Accepted Manuscript Antibiotic Prophylaxis Guidelines and Infective Endocarditis – Cause for Concern? Dr Mark Dayer, Consultant Cardiologist, BSc (Hons), MBBS (Hons), PhD, Professor Martin Thornhill, Professor of Translational Research in Dentistry, MBBS, BDS, MSc (Hons) Eng, PhD. PII:
S0735-1097(15)01545-4
DOI:
10.1016/j.jacc.2015.03.535
Reference:
JAC 21190
To appear in:
Journal of the American College of Cardiology
Received Date: 14 March 2015 Accepted Date: 18 March 2015
Please cite this article as: Dayer M, Thornhill M, Antibiotic Prophylaxis Guidelines and Infective Endocarditis – Cause for Concern?, Journal of the American College of Cardiology (2015), doi: 10.1016/ j.jacc.2015.03.535. 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.
ACCEPTED MANUSCRIPT
Antibiotic Prophylaxis Guidelines and Infective Endocarditis – Cause for Concern?
RI PT
Dr Mark Dayer, Consultant Cardiologist, BSc (Hons), MBBS (Hons), PhD Department of Cardiology, Taunton and Somerset NHS Trust.
Brief Title: IE and Antibiotic Prophylaxis Guidelines Cover Title: Are the IE Guidelines a Cause for Concern?
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Corresponding Author: Dr Mark Dayer Department of Cardiology Taunton and Somerset NHS Trust Musgrove Park, Taunton, TA1 5DA United Kingdom Telephone: 07428690564 Fax 01823 344916 E-mail: [email protected]
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Neither author has any conflict of interests.
SC
Professor Martin Thornhill, Professor of Translational Research in Dentistry, MBBS, BDS, MSc (Hons) Eng, PhD. Academic Unit of Oral and Maxillofacial Medicine & Surgery, University of Sheffield School of Clinical Dentistry
1
ACCEPTED MANUSCRIPT
In 1923, Lewis and Grant were the first to suggest that bacteria, released into the circulation as a consequence of a dental procedure, might cause infective endocarditis (IE) (1). In 1955, the first American Heart Association (AHA) guidelines recommending antibiotic
RI PT
prophylaxis to reduce the risk of IE following invasive procedures were published (2). Since that time, there has been a gradual reduction in the intensity and duration of antibiotic prophylaxis and the number of patients for whom it is recommended has reduced.
SC
In April 2007, the latest iteration of the AHA guidelines (3) provided an update on the previous guidelines from 1997 (4). The authors of the most recent guidelines felt that the benefits of
M AN U
antibiotic prophylaxis were likely to be small, and that only patients at the highest risk of an adverse outcome should be offered prophylaxis for invasive dental procedures. Prophylaxis for those at moderate risk of an adverse outcome, and/or for those having genitourinary or gastrointestinal tract procedures was no longer recommended. In the final paragraph of the
TE D
document, the AHA urged that studies to document the impact be instituted promptly, “so that any change in incidence may be detected sooner rather than later”. Since 2007, a number of studies have been published that have examined the impact of
EP
the AHA guidelines. Rogers et al., reporting on their experience in a San Francisco medical center in 2008 (5), demonstrated no increase in the number of admissions 9 months after the
AC C
guideline change. A study by Bor et al., which used National Inpatient Sample Data to assess a broad sample of patients from 1998-2009, did not show any inflection in the rise of infective endocarditis after the guideline change, nor an increase in the number of cases secondary to streptococcal infections, but only looked out to 2 years after the change (6). DeSimone et al., looking at data from the start of 1999 to the end of 2010 (7), used very detailed data from the Rochester Epidemiology Project. They concluded that there was no perceivable increase in the
2
ACCEPTED MANUSCRIPT
incidence of viridans group streptococci (VGS) in their sample, but the small sample size must be considered; there were only 3 documented cases of VGS-IE in their sample between 2007 and 2010. Pasquali et al., looking specifically at IE in children across 37 hospitals between 2003 and
RI PT
2010, found no significant change in the absolute numbers of cases before and after the guideline change. Finally, Bikdeli et al. looked at admissions in patients over the age of 65 using Medicare inpatient Standard Analytic Files (9). They recorded a reduction in the absolute numbers, but no
SC
correction was made for the absolute numbers of patients enrolled in Medicare and eligible for treatment. They commented, “our analysis, however, was not meant to be a comparative
M AN U
effectiveness study to prove the non-inferiority of more restrictive use of antibiotics for endocarditis prophylaxis”.
