- Email: [email protected]
SELECTIONS FROM THE CURRENT LITERATURE
JOURNALSCAN
SELECTIONS
FROM
THE
CURRENT
LITERATURE
Compiled by Bruce Pihlstrom, DDS, MS
PRAGMATIC CLINICAL TRIALS
Ware JH, Hamel MB. Pragmatic trials: guides to better patient care? N Engl J Med 2011;364(18):1685-1687. ackground. Randomized clinical trials are the highest level of evidence in clinical research. However, these trials often address efficacy in homogenous patient populations and require that standardized treatments be followed rigidly in a randomized and masked manner in which neither patients nor clinicians are aware of the treatment being administered. Because such trials are conducted under well-controlled and sometimes artificial conditions, they may not reflect actual clinical practice. Methods. In this article, Ware and Hamel discuss their perspective concerning the advantages and disadvantages of randomized controlled trials, which are designed to establish efficacy, as compared with pragmatic trials, which are conducted to determine effectiveness in real-world practice situations. Results. The authors argue that because randomized controlled trials that seek to establish efficacy are performed under wellcontrolled conditions, they do not reflect the complexity and diversity of clinical practice. They also note that whereas placebo-controlled trials may help to establish efficacy of a specific treatment or new drug, they do not offer evidence regarding the advantages of using one treatment or drug over another. On the other hand, pragmatic or practical clinical trials are conducted in the real world of clinical practice and are designed and conducted
B
to answer important clinical questions for patients, clinicians and policymakers.1 Investigators in these trials use broad enrollment criteria, recruit patients from varied practice settings and manage patient care in a manner that is consistent with usual clinical practice. However, practical clinical trials may be more likely to have unknown bias than do efficacy trials because they are not controlled as tightly. Ware and Hamel state that pragmatic clinical trials are stronger when they include objective measures of treatment outcome, such as test results and survival rates, in addition to more subjective measures, such as qualityof-life assessments. The authors note that because pragmatic trials are not as controlled as are efficacy trials, they have less internal validity but greater generalizability than do efficacy trials. Why is this study important? Patients, clinicians and policymakers need evidence on which to base important decisions regarding prevention and treatment of disease. While the randomized clinical trials provide the best evidence of efficacy, their results may not be directly applicable to everyday practice. The “pragmatic” or “practical” clinical trial may be more likely to introduce unknown bias, but it is conducted under real-world conditions of clinical practice that may be more reflective of actual clinical practice. Both types of trials have advantages and disadvantages, and it is important that clinicians understand these differences when evaluating clinical evidence. 1. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and public health policy. JAMA 2003;290(12):1624-1632.
JADA 142(11)
http://jada.ada.org
Copyright © 2011 American Dental Association. All rights reserved.
November 2011
1297
JOURNALSCAN
A PRAGMATIC STUDY OF CONVENTIONAL VERSUS IMPLANT-SUPPORTED OVERDENTURES
Rashid F, Awad MA, Thomason JM, et al. The effectiveness of 2-implant overdentures: a pragmatic international multicentre study. J Oral Rehabil 2011;38(3):176-184. ackground. Although randomized clinical trials (RCTs) offer the highest level of clinical research evidence, their results may not always reflect effectiveness in clinical practice. As noted by the authors of this article, investigators in several controlled clinical trials have compared the efficacy of implant-supported overdentures with that of conventional dentures. However, there is relatively little evidence regarding the effectiveness of implant-supported dentures compared with that of conventional dentures in community settings. The purpose of this prospective observational study was to determine patient satisfaction with either mandibular two-implant–supported dentures or conventional dentures in real-world practice settings. Methods. Rashid and colleagues enrolled 203 patients with a mean age of 68.8 years (standard deviation = 10.4 years) at a total of eight centers at academic dental schools in Montreal (n = 23); Ann Arbor, Mich. (n = 15); Buenos Aires, Argentina (n = 29); Geneva and Berne, Switzerland (n = 18); Breda, Netherlands (n = 24); Cork, Ireland (n = 25); Freiburg, Germany (n = 37); and Newcastle, England (n = 32). They did not assign participants to the treatments randomly. The decision to provide either treatment was based on agreement between the patient and clinician, as would be the case in routine clinical practice. Moreover, clinicians were free to treat each patient on a case-by-case basis as they normally would do in clinical practice. Participants used a visual analog scale questionnaire at baseline and at various intervals after receiving their prostheses to measure general satisfaction; ability to clean, speak and chew; and comfort, esthetics and stability of dentures. This article presents six-month follow-up data. Results. The authors analyzed satisfaction data from patients who had complete baseline and six-month follow-up questionnaires available (n = 102; 50.2 percent of 203 participants enrolled at baseline). When adjusted for age, sex and pretreatment satisfaction, data indicated that implant-supported overdentures were rated significantly higher (P < .05) than conventional dentures in terms of general satisfaction, speaking ability, comfort, denture stability and chewing ability. There was no statistically sig-
