Antibiotic prophylaxis and the incidence of infective endocarditis following invasive dental procedures

1 Antibiotic prophylaxis and the incidence of infective endocarditis following invasive dental 1 procedures 2 3 Subtitle: A systematic review and meta-analysis from the World Workshop on Oral Medicine VIII 4 5 6 Francesca Sperotto*, MD, PhD, Katherine France*, DMD, MBE, Margherita Gobbo, DMD, MSc, 7 Mohammed Bindakhil, DDS, MS, Kununya Pimolbutr, DDS, MSc, PhD, Haly Holmes, BDS, MSc, 8 MChD, Luis Monteiro, DDS, MSc, PhD, Laurel Graham, MLS, ML, Catherine HL Hong, BDS, MS, 9 Thomas P Sollecito, DMD, Giovanni Lodi, PhD, Peter B Lockhart, DDS, Martin Thornhill, MBBS, BDS, 10 PhD, Pedro Diz Dios, MD, DDS, PhD, Federica Turati#, PhD, Valeria Edefonti#, PhD 11 12 *equally contributed as first authors 13 #equally contributed as last authors 14 15 16 Affiliations 17 Francesca Sperotto – Department of Cardiology, Boston Children’s Hospital, and Department of 18 Pediatrics, Harvard Medical School, Boston, USA; [email protected] 19 Katherine France – Department of Oral Medicine, University of Pennsylvania, Philadelphia, USA; 20 [email protected] 21 Margherita Gobbo – Unit of Oral and Maxillofacial Surgery, Ca’ Foncello Hospital, Treviso, Italy; 22 [email protected].it 23 Mohammed Bindakhil – Division of Oral Medicine, Department of Oral Biology and Diagnostic 24 Sciences, Augusta University, Augusta, USA; [email protected] 25 Kununya Pimolbutr – Department of Oral Medicine and Periodontology, Mahidol University, Bangkok, 26 Thailand; kununy[email protected] 27 Haly Holmes – Department of Oral Medicine and Periodontology, University of the Western Cape, Cape 28 Town, South Africa; hhol[email protected] 29 Luis Monteiro – University Institute of Health Sciences (CESPU), Porto, Portugal; 30 [email protected] 31 Laurel Graham – Dental Medicine Library, University of Pennsylvania, Philadelphia, USA; 32 [email protected] 33 2 Catherine HL Hong – Faculty of Dentistry, National University of Singapore, Singapore; 34 [email protected] 35 Thomas P Sollecito – Department of Oral Medicine, University of Pennsylvania, Philadelphia, USA; 36 [email protected] 37 Giovanni Lodi – Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli 38 Studi di Milano, Milan, Italy; giovann[email protected] 39 Peter B Lockhart – Department of Otolaryngology, Wake Forest University School of Medicine, Atrium 40 Health, Charlotte, USA; [email protected] 41 Martin Thornhill – Department of Oral & Maxillofacial Medicine, Surgery and Pathology, University of 42 Sheffield School of Clinical Dentistry, Sheffield, UK; [email protected] 43 Pedro Diz Dios – Medical-Surgical Dentistry Research Group (OMEQUI), Health Research Institute of 44 Santiago de Compostela (IDIS), School of Medicine and Dentistry, Santiago de Compostela University, 45 Santiago de Compostela, Spain; [email protected] 46 Federica Turati – Branch of Medical Statistics, Biometry, and Epidemiology “G.A. Maccacaro”, 47 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy; 48 [email protected] 49 Valeria Edefonti – Branch of Medical Statistics, Biometry, and Epidemiology “G.A. Maccacaro”, 50 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Fondazione 51 IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; [email protected] 52 53 54 Corresponding authors: 55 - Federica Turati, PhD, Branch of Medical Statistics, Biometry, and Epidemiology “G.A. Maccacaro”, 56 Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy; 57 [email protected] 58 - Katherine France, DMD, MBE, Department of Oral Medicine, University of Pennsylvania, Philadelphia, 59 USA; [email protected] 60 61 62 Manuscript word count: 3,092 63 3 Key points 64 Question: Is antibiotic prophylaxis effective in preventing infective endocarditis after invasive dental 65 procedures? 66 Findings: This systematic review and meta-analysis including data on 1,152,345 cases of infective 67 endocarditis demonstrated that antibiotic prophylaxis is protective against infective endocarditis following 68 invasive dental procedures in high-risk subjects. 69 Meaning: These findings support the use of antibiotic prophylaxis for high-risk subjects undergoing 70 invasive dental procedures, supporting current American Heart Association and European Society of 71 Cardiology guidelines. 