The latest study to look at the impact of the 2007 guidelines is published in this edition of JACC (10). The data have been extracted from the National Inpatient Sample, as in the Bor et al.
TE D
study. The authors have looked between 2000 and 2011, extending the follow-up time after the change in guidelines to 4 years. The data confirm a steady rise in the number of cases of IE. Importantly, there has been no acceleration in this rise, unlike in the United Kingdom (11). The
EP
reasons for the rise are, almost certainly, multifactorial. It probably reflects a lowered diagnostic threshold, an aging population, and an increase in the number of procedures that can predispose
AC C
to the development of IE. There may be some artefact in this rise too, with double (or more) counting from changes in hospital practice, with patients being transferred between hospitals, or discharged and brought back on a daily basis for outpatient-based antimicrobial therapy. Indeed, in the aforementioned Rochester Epidemiology Project, IE incidence has been falling (7). As in the Bor et al. study, the authors have attempted to look at the microbiology of infective endocarditis. This is difficult for 2 reasons, as the proportions of patients coded as
3
ACCEPTED MANUSCRIPT
having a causative organism has changed over time, and also the organism coded is not necessarily the organism that caused IE. Nonetheless, what is disconcerting is that the number of streptococcal cases appears to be rising significantly, raising the possibility that the change in
RI PT
guidelines has resulted in an increase in the number of streptococcal cases.
Looking over a longer time frame is potentially important. In the United Kingdom in March 2008, the National Institute for Health and Care Excellence (NICE) recommended that
SC
antibiotic prophylaxis should no longer be used for anyone. Dental protection societies rapidly withdrew insurance cover for reactions to prophylactic antibiotics, and there was a dramatic fall
M AN U
in their prescription. In 2011, we published a study looking at 2 years of follow-up and found no difference in the incidence of infective endocarditis (12), but a subsequent study, looking 5 years post the guideline change demonstrated a significant increase in the number of cases above the baseline trend (12).
TE D
The problems with the trials enrolling large numbers of patients, relying on coding data, is that there are likely to be inaccuracies in the database, which may affect the results, although the numbers, and hopefully the lack of systematic bias, minimizes this effect; there are data to
EP
suggest that the coding of IE in similar databases is quite accurate (13). Also, there is no estimation in the paper of the impact of the 2007 AHA guidelines on the prescribing of antibiotic
AC C
prophylaxis. It remains unclear how practice has changed, if at all, and who continues to get antibiotic prophylaxis, although there is a suggestion that there has been some shift, at least among dentists (14). Furthermore, correlation does not equal causation, and there is no proof the effect seen is the result of the guideline change. This is an important study, which raises important questions about the impact of the AHA guidelines and underlines the need for on going monitoring of both antibiotic prophylaxis
4
ACCEPTED MANUSCRIPT
prescribing practice and the incidence of IE. As the authors point out, however, the fundamental problem is that there has never been a randomized controlled clinical trial into the efficacy of antibiotic prophylaxis, and so there is no reliable evidence to support its use. The time for this to
AC C
EP
TE D
M AN U
SC
RI PT
change is long overdue.
5
ACCEPTED MANUSCRIPT
REFERENCES: 1.
Lewis T, Grant RT. Observations relating to subacute infective endocarditis. British heart journal 1923;10:21-77. Jones TD, Baumgartner L, Bellows MT, et al. Prevention of rheumatic fever and
RI PT
2.
bacterial endocarditis through control of streptococcal infections. Circulation 1955;11:317-20.
Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis:
SC
3.
guidelines from the American Heart Association: a guideline from the American
M AN U
Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation
4.
TE D
2007;116:1736-54.
Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. Clin Infect Dis. 1997;25:1448-
5.
EP
58.
Rogers AM, Schiller NB. Impact of the first nine months of revised infective
AC C
endocarditis prophylaxis guidelines at a university hospital: so far so good. J Am Soc Echocardiog. 2008; 21: 775.
6.