B
1298 JADA 142(11)
http://jada.ada.org
nificant difference in participants’ assessments of ability to clean their dentures or in selfperceived esthetic appearance of their dentures. Why is this study important? There are several important aspects to this pragmatic study that make it important. It was prospective in design, it was conducted in several countries with a heterogeneous sample of patients and it used patient-centered outcomes to measure effectiveness. Decisions regarding treatment were made by clinicians and patients together, and treatment was delivered by practitioners with varied levels of practice experience in an environment that was similar to that of real-world dental practice. As noted by the authors, results of this study should be useful to dentists who must make decisions about prosthodontic care for their edentulous patients. Although the study does not have the same level of internal validity that an RCT may achieve, it is likely to have greater external validity or generalizability to clinical practice. As also noted by the authors, these types of studies are not a substitute for RCTs, which are intended to determine efficacy; rather, they complement RCTs with real-world effectiveness information that efficacy trials are unable to capture. GENOMEWIDE ASSOCIATION STUDIES OF C-REACTIVE PROTEIN
Dehghan A, Dupuis J, Barbalic M, et al. Meta-analysis of genome-wide association studies in > 80,000 subjects identifies multiple loci for C-reactive protein levels. Circulation 2011;123(7):731-738. ackground. C-reactive protein (CRP) is a blood serum protein that is elevated during systemic inflammation and in a broad range of chronic diseases1 that include rheumatoid arthritis,2 stroke,3 coronary heart disease4 and periodontal disease.5 The authors of this study sought to determine if specific genetic variants or gene loci are associated with CRP levels. Methods. Dehghan and colleagues performed a genome-wide association meta-analysis, by using data from 15 population-based studies involving a total of 66,185 participants, to identify genetic loci for circulating levels of CRP. They also conducted a genome-wide association study of an additional 16,540 participants in 10 independent studies to determine if they could replicate results of their meta-analysis. Results. The authors found 18 genome-wide significant loci for CRP and were able to replicate their findings for eight of the genetic loci. A
B
November 2011
Copyright © 2011 American Dental Association. All rights reserved.
JOURNALSCAN
genetic risk score based on alleles at these 18 loci explained only about 5 percent of the observed variation in CRP levels. The authors noted that several of the genes identified were shown previously to be related to metabolic pathways involved in diabetes mellitus or the inflammatory immune response. Although the authors reported that body mass index (BMI) modified the association between one genetic locus and CRP, they found no association between the genetic risk score and risk of experiencing myocardial infarction or coronary heart disease. Why is this study important? Very large studies are needed to document the association of clinical observations with specific gene locations in the human genome. By using a metaanalysis of data from more than 80,000 participants, the authors were able to identify 18 gene loci associated with CRP levels. Alleles at these loci explained only a small percentage of the variation in CRP levels in the population. However, the authors were able to identify one gene that affected serum CRP levels differently in the presence of high or low BMI. Taken together, the findings indicate that CRP levels are determined in part by genetic factors. This has implications for oral health research, because investigators in future studies of the association between inflammatory oral disease and serum CRP levels may need to consider both genetic and nongenetic influences on CRP levels. 1. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant metaanalysis. Lancet 2010;375(9709):132-140. 2. Emery P, Gabay C, Kraan M, Gomez-Reino J. Evidence-based review of biologic markers as indicators of disease progression and remission in rheumatoid arthritis. Rheumatol Int 2007;27(9):793-806. 3. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of Creactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001;32(11):2575-2579. 4. Ridker PM, Silvertown JD. Inflammation, C-reactive protein, and atherothrombosis. J Periodontol 2008;79(8 suppl):1544-1551. 5. Slade GD, Offenbacher S, Beck JD, et al. Acute-phase inflammatory response to periodontal disease in the US population. J Dent Res 2000;79(1):49-57.
A NEWLY DISCOVERED CARIES PATHOGEN
Tanner AC, Mathney JM, Kent RL, et al. Cultivable anaerobic microbiota of severe early childhood caries. J Clin Microbiol 2011;49(4):1464-1474.