72 73 74 75 Tweet: This #metaanalysis demonstrated that #antibioticprophylaxis is protective against 76 #infectiveendocarditis following invasive #dentalprocedures in high-risk subjects, supporting current 77 #AHA and #ESC guidelines. 78 4 Abstract 79 Importance: The association between antibiotic prophylaxis (AP) and infective endocarditis (IE) after 80 invasive dental procedures (IDPs) is still unclear. Indications for AP were restricted by guidelines 81 beginning in 2007. 82 Objective: To systematically review and analyse existing evidence on the association between AP and IE 83 following IDPs. 84 Data Sources: We systematically searched PubMed, Cochrane-CENTRAL, Scopus, Web of Science, 85 Proquest, Embase, Dentistry and Oral Sciences Source, and clinicaltrials.gov, from inception to May 86 2023. 87 Study selection: Studies on the role of AP and IE following IDPs or time-trend analyses of IE incidence 88 preand post-current AP guidelines were included. 89 Data Extraction and Synthesis: Study quality was evaluated using structured tools. Data were extracted 90 by independent observers. A pooled-relative risk (RR) of developing IE following IDPs in patients 91 receiving AP versus not was computed by random-effects meta-analysis. 92 Main Outcomes and Measures: The outcome of interest was the incidence of IE following IDPs, in 93 relation to AP. 94 Results: Of 11,217 records identified, 30 were included (1,152,345 IE cases). Of them, 8 (including 12 95 sub-studies) were either case-control/crossover, cohort studies, or self-controlled case-series, while 22 96 were time-trend studies; all were of good quality. Eight of the 12 case-control/crossover, cohort or self97 controlled case-series sub-studies supported a protective role of AP, especially among high-risk subjects, 98 while 3 did not. By meta-analysis, AP was associated with a significantly lower risk of IE after IDPs in 99 high-risk subjects (pooled-RR=0.41, 95% confidence interval 0.29-0.57; p for heterogeneity=0.513; 100 I2=0%). Nineteen of the 22 time-trend studies performed a formal pre-post statistical analysis; 9 found no 101 significant changes in IE incidence, 7 demonstrated a significant increase for the overall population or 102 sub-populations (highand moderate-risk subjects, Streptococcus-IE, and viridans group streptococci-IE), 103 whereas 3 found a significant decrease for the overall population and among oral Streptococcus-IE. 104 5 Conclusions and Relevance: While results from time-trend studies are inconsistent, data from case105 control/crossover, cohort, and self-controlled studies showed that AP is protective against IE following 106 IDPs in high-risk subjects, supporting the use of AP in these subjects. Currently, there is insufficient data 107 to support any benefit of AP in subjects at moderate risk. 108 109 Keywords: Infective endocarditis; Antibiotic prophylaxis; Invasive dental procedures; Evidence-based 110 policy development; Guidelines; Systematic review; Meta-analysis. 111 6 Introduction 112 Infective endocarditis (IE) is a rare but life-threatening condition1,2. The estimated global crude incidence 113 ranges from 1.5 to 11.6 cases/100,000 person-years3, but recent studies suggest the incidence is rising4–10. 114 Incidence rates are higher in subjects with underlying cardiac conditions such as prosthetic heart valves, 115 congenital heart disease (CHD), or non-cardiac conditions such as presence of central venous catheters, 116 haemodialysis for renal failure, and intravenous drug use1. Despite optimal treatment, IE is associated 117 with high morbidity and an estimated mortality rate at one year of 30-40%1,2,11–13. Therefore, the 118 identification of effective prevention strategies is crucial. 