Bor DH, Woolhandler S, Nardin R, et al. Infective endocarditis in the U.S., 19982009: a nationwide study. PloS One. 2013;8:e60033.
7.
Desimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endocarditis caused by viridans group streptococci before and after publication of the
6
ACCEPTED MANUSCRIPT
2007 American Heart Association's endocarditis prevention guidelines. Circulation 2012;126:60-4. 8.
Pasquali SK, He X, Mohamad Z, et al. Trends in endocarditis hospitalizations at US
Prophylaxis Guidelines. Am Heart J. 2012;163:894-9. 9.
RI PT
children's hospitals: impact of the 2007 American Heart Association Antibiotic
Bikdeli B, Wang Y, Kim N, et al. Trends in hospitalization rates and outcomes of
10.
SC
endocarditis among Medicare beneficiaries. J Am Coll Cardiol. 2013;62:2217-26. Pant S, Patel NJ, Deshmukh A et al. Trends in Infective Endocarditis Incidence,
M AN U
Microbiology and Valve Replacement in the United States from 2000-2011. J Am Coll Cardiol. 2015;65:Current Issue 11.
Dayer MJ, Jones S, Prendergast B et al. Incidence of infective endocarditis in England, 2000-13: a secular trend, interrupted time-series analysis. Lancet. [ePub 18
12.
TE D
November 2014.] DOI: http://dx.doi.org/10.1016/S0140-6736(14)62007-9 Thornhill MH, Dayer MJ, Forde JM et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective
13.
EP
endocarditis: before and after study. BMJ. 2011;342:d2392. Fedeli U, Schievano E, Buonfrate D et al. Increasing incidence and mortality of
AC C
infective endocarditis: a population-based study through a record-linkage system. BMC infectious diseases 2011;11:48.
14.
Lockhart PB, Hanson NB, Ristic H et al. Acceptance among and impact on dental practitioners and patients of American Heart Association recommendations for antibiotic prophylaxis. J Am Dent Assoc. 2013;144:1030-5.
7
S0735-1097(15)01545-4
DOI:
10.1016/j.jacc.2015.03.535
Reference:
JAC 21190
To appear in:
Journal of the American College of Cardiology
Received Date: 14 March 2015 Accepted Date: 18 March 2015
Please cite this article as: Dayer M, Thornhill M, Antibiotic Prophylaxis Guidelines and Infective Endocarditis – Cause for Concern?, Journal of the American College of Cardiology (2015), doi: 10.1016/ j.jacc.2015.03.535. 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.
ACCEPTED MANUSCRIPT
Antibiotic Prophylaxis Guidelines and Infective Endocarditis – Cause for Concern?
RI PT
Dr Mark Dayer, Consultant Cardiologist, BSc (Hons), MBBS (Hons), PhD Department of Cardiology, Taunton and Somerset NHS Trust.
Brief Title: IE and Antibiotic Prophylaxis Guidelines Cover Title: Are the IE Guidelines a Cause for Concern?
AC C
EP
TE D
Corresponding Author: Dr Mark Dayer Department of Cardiology Taunton and Somerset NHS Trust Musgrove Park, Taunton, TA1 5DA United Kingdom Telephone: 07428690564 Fax 01823 344916 E-mail: [email protected]
M AN U
Neither author has any conflict of interests.
SC
Professor Martin Thornhill, Professor of Translational Research in Dentistry, MBBS, BDS, MSc (Hons) Eng, PhD. Academic Unit of Oral and Maxillofacial Medicine & Surgery, University of Sheffield School of Clinical Dentistry
1
ACCEPTED MANUSCRIPT
In 1923, Lewis and Grant were the first to suggest that bacteria, released into the circulation as a consequence of a dental procedure, might cause infective endocarditis (IE) (1). In 1955, the first American Heart Association (AHA) guidelines recommending antibiotic
RI PT
prophylaxis to reduce the risk of IE following invasive procedures were published (2). Since that time, there has been a gradual reduction in the intensity and duration of antibiotic prophylaxis and the number of patients for whom it is recommended has reduced.
