016), and you use the PubMed filter to select documents based on systematic reviews. You find two potentially relevant systematic reviews on this topic,23,24
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and one of these reviews23 is related directly to your concern. You focus on this systematic review and find that several cases of nerve damage, some with permanent loss of sensation, were reported in the primary studies included. To answer the patient’s question, you also quickly search the Medline database for information on the concept of the shortened dental
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arch using the keyword “shortened dental arch” and the “systematic review” filter. The system retrieves six documents (as searched on 11 March 2016), and you select the two most recent systematic reviews related directly to the question.25,26 Both reviews suggest that the
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creation of a shortened dental arch is a reasonable treatment approach that provides patients with good masticatory function. Furthermore, potential long-term complications, such as peri-
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implantitis,27 related to dental implant therapy make you less confident that dental implantation in this area is the best option for this patient. Finally, although your literature search did not yield accurate information about the prevalence of nerve damage after dental implant placement in this area, you realize that a substantial number of cases (n = 157) included in the systematic review involved nerve injury. After carefully weighing the benefits and harm of dental implant surgery, you return to the patient and inform him about the potential adverse effects. The patient is averse to risk, and his final decision is to take a noninterventional (wait-and-see) approach.
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ACCEPTED MANUSCRIPT Bounded edentulous space (BES) is another clinical situation in which a posterior tooth has been lost and the edentulous space is limited by adjacent teeth. Some evidence suggests that this condition can be stable in the long term in some cases, and that the replacement of the lost tooth is not a sine qua non condition.28 Four main options are available as acceptable
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therapeutic interventions for the management of a BES case. Figure 1 shows a potential
decision pathway for BES management from the perspective of consideration of the therapies’ benefits and harm. When the benefits of one therapy clearly outweigh the potential harm in
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comparison with other alternatives, then the clinical decision is relatively easy. In the case of balance among therapies regarding benefits and harm, the decision will also be based on the
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patient’s profile. “Risk takers” will likely choose therapies with greater risks of side effects, but with some advantages (even those that are not very prominent), over alternatives. Conclusions
This article intended to provide dental practitioners with basic information on how to
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address potential side effects of clinical interventions. Decision making on therapies that takes only information on effectiveness into account may place patients at risk, sometimes with lifelong consequences. Comprehensive information about the potential harm and benefits of
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therapies should be discussed thoroughly with patients before therapeutic decisions are made.
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ACCEPTED MANUSCRIPT References 1. Neumann I, Santesso N, Akl EA, Rind DM, Vandvik PO, Alonso-Coello P, Agoritsas T, Mustafa RA, Alexander PE, Schünemann H, Guyatt GH. A guide for health professionals to interpret and use recommendations in guidelines developed with the GRADE approach. J Clin Epidemiol. 2016 Apr;72:45-55.
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2. Higgins JP, Altman D. Assessing the risk of bias in included studies. J. Higgins, S. Green (Eds.), Cochrane handbook for systematic reviews of interventions 5.0.1, John Wiley & Sons, Chichester, UK (2008).
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3. Sterne, J. A., Egger, M. and Moher, D. (2008) Addressing Reporting Biases, in Cochrane Handbook for Systematic Reviews of Interventions: Cochrane Book Series (eds J. P. Higgins and S. Green), John Wiley & Sons, Ltd, Chichester, UK. doi: 10.1002/9780470712184.ch10
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4. Edwards IR and Aronson JK. Adverse drug reactions: definitions, diagnosis, and management. Lancet. 2000 Oct 7;356(9237):1255-9. 5. McNaughton R, Huet G, Shakir S. An investigation into drug products withdrawn from the EU market between 2002 and 2011 for safety reasons and the evidence used to support the decision-making. BMJ Open. 2014 Jan 15;4(1):e004221.
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6. Trelle S, Reichenbach S, Wandel S, Hildebrand P, Tschannen B, Villiger PM, Egger M, Jüni P. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011 Jan 11;342:c7086. doi: 10.1136/bmj.c7086.
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7. Bombardier C, Laine L, Reicin A, Shapiro D, Burgos-Vargas R, Davis B, Day R, Ferraz MB, Hawkey CJ, Hochberg MC, Kvien TK, Schnitzer TJ; VIGOR Study Group. Comparison of upper gastrointestinal toxicity of rofecoxib and naproxen in patients with rheumatoid arthritis. VIGOR Study Group. N Engl J Med. 2000 Nov 23;343(21):1520-8, 2 p following 1528.
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8. Jüni P, Nartey L, Reichenbach S, Sterchi R, Dieppe PA, Egger M. Risk of cardiovascular events and rofecoxib: cumulative meta-analysis. Lancet. 2004 Dec 410;364(9450):2021-9. 9. Singh D. Merck withdraws arthritis drug worldwide. BMJ. 2004 Oct 9;329(7470):816. 10. Kim JH, Scialli AR. Thalidomide: the tragedy of birth defects and the effective treatment of disease. Toxicol Sci. 2011 Jul;122(1):1-6. 11. Gartlehner G, Hansen RA, Nissman D, Lohr KN, Carey TS. Criteria for Distinguishing Effectiveness From Efficacy Trials in Systematic Reviews. Technical Review 12 (Prepared by the RTI-International–University of North Carolina Evidence-based Practice Center under Contract No. 290-02-0016.) AHRQ Publication No. 06-0046. Rockville, MD: Agency for Healthcare Research and Quality. April 2006
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ACCEPTED MANUSCRIPT 12. Faggion CM Jr, Tu YK, Giannakopoulos NN. Reporting adverse events in randomized controlled trials in periodontology: a systematic review. J Clin Periodontol. 2013 Sep;40(9):889-95. 13. Ioannidis JP, Evans SJ, Gøtzsche PC, O'Neill RT, Altman DG, Schulz K, Moher D; CONSORT Group. Better reporting of harms in randomized trials: an extension of the CONSORT statement. Ann Intern Med 2004 Nov 16;141(10):781-8.