B
Streptococcus mutans bacteria, but other microorganisms also may be associated with ECC. By using polymerase chain reaction (PCR) to amplify a few pieces of bacterial DNA into thousands or millions of copies and molecular methods of identification, the investigators in this study sought to determine whether bacteria other than S. mutans could be associated significantly with caries. Methods. Tanner and colleagues compared the microbial composition of dental plaque from 42 children with severe ECC with that of 40 caries-free children by growing plaque cultures under anaerobic conditions and using PCR DNA amplification and molecular methods to identify and compare bacterial species in dental plaque from children with and without ECC. Results. The authors reported that the major bacterial species associated with severe ECC included S. mutans, Scardovia wiggsiae, Veillonella parvula, Streptococcus cristatus and Actinomyces gerencseriae. S. wiggsiae was significantly associated with severe cases of ECC in the presence and absence of detected S. mutans. The authors concluded that major caries-associated species were S. mutans and S. wiggsiae and that S. wiggsiae should be considered a new candidate as a pathogen involved in the development of dental caries. Why is this study important? This is one of the largest culture-based studies ever published regarding the microbiota of EEC. S. mutans has been considered to be the primary bacterial risk indicator for dental caries. However, the bacterial ecology of dental plaque is extremely complex, and this study expands our understanding of the biodiversity of dental plaque and the bacteriology of dental caries. Although additional research is needed, the findings may indicate that S. wiggsiae is another important pathogen and a newly identified risk factor for dental caries. ■ Dr. Pihlstrom is a professor emeritus, Department of Surgical and Developmental Sciences, School of Dentistry, University of Minnesota, Minneapolis. He also is the associate editor, research, for The Journal of the American Dental Association, as well as an independent oral health research consultant. Address reprint requests to Dr. Pihlstrom, 4801 Fairmont Ave., #902, Bethesda, Md. 20814, e-mail “[email protected]”. Disclosure. Dr. Pihlstrom did not report any disclosures.
ackground. Severe early childhood caries (ECC) has been strongly associated with
JADA 142(11)
http://jada.ada.org
Copyright © 2011 American Dental Association. All rights reserved.
November 2011
1299
SELECTIONS
FROM
THE
CURRENT
LITERATURE
Compiled by Bruce Pihlstrom, DDS, MS
PRAGMATIC CLINICAL TRIALS
Ware JH, Hamel MB. Pragmatic trials: guides to better patient care? N Engl J Med 2011;364(18):1685-1687. ackground. Randomized clinical trials are the highest level of evidence in clinical research. However, these trials often address efficacy in homogenous patient populations and require that standardized treatments be followed rigidly in a randomized and masked manner in which neither patients nor clinicians are aware of the treatment being administered. Because such trials are conducted under well-controlled and sometimes artificial conditions, they may not reflect actual clinical practice. Methods. In this article, Ware and Hamel discuss their perspective concerning the advantages and disadvantages of randomized controlled trials, which are designed to establish efficacy, as compared with pragmatic trials, which are conducted to determine effectiveness in real-world practice situations. Results. The authors argue that because randomized controlled trials that seek to establish efficacy are performed under wellcontrolled conditions, they do not reflect the complexity and diversity of clinical practice. They also note that whereas placebo-controlled trials may help to establish efficacy of a specific treatment or new drug, they do not offer evidence regarding the advantages of using one treatment or drug over another. On the other hand, pragmatic or practical clinical trials are conducted in the real world of clinical practice and are designed and conducted
B
to answer important clinical questions for patients, clinicians and policymakers.1 Investigators in these trials use broad enrollment criteria, recruit patients from varied practice settings and manage patient care in a manner that is consistent with usual clinical practice. However, practical clinical trials may be more likely to have unknown bias than do efficacy trials because they are not controlled as tightly. Ware and Hamel state that pragmatic clinical trials are stronger when they include objective measures of treatment outcome, such as test results and survival rates, in addition to more subjective measures, such as qualityof-life assessments. The authors note that because pragmatic trials are not as controlled as are efficacy trials, they have less internal validity but greater generalizability than do efficacy trials. Why is this study important? Patients, clinicians and policymakers need evidence on which to base important decisions regarding prevention and treatment of disease. While the randomized clinical trials provide the best evidence of efficacy, their results may not be directly applicable to everyday practice. The “pragmatic” or “practical” clinical trial may be more likely to introduce unknown bias, but it is conducted under real-world conditions of clinical practice that may be more reflective of actual clinical practice. Both types of trials have advantages and disadvantages, and it is important that clinicians understand these differences when evaluating clinical evidence. 1. Tunis SR, Stryer DB, Clancy CM. Practical clinical trials: increasing the value of clinical research for decision making in clinical and public health policy. JAMA 2003;290(12):1624-1632.