SC
In April 2007, the latest iteration of the AHA guidelines (3) provided an update on the previous guidelines from 1997 (4). The authors of the most recent guidelines felt that the benefits of
M AN U
antibiotic prophylaxis were likely to be small, and that only patients at the highest risk of an adverse outcome should be offered prophylaxis for invasive dental procedures. Prophylaxis for those at moderate risk of an adverse outcome, and/or for those having genitourinary or gastrointestinal tract procedures was no longer recommended. In the final paragraph of the
TE D
document, the AHA urged that studies to document the impact be instituted promptly, “so that any change in incidence may be detected sooner rather than later”. Since 2007, a number of studies have been published that have examined the impact of
EP
the AHA guidelines. Rogers et al., reporting on their experience in a San Francisco medical center in 2008 (5), demonstrated no increase in the number of admissions 9 months after the
AC C
guideline change. A study by Bor et al., which used National Inpatient Sample Data to assess a broad sample of patients from 1998-2009, did not show any inflection in the rise of infective endocarditis after the guideline change, nor an increase in the number of cases secondary to streptococcal infections, but only looked out to 2 years after the change (6). DeSimone et al., looking at data from the start of 1999 to the end of 2010 (7), used very detailed data from the Rochester Epidemiology Project. They concluded that there was no perceivable increase in the
2
ACCEPTED MANUSCRIPT
incidence of viridans group streptococci (VGS) in their sample, but the small sample size must be considered; there were only 3 documented cases of VGS-IE in their sample between 2007 and 2010. Pasquali et al., looking specifically at IE in children across 37 hospitals between 2003 and
RI PT
2010, found no significant change in the absolute numbers of cases before and after the guideline change. Finally, Bikdeli et al. looked at admissions in patients over the age of 65 using Medicare inpatient Standard Analytic Files (9). They recorded a reduction in the absolute numbers, but no
SC
correction was made for the absolute numbers of patients enrolled in Medicare and eligible for treatment. They commented, “our analysis, however, was not meant to be a comparative
M AN U
effectiveness study to prove the non-inferiority of more restrictive use of antibiotics for endocarditis prophylaxis”.
The latest study to look at the impact of the 2007 guidelines is published in this edition of JACC (10). The data have been extracted from the National Inpatient Sample, as in the Bor et al.
TE D
study. The authors have looked between 2000 and 2011, extending the follow-up time after the change in guidelines to 4 years. The data confirm a steady rise in the number of cases of IE. Importantly, there has been no acceleration in this rise, unlike in the United Kingdom (11). The
EP
reasons for the rise are, almost certainly, multifactorial. It probably reflects a lowered diagnostic threshold, an aging population, and an increase in the number of procedures that can predispose
AC C
to the development of IE. There may be some artefact in this rise too, with double (or more) counting from changes in hospital practice, with patients being transferred between hospitals, or discharged and brought back on a daily basis for outpatient-based antimicrobial therapy. Indeed, in the aforementioned Rochester Epidemiology Project, IE incidence has been falling (7). As in the Bor et al. study, the authors have attempted to look at the microbiology of infective endocarditis. This is difficult for 2 reasons, as the proportions of patients coded as
3
ACCEPTED MANUSCRIPT
having a causative organism has changed over time, and also the organism coded is not necessarily the organism that caused IE. Nonetheless, what is disconcerting is that the number of streptococcal cases appears to be rising significantly, raising the possibility that the change in
RI PT
guidelines has resulted in an increase in the number of streptococcal cases.
Looking over a longer time frame is potentially important. In the United Kingdom in March 2008, the National Institute for Health and Care Excellence (NICE) recommended that
SC
antibiotic prophylaxis should no longer be used for anyone. Dental protection societies rapidly withdrew insurance cover for reactions to prophylactic antibiotics, and there was a dramatic fall
M AN U
in their prescription. In 2011, we published a study looking at 2 years of follow-up and found no difference in the incidence of infective endocarditis (12), but a subsequent study, looking 5 years post the guideline change demonstrated a significant increase in the number of cases above the baseline trend (12).