119 For several decades, the evidence surrounding antibiotic prophylaxis (AP) for IE prevention has 120 undergone substantial evolution, prompting a reassessment of traditional approaches. In 1955, the 121 American Heart Association (AHA) issued the first statement on prevention of IE14: AP was 122 recommended for all subjects with rheumatic or CHD undergoing dental extractions and other dental 123 manipulations which disturb the gums, the removal of tonsils and adenoids, the delivery of pregnant 124 women, and operations on the gastrointestinal or urinary tracts14. In the ensuing 50 years, AP was 125 recommended to a wide range of subjects, with controversies regarding subject and procedure selections, 126 choice of antibiotics, and overall risk-benefit ratio15,16. Between 2007 and 2009, the AHA, the European 127 Society of Cardiology (ESC), and the National Institute for Health and Care Excellence (NICE) 128 recommended restriction to AP to different degrees. The AHA and ESC recommended AP to be 129 considered only in subjects at the highest risk (i.e. those with a previous history of IE, prosthetic heart 130 valves or prosthetic material used in cardiac valve repair, unrepaired cyanotic CHD, CHD subjects with 131 prosthetic materials/devices placed in the previous six months or with residual defects and those 132 undergoing surgical or interventional procedures) who undergo an invasive dental procedure (IDP), 133 defined as procedure that involve manipulation of the gingival tissue, periapical region of teeth or 134 perforation of the oral mucosa17,18. Conversely, AP was no longer recommended for subjects at moderate 135 risk, i.e. subjects with acquired valvular heart disease, hypertrophic cardiomyopathy, and most of the 136 other CHDs. This message was later reinforced in updated statements19,20. In parallel, in 2008, NICE 137 7 advised against routine AP use21, although in 2016 this message was revised with a softer statement 138 suggesting AP not be routinely recommended22. 139 The longstanding dispute over the effectiveness of AP to prevent IE following IDPs persists due to the 140 scarcity of robust data and absence of randomised controlled trials (RCTs). In this setting, a 141 comprehensive analysis of existing evidence is valuable. Herein, we reviewed and meta-analysed the 142 existing evidence to evaluate the association of AP and the incidence of IE following IDPs. In particular, 143 we explored if AP is able to influence the association between IDP and IE (case-control/crossover, cohort 144 studies, and self-controlled case-series) and if changes in the AP guidelines had influenced IE incidence 145 over time (time-trend studies). Particular attention was given to stratified analyses by patient risk profile. 146 147 Methods 148 Data collection and reporting followed the guidelines for Systematic Review and Meta-Analysis of 149 Observational Studies (MOOSE)23 and the Preferred Reporting Items for Systematic Reviews and Meta150 Analysis (PRISMA) guidelines24. The study was registered in the National Institute for Health and Care 151 Research (NIHR) International Prospective Register of Systematic Reviews (PROSPERO, 152 CRD4202017398, https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=272740). 153 154 Data sources and search strategy 155 A systematic search of PubMed, Cochrane-CENTRAL, Scopus, Web of Science, Proquest, Embase, 156 Dentistry and Oral Sciences Source (DOSS), and clinicaltrials.gov was conducted from inception to May 157 17-19, 2023. The search strategy was developed with the help of a dental librarian (L.G.) using both 158 keywords and controlled vocabulary terms around the topics of infective endocarditis, antibiotic 159 prophylaxis, guideline, and dental procedure (eMethods 1). References of selected articles were screened 160 by hand to identify additional articles. Covidence software (Veritas Health Innovation, Melbourne, 161 Australia) was used to support the review process. 162 163 8 Study selection 164 Studies were screened by two independent investigators (K.F., M.B., M.G., H.H., L.M., V.E.) at the title 165 and abstract level. The same reviewers independently performed the full-text review. Reasons for 166 exclusion were systematically recorded. Disagreements were discussed with senior investigators (G.L., 167 P.D.D.) until consensus was reached. 