JADA 142(11)
http://jada.ada.org
Copyright © 2011 American Dental Association. All rights reserved.
November 2011
1297
JOURNALSCAN
A PRAGMATIC STUDY OF CONVENTIONAL VERSUS IMPLANT-SUPPORTED OVERDENTURES
Rashid F, Awad MA, Thomason JM, et al. The effectiveness of 2-implant overdentures: a pragmatic international multicentre study. J Oral Rehabil 2011;38(3):176-184. ackground. Although randomized clinical trials (RCTs) offer the highest level of clinical research evidence, their results may not always reflect effectiveness in clinical practice. As noted by the authors of this article, investigators in several controlled clinical trials have compared the efficacy of implant-supported overdentures with that of conventional dentures. However, there is relatively little evidence regarding the effectiveness of implant-supported dentures compared with that of conventional dentures in community settings. The purpose of this prospective observational study was to determine patient satisfaction with either mandibular two-implant–supported dentures or conventional dentures in real-world practice settings. Methods. Rashid and colleagues enrolled 203 patients with a mean age of 68.8 years (standard deviation = 10.4 years) at a total of eight centers at academic dental schools in Montreal (n = 23); Ann Arbor, Mich. (n = 15); Buenos Aires, Argentina (n = 29); Geneva and Berne, Switzerland (n = 18); Breda, Netherlands (n = 24); Cork, Ireland (n = 25); Freiburg, Germany (n = 37); and Newcastle, England (n = 32). They did not assign participants to the treatments randomly. The decision to provide either treatment was based on agreement between the patient and clinician, as would be the case in routine clinical practice. Moreover, clinicians were free to treat each patient on a case-by-case basis as they normally would do in clinical practice. Participants used a visual analog scale questionnaire at baseline and at various intervals after receiving their prostheses to measure general satisfaction; ability to clean, speak and chew; and comfort, esthetics and stability of dentures. This article presents six-month follow-up data. Results. The authors analyzed satisfaction data from patients who had complete baseline and six-month follow-up questionnaires available (n = 102; 50.2 percent of 203 participants enrolled at baseline). When adjusted for age, sex and pretreatment satisfaction, data indicated that implant-supported overdentures were rated significantly higher (P < .05) than conventional dentures in terms of general satisfaction, speaking ability, comfort, denture stability and chewing ability. There was no statistically sig-
B
1298 JADA 142(11)
http://jada.ada.org
nificant difference in participants’ assessments of ability to clean their dentures or in selfperceived esthetic appearance of their dentures. Why is this study important? There are several important aspects to this pragmatic study that make it important. It was prospective in design, it was conducted in several countries with a heterogeneous sample of patients and it used patient-centered outcomes to measure effectiveness. Decisions regarding treatment were made by clinicians and patients together, and treatment was delivered by practitioners with varied levels of practice experience in an environment that was similar to that of real-world dental practice. As noted by the authors, results of this study should be useful to dentists who must make decisions about prosthodontic care for their edentulous patients. Although the study does not have the same level of internal validity that an RCT may achieve, it is likely to have greater external validity or generalizability to clinical practice. As also noted by the authors, these types of studies are not a substitute for RCTs, which are intended to determine efficacy; rather, they complement RCTs with real-world effectiveness information that efficacy trials are unable to capture. GENOMEWIDE ASSOCIATION STUDIES OF C-REACTIVE PROTEIN
Dehghan A, Dupuis J, Barbalic M, et al. Meta-analysis of genome-wide association studies in > 80,000 subjects identifies multiple loci for C-reactive protein levels. Circulation 2011;123(7):731-738. ackground. C-reactive protein (CRP) is a blood serum protein that is elevated during systemic inflammation and in a broad range of chronic diseases1 that include rheumatoid arthritis,2 stroke,3 coronary heart disease4 and periodontal disease.5 The authors of this study sought to determine if specific genetic variants or gene loci are associated with CRP levels. Methods. Dehghan and colleagues performed a genome-wide association meta-analysis, by using data from 15 population-based studies involving a total of 66,185 participants, to identify genetic loci for circulating levels of CRP. They also conducted a genome-wide association study of an additional 16,540 participants in 10 independent studies to determine if they could replicate results of their meta-analysis. Results. The authors found 18 genome-wide significant loci for CRP and were able to replicate their findings for eight of the genetic loci. A
B
November 2011
Copyright © 2011 American Dental Association. All rights reserved.