TE D
The problems with the trials enrolling large numbers of patients, relying on coding data, is that there are likely to be inaccuracies in the database, which may affect the results, although the numbers, and hopefully the lack of systematic bias, minimizes this effect; there are data to
EP
suggest that the coding of IE in similar databases is quite accurate (13). Also, there is no estimation in the paper of the impact of the 2007 AHA guidelines on the prescribing of antibiotic
AC C
prophylaxis. It remains unclear how practice has changed, if at all, and who continues to get antibiotic prophylaxis, although there is a suggestion that there has been some shift, at least among dentists (14). Furthermore, correlation does not equal causation, and there is no proof the effect seen is the result of the guideline change. This is an important study, which raises important questions about the impact of the AHA guidelines and underlines the need for on going monitoring of both antibiotic prophylaxis
4
ACCEPTED MANUSCRIPT
prescribing practice and the incidence of IE. As the authors point out, however, the fundamental problem is that there has never been a randomized controlled clinical trial into the efficacy of antibiotic prophylaxis, and so there is no reliable evidence to support its use. The time for this to
AC C
EP
TE D
M AN U
SC
RI PT
change is long overdue.
5
ACCEPTED MANUSCRIPT
REFERENCES: 1.
Lewis T, Grant RT. Observations relating to subacute infective endocarditis. British heart journal 1923;10:21-77. Jones TD, Baumgartner L, Bellows MT, et al. Prevention of rheumatic fever and
RI PT
2.
bacterial endocarditis through control of streptococcal infections. Circulation 1955;11:317-20.
Wilson W, Taubert KA, Gewitz M, et al. Prevention of infective endocarditis:
SC
3.
guidelines from the American Heart Association: a guideline from the American
M AN U
Heart Association Rheumatic Fever, Endocarditis, and Kawasaki Disease Committee, Council on Cardiovascular Disease in the Young, and the Council on Clinical Cardiology, Council on Cardiovascular Surgery and Anesthesia, and the Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation
4.
TE D
2007;116:1736-54.
Dajani AS, Taubert KA, Wilson W, et al. Prevention of bacterial endocarditis: recommendations by the American Heart Association. Clin Infect Dis. 1997;25:1448-
5.
EP
58.
Rogers AM, Schiller NB. Impact of the first nine months of revised infective
AC C
endocarditis prophylaxis guidelines at a university hospital: so far so good. J Am Soc Echocardiog. 2008; 21: 775.
6.
Bor DH, Woolhandler S, Nardin R, et al. Infective endocarditis in the U.S., 19982009: a nationwide study. PloS One. 2013;8:e60033.
7.
Desimone DC, Tleyjeh IM, Correa de Sa DD, et al. Incidence of infective endocarditis caused by viridans group streptococci before and after publication of the
6
ACCEPTED MANUSCRIPT
2007 American Heart Association's endocarditis prevention guidelines. Circulation 2012;126:60-4. 8.
Pasquali SK, He X, Mohamad Z, et al. Trends in endocarditis hospitalizations at US
Prophylaxis Guidelines. Am Heart J. 2012;163:894-9. 9.
RI PT
children's hospitals: impact of the 2007 American Heart Association Antibiotic
Bikdeli B, Wang Y, Kim N, et al. Trends in hospitalization rates and outcomes of
10.
SC
endocarditis among Medicare beneficiaries. J Am Coll Cardiol. 2013;62:2217-26. Pant S, Patel NJ, Deshmukh A et al. Trends in Infective Endocarditis Incidence,
M AN U
Microbiology and Valve Replacement in the United States from 2000-2011. J Am Coll Cardiol. 2015;65:Current Issue 11.
Dayer MJ, Jones S, Prendergast B et al. Incidence of infective endocarditis in England, 2000-13: a secular trend, interrupted time-series analysis. Lancet. [ePub 18
12.
TE D
November 2014.] DOI: http://dx.doi.org/10.1016/S0140-6736(14)62007-9 Thornhill MH, Dayer MJ, Forde JM et al. Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective
13.
EP
endocarditis: before and after study. BMJ. 2011;342:d2392. Fedeli U, Schievano E, Buonfrate D et al. Increasing incidence and mortality of
AC C
infective endocarditis: a population-based study through a record-linkage system. BMC infectious diseases 2011;11:48.
14.
Lockhart PB, Hanson NB, Ristic H et al. Acceptance among and impact on dental practitioners and patients of American Heart Association recommendations for antibiotic prophylaxis. J Am Dent Assoc. 2013;144:1030-5.
7