168 Studies were selected if they included data on IE incidence and either: (1) data on the association between 169 AP and IE following IDPs, or (2) a time-trend analysis of IE incidence around the time of AP guidelines 170 implementation. The main outcome of interest was the IE incidence following IDPs, in relation to AP. 171 Clinical trials, observational prospective or retrospective cohort studies, case-crossover studies, case172 control studies, self-controlled case-series, or longitudinal ecological time-trend studies were all 173 candidates for inclusion. Reviews, case reports, case-series (n≤10 to eliminate positive outcome bias), 174 letters, editorials, animal studies, and conference abstracts were excluded. Criteria for exclusion are listed 175 in eFigure 1. 176 177 Quality assessment 178 Quality of selected studies were independently assessed by two investigators (K.F., M.B.) and reviewed 179 by two senior investigators (F.T., F.S.). The following quality assessment tools were adapted following a 180 consensus process involving all authors: (1) the Effective Practice and Organization of Care (EPOC) 181 criteria developed by the Cochrane Collaboration for time-trend studies; (2) the National Heart Lung and 182 Blood Institutes (NHLBI) Quality Assessment Tool for Observational Cohort Studies and the NHLBI 183 Quality Assessment Tool for Case-Control Studies for cohort/self-controlled case-series and case184 control/crossover studies, respectively25,26 (eMethods 2-4). 185 186 Data extraction and visualization 187 Data extraction was performed independently by two investigators (M.B., M.G., H.H., K.F., G.L, F.S., 188 F.T.). Disagreements were discussed with senior investigators (G.L., P.D.D., V.E.) until consensus was 189 9 reached. Data were collected and summarized in structured tables, approved by all investigators. Sub190 analyses based on pathogen or risk profile were also extracted. Records with overlapping data were 191 flagged. 192 From case-control, case-crossover and cohort studies, we extracted results of the two possible types of 193 assessment for the association between AP and IE incidence: (1) direct assessment: single comparison 194 between subjects who underwent IDPs and received AP versus subjects who did not receive AP before 195 IDPs, and (2) indirect assessment: the two-fold comparison between subjects who did or did not receive 196 AP before IDPs, both versus subjects who did not undergo IDPs. Results from the indirect assessment 197 were plotted using a forest plot. For time-trend studies, we extracted any measure of IE incidence changes 198 (e.g., incidence rate ratios, differences in slope, differences in annual percentage change) preand post199 AP guidelines. These results were visually summarized in a dedicated figure. 200 201 Statistical analysis 202 For the direct assessment, we performed a random-effects meta-analysis of relative risk (RR) estimates 203 (RR, odds ratio [OR], or incidence rate ratio [IRR]) of developing IE in high-risk subjects who underwent 204 IDPs and received AP versus subjects who did not receive AP before IDPs, by using the Der Simonian 205 and Laird method27. Heterogeneity among studies was assessed using the χ2 test and inconsistency was 206 quantified using the I2 statistic28. All statistical analyses were performed using Stata Statistical Software 207 (version 18; Stata Corp., College Station, TX). 208 209 Results 210 Study selection and characteristics 211 A total of 11,217 records were identified. Following removal of duplicates (n=7,331), 3,886 titles and 212 abstracts were screened. Of the remaining 123 full-text articles, 30 records were included, for a total of 213 1,152,345 IE cases (eFigure 1)4-13,29–48. All studies were observational: 8 were either case-control, case214 crossover, cohort studies, or self-controlled case-series (4 included two separate sub-studies with different 215 16 Acknowledgement Section 354 355 Contributors 356 FS, KF, FT, CHLH, TPS, GL, PBL, MT, PDD and VE contributed to the design and conceptualization of 357 the study. FS, KF, FT, MG, MB, HH, LM, and VE contributed to data collection and verified the 358 underlying data reported in the manuscript. FS, KF, FT, and VE contributed to data analysis or 359 interpretation. VE led the World Workshop on Oral Medicine (WWOM) VIII group on infective 360 endocarditis and had primary responsibility for the final content of the manuscript. All authors 361 contributed to drafting the work or revising it critically for important intellectual content and approved the 362 final version. All authors had full access to all the data, accept full responsibility of ensuring accuracy or 363 integrity of any part of the work, approved the final version of the manuscript and agreed to submit it for 364 publication. 