JOURNALSCAN
genetic risk score based on alleles at these 18 loci explained only about 5 percent of the observed variation in CRP levels. The authors noted that several of the genes identified were shown previously to be related to metabolic pathways involved in diabetes mellitus or the inflammatory immune response. Although the authors reported that body mass index (BMI) modified the association between one genetic locus and CRP, they found no association between the genetic risk score and risk of experiencing myocardial infarction or coronary heart disease. Why is this study important? Very large studies are needed to document the association of clinical observations with specific gene locations in the human genome. By using a metaanalysis of data from more than 80,000 participants, the authors were able to identify 18 gene loci associated with CRP levels. Alleles at these loci explained only a small percentage of the variation in CRP levels in the population. However, the authors were able to identify one gene that affected serum CRP levels differently in the presence of high or low BMI. Taken together, the findings indicate that CRP levels are determined in part by genetic factors. This has implications for oral health research, because investigators in future studies of the association between inflammatory oral disease and serum CRP levels may need to consider both genetic and nongenetic influences on CRP levels. 1. Emerging Risk Factors Collaboration, Kaptoge S, Di Angelantonio E, et al. C-reactive protein concentration and risk of coronary heart disease, stroke, and mortality: an individual participant metaanalysis. Lancet 2010;375(9709):132-140. 2. Emery P, Gabay C, Kraan M, Gomez-Reino J. Evidence-based review of biologic markers as indicators of disease progression and remission in rheumatoid arthritis. Rheumatol Int 2007;27(9):793-806. 3. Rost NS, Wolf PA, Kase CS, et al. Plasma concentration of Creactive protein and risk of ischemic stroke and transient ischemic attack: the Framingham study. Stroke 2001;32(11):2575-2579. 4. Ridker PM, Silvertown JD. Inflammation, C-reactive protein, and atherothrombosis. J Periodontol 2008;79(8 suppl):1544-1551. 5. Slade GD, Offenbacher S, Beck JD, et al. Acute-phase inflammatory response to periodontal disease in the US population. J Dent Res 2000;79(1):49-57.
A NEWLY DISCOVERED CARIES PATHOGEN
Tanner AC, Mathney JM, Kent RL, et al. Cultivable anaerobic microbiota of severe early childhood caries. J Clin Microbiol 2011;49(4):1464-1474.
B
Streptococcus mutans bacteria, but other microorganisms also may be associated with ECC. By using polymerase chain reaction (PCR) to amplify a few pieces of bacterial DNA into thousands or millions of copies and molecular methods of identification, the investigators in this study sought to determine whether bacteria other than S. mutans could be associated significantly with caries. Methods. Tanner and colleagues compared the microbial composition of dental plaque from 42 children with severe ECC with that of 40 caries-free children by growing plaque cultures under anaerobic conditions and using PCR DNA amplification and molecular methods to identify and compare bacterial species in dental plaque from children with and without ECC. Results. The authors reported that the major bacterial species associated with severe ECC included S. mutans, Scardovia wiggsiae, Veillonella parvula, Streptococcus cristatus and Actinomyces gerencseriae. S. wiggsiae was significantly associated with severe cases of ECC in the presence and absence of detected S. mutans. The authors concluded that major caries-associated species were S. mutans and S. wiggsiae and that S. wiggsiae should be considered a new candidate as a pathogen involved in the development of dental caries. Why is this study important? This is one of the largest culture-based studies ever published regarding the microbiota of EEC. S. mutans has been considered to be the primary bacterial risk indicator for dental caries. However, the bacterial ecology of dental plaque is extremely complex, and this study expands our understanding of the biodiversity of dental plaque and the bacteriology of dental caries. Although additional research is needed, the findings may indicate that S. wiggsiae is another important pathogen and a newly identified risk factor for dental caries. ■ Dr. Pihlstrom is a professor emeritus, Department of Surgical and Developmental Sciences, School of Dentistry, University of Minnesota, Minneapolis. He also is the associate editor, research, for The Journal of the American Dental Association, as well as an independent oral health research consultant. Address reprint requests to Dr. Pihlstrom, 4801 Fairmont Ave., #902, Bethesda, Md. 20814, e-mail “[email protected]”. Disclosure. Dr. Pihlstrom did not report any disclosures.
ackground. Severe early childhood caries (ECC) has been strongly associated with
JADA 142(11)
http://jada.ada.org
Copyright © 2011 American Dental Association. All rights reserved.
November 2011
1299