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14. Zorzela L, Loke YK, Ioannidis JP, Golder S, Santaguida P, Altman DG, Moher D, Vohra S; PRISMA harms group. PRISMA harms checklist: improving harms reporting in systematic reviews. BMJ. 2016;352:i157.
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15. Faggion CM Jr. Informing the patient: the "forgotten" link. J Clin Epidemiology. In press.
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16. Saini P, Loke YK, Gamble C, Altman DG, Williamson PR, Kirkham JJ. Selective reporting bias of harm outcomes within studies: findings from a cohort of systematic reviews. BMJ. 2014 Nov 21;349:g6501. 17. Brouwers M, Kho ME, Browman GP, Burgers JS, Cluzeau F, Feder G, Fervers B, Graham ID, Grimshaw J, Hanna S, Littlejohns P, Makarski J, Zitzelsberger L for the AGREE Next Steps Consortium. AGREE II: Advancing guideline development, reporting and evaluation in healthcare. Can Med Assoc J. 2010. Dec 2010; 182:E839-842.
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18. Anavi Y, Allon DM, Avishai G, Calderon S. Complications of maxillary sinus augmentations in a selective series of patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2008 Jul;106(1):34-8.
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19. Kolgeci L, Mericske E, Worni A, Walker P, Katsoulis J, Mericske-Stern R. Technical complications and failures of zirconia-based prostheses supported by implants followed up to 7 years: a case series. Int J Prosthodont. 2014 Nov-Dec;27(6):544-52.
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20. Elangovan S, Prakasam S, Gajendrareddy P, Allareddy V. A Risk of Bias Assessment of Randomized Controlled Trials (RCTs) on Periodontal Regeneration Published in 2013. J Evid Based Dent Pract. 2016 Mar;16(1):30-40. 21. Pandis N, Fleming PS, Worthington H, Dwan K, Salanti G. Discrepancies in Outcome Reporting Exist Between Protocols and Published Oral Health Cochrane Systematic Reviews. PLoS One. 2015 Sep 14;10(9):e0137667. 22. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. BMJ. 2011 Oct 18;343:d5928. 23. Shavit I, Juodzbalys G. Inferior alveolar nerve injuries following implant placement importance of early diagnosis and treatment: a systematic review. J Oral Maxillofac Res. 2014 Dec 29;5(4):e2.
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ACCEPTED MANUSCRIPT 24. Wanner L, Manegold-Brauer G, Brauer HU. Review of unusual intraoperative and postoperative complications associated with endosseous implant placement. Quintessence Int. 2013 Nov-Dec;44(10):773-81. 25. Faggion CM Jr. The shortened dental arch revisited: from evidence to recommendations by the use of the GRADE approach. J Oral Rehabil. 2011 Dec;38(12):940-9.
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26. Khan S, Musekiwa A, Chikte UM, Omar R. Differences in functional outcomes for adult patients with prosthodontically-treated and -untreated shortened dental arches: a systematic review. PLoS One. 2014 Jul 3;9(7):e101143.
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27. Atieh MA, Alsabeeha NH, Faggion CM Jr, Duncan WJ. The frequency of peri-implant diseases: a systematic review and meta-analysis. J Periodontol. 2013 Nov;84(11):1586-98.
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28. Faggion CM Jr, Giannakopoulos NN, Listl S. How strong is the evidence for the need to restore posterior bounded edentulous spaces in adults? Grading the quality of evidence and the strength of recommendations. J Dent. 2011 Feb;39(2):108-16.
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ACCEPTED MANUSCRIPT Figure 1. Decision path for managing a bounded edentulous space (BES) with focus on benefits and harm of therapies. BES 46
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Check benefits and harm (short- and long-term)
„Wait and see“
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Removable prosthesis
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Fixed bridge 45-47
Implant + crown
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Benefits clearly outweighs harm
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Analyze patient´s profile (risk-taking or risk-averse)
Select the best therapy
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Balanced benefits and harm
Risktaker
Select the therapy with „greatest“ effectiveness
Riskaverse
Select the therapy with least risk
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ACCEPTED MANUSCRIPT Appendix Table 1. Methodological tools reported in this article
AGREE II17
Checklist consisted of the original PRISMA checklist for systematic reviews plus four reporting elements directly related to harm reporting Instrument with 23-items, distributed in six domains. Items are rated using a seven-point response scale The instrument cover six domains of bias with the assessment of ROB performed in two parts: firstly, assessors generate the support for judgement; secondly, assessors assign a judgement of ROB, based on the information provided in the first part
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Cochrane ROB22
Rationale Checklist with 10 recommendations about reporting harm-related issues
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PRISMA harms* 14
Objective To evaluate the report of harm in randomized trials To improve to improve harm reporting in systematic reviews To assess the quality and reporting of practice guidelines To asses risk of bias in randomized trials
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Tool CONSORT harms*13
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* Authors of these tools use the term “harms”. In the present article the term used was harm (singular)
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ACCEPTED MANUSCRIPT Table 2. List of acronyms
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RCT: randomized controlled trial EQUATOR: Enhancing the QUAlity and Transparency Of health Research CONSORT: CONsolidated Standards Of Reporting Trials ROB: risk of bias BES: bounded edentulous space AGREE: Appraisal of Guidelines for Research & Evaluation
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• • • • • •