365 366 Funding/Support 367 The WWOM VIII Steering Committee gratefully acknowledges the following organizations, companies, 368 and subjects that provided financial support for WWOM VIII: American Academy of Oral Medicine, 369 European Association of Oral Medicine, Church & Dwight Co. Inc., Colgate Palmolive, and patients of 370 Dr. Ross Kerr. 371 372 Non-author contributions 373 The WWOM VIII Steering Committee provided the conceptual framework and logistical support to 374 produce the WWOM VIII Conference in May 2022 in Memphis, Tennessee, USA. In addition, the 375 Steering Committee provided scientific and editorial critiques of this manuscript. The Steering Committee 376 is listed below, in alphabetical order: Arwa M Farag (Saudi Arabia/USA), Timothy A Hodgson 377 (UK), Catherine HL Hong (Singapore), Siri B Jensen (Denmark), Kerr A Ross (USA), Giovanni Lodi 378 (Italy), Richeal N Riordain (Ireland), and Thomas P Sollecito (USA). 379 17 380 Access to Data and Data Analysis Statement 381 Valeria Edefonti, Francesca Sperotto, and Federica Turati had full access to all the data in the study and 382 takes responsibility for the integrity of the data and the accuracy of the data analysis. 383 384 Data sharing statement 385 Data are extracted from literature and are publicly available. 386 387 Conflict of interest disclosures 388 MT has research grant funding from the National Institutes for Health (USA), Delta Dental of Michigan 389 Research and Data Institute’s Research Committee, and Renaissance Health Service Corporation (USA). 390 PBL was the liaison from the American Dental Association (ADA) to the American Heart Association 391 (AHA) and served on the Guidelines Committees for the 2007 and 2021; he also has research grant 392 funding from the National Institutes for Health, National Institute of Dental and Craniofacial Research 393 (USA). 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Eur Heart J. 2019;40(17):1355-1361. doi:10.1093/eurheartj/ehy629 547 54. Kim JY, Park SJ, Lee SH, Seo GH, Jang SW. Risk of infective endocarditis associated with 548 invasive dental procedures in patients with cardiac rhythm devices. Europace. 2022;24(12):1967549 1972. doi:10.1093/europace/euac086 550 551 24 Figure Titles and Legends 552 553 Figure 1. Forest plot and meta-analysis of relative risk measures comparing the risk of developing 554 infective endocarditis after invasive dental procedure in high-risk patients who received antibiotic 555 prophylaxis versus patients who did not (direct assessment). Relative risks and 95% confidence 556 intervals are showed for each study using black squares and bars, respectively. The white diamond 557 represents the pooled-relative risk and 95% confidence intervals. AP: antibiotic prophylaxis; CI: 558 confidence interval; IDP: invasive dental procedure; RR: relative risk. 559 560 Figure 2. Visual summary of trends in incidence of infective endocarditis in North America before 561 and after the release of updated antibiotic prophylaxis guidelines recommending antibiotic 562 prophylaxis restriction. Colors represent countries, gradients represent trends of incidence with darker 563 colors indicating increased incidence, blue tilde indicates no statistical significance, arrows indicate 564 significance changes in trends over time in respect to guidelines (bold: overall study population, slim: 565 subpopulations). Guidelines of reference: AHA: American Heart Association. Other abbreviations: hosp.: 566 hospitalization; IE: infective endocarditis; IRR: incidence rate ratio; mod: moderate; NS: not significant; 567 OS: oral Streptococcus; strept: Streptococcus; VGS: viridans group Streptococcus. *2008 vs 2007: IRR 568 0.97 (95% CI 0.94-0.99), 2009 vs 2007: IRR 0.91 (95% CI 0.89-0.93), and 2010 vs 2007: IRR 0.86 (95% 569 CI 0.84-0.88); † Significant increase in Streptococcus IE incidence (p=0.002); ‡ Significant increase in 570 VGS-IE incidence for ≥10 years (p<0.01); § Significant increase in IE incidence among high- (177% 571 estimated increase) and moderate-risk subjects (75% estimated increase); ¶ Significant decrease in IE 572 incidence overall and significant decrease in OS-IE incidence in sub-analyses (p=0.002);** Significant 573 increase in IE incidence after 2010 in both high and moderate-risk patients. 574 575 Figure 3. Visual summary of trends in incidence of infective endocarditis in Europe before and 576 after the release of updated antibiotic prophylaxis guidelines recommending antibiotic prophylaxis 577 25 restriction. Colors represent countries, gradients represent trends of incidence with darker colors 578 indicating increased incidence, blue tilde indicates no statistical significance, arrows indicate significance 579 changes in trends over time in respect to guidelines (bold: overall study population, slim: subpopulations). 580 Guidelines of reference: AHA: American Heart Association; ESC: European Society of Cardiology; Nat: 581 national; NICE: National Institute for Health and Care Excellence. Other abbreviations: CHD: coronary 582 heart disease; hosp.: hospitalization; IE: infective endocarditis; MV: mitral valve; NS: not significant; OS: 583 oral Streptococcus; sign.: significant; strept: Streptococcus. *Significant decrease in OS-IE for those with 584 previously known native heart disease (p=0.03), but not in the other pathogen-specific or high-risk 585 specific subpopulations investigated; † Significant increase in IE incidence confirmed also in sub-analysis 586 of high-risk (p=0.025) and moderate/low-risk (p=0.0002) subjects; ‡ Comparison of IE incidence was not 587 possible before and after the guidelines change because data for the period before were not available. 588 Overall (I-squared = 0.0%, p = 0.513) Thornill et al. 2022 (cohort, high-risk) [32] Thornill et al. 2023 (cohort, high-risk) [36] Thornill et al. 2023 (case-crossover, high-risk) [36] Thornill et al. 2022 (case-crossover, high-risk) [32] Reference IDPs with AP vs IDPs without AP IDPs with AP vs IDPs without AP IDPs with AP vs IDPs without AP IDPs with AP vs IDPs without AP Comparison 0.41 (0.29, 0.57) 0.38 (0.22, 0.62) 0.20 (0.06, 0.53) 0.50 (0.17, 1.49) 0.49 (0.29, 0.85) RR (95% CI) 100.00 41.98 9.49 9.56 38.97 Weight (%) 0.41 (0.29, 0.57) 0.38 (0.22, 0.62) 0.20 (0.06, 0.53) 0.50 (0.17, 1.49) 0.49 (0.29, 0.85) RR (95% CI) 100.00 41.98 9.49 9.56 38.97 Weight 1.1 .5 2 5 Country Study, setting Case definition Time IE change United States Bates, 2017 Multicenter [6] OS-IE hosp. 5-18 years NS Bikdeli, 2013 National data [11] IE hosp. ≥ 65 years Sign. decrease (IRRs <1)* DeSimone, 2015 National data [12] VGS-IE hosp. adults NS DeSimone, 2021 National data [41] VGS-IE hosp. adults NS Pant, 2015 National data [39] IE hosp. NS (Sign. increase in strept-IE p=0.002)† Pasquali,2012 Multicenter [38] IE hosp. <18 years NS Rogers, 2008 Single center [37] IE hosp. No apparent change (no statistical analysis) Sakai-Bizmark, 2017 National data [7] IE hosp. < 18 years NS ( Sign. Increase in VGS-IE p<0.01)‡ Thornhill, 2018 National data [40] IE hosp. > 18 years Sign. increase in high-and mod-risk § Toyoda, 2017 Multicenter [13] IE hosp. Sign. decrease (p=0.004)¶ Canada Garg, 2019 Multicenter [8] IE hosp. ≥ 18 years NS (Sign. increase in high and mod - risk)** Mackie, 2016 National data [42] IE hosp. NS Year 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 AHA Country Study setting Case defini tion IE change France Duval, 2012 Multicenter [46] IE hosp. ≥ 20 years NS (Sign. decrease in OS-IE p=0.002) Switzerland Knirsch , 2020 Single center [43] IE hosp. <20 yrs with CHD NS England Dayer , 2015 National data [47] IE hosp. Sign. increase (p<0.0001)† Quan, 2020 National data [9] IE hosp. NS Scotland Shah, 2020 National data [48] IE hosp. ≥ 20 years NS Germany Keller, 2017 National data [4] IE hosp. Relative increase (no statistical analysis) Weber, 2022 Multicenter [44] Valve surgery for IE Sign. increase in MV IE and strept. IE (p=0.035, 0.002) The Netherlands Van den Brink, 2017 National data [5] IE hosp. Sign increase (p<0.001) Krul ,2015 Single center [45] IE hosp. ≥ 18 years No statistical analysis ‡ Sweden Vähäsarja , 2020 National data [10] IE hosp. > 16 years NS 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 2018 AHA Nat Nat NICE ESC Nat