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Trends in occurrence and 30-day mortality of infective endocarditis in adults: population-based registry study in Finland

Objectives Infective endocarditis (IE) is a life-threatening disease associated with significant mortality. We studied recent temporal trends and age and sex differences in the occurrence and short-term mortality of IE. Design Population based retrospective cohort study. Setting Data of IE hospital admissions in patients aged ≥18 years in Finland during 2005–2014 and 30-day all-cause mortality data were retrospectively collected from mandatory nationwide registries from 38 hospitals. Outcomes Trends and age and sex differences in occurrence. Thirty-day mortality. Results There were 2611 cases of IE during the study period (68.2% men, mean age 60 years). Female patients were significantly older than males (62.0 vs 59.0 years, p=0.0004). Total standardised annual incidence rate of IE admission was 6.33/100 000 person-years. Men had significantly higher risk of IE compared with women (9.5 vs 3.7/100 000; incidence rate ratios [IRR] 2.49; p<0.0001) and difference was most prominent at age 40–59 years (IRR 4.49; p<0.0001). Incidence rate varied from 5.7/100 000 in 2005 to 7.1/100 000 in 2012 with estimated average 2.1% increase per year (p=0.036) and similar trends in both sexes. Significant increasing trend was observed in patients aged 18–29 years and 30–39 years (estimated annual increase 7.6% and 7.2%, p=0.002) and borderline in patients aged 40–49 years (annual increase 3.8%, p=0.08). In older population, IE incidence rate remained stable. The overall 30-day mortality after IE admission was 11.3%. Mortality was similar between sexes, increased with ageing, and remained similar during the study period. Conclusions Occurrence of IE is increasing in young adults in Finland. Men, especially middle-aged, are at higher risk for IE compared with women. Thirty-day mortality has remained stable at 11%, increased with ageing, and was similar between sexes.

1. In the Article Summary, although the strengths and weaknesses of the study are listed in 4 bullet points, the main result is not given. The summery would benefit from at least on bullet point summarizing the main results of the study. 2. Several relatively recent large population-based studies on infective endocarditis, relevant to this study have not been referenced. In particular, the following large European studies using national data for respectively the Netherlands, Germany and the UK, are relevant: a. Florsi S. van  These papers are relevant to: i. The statements about the incidence of IE and the incidence trends mentioned in the first 4 lines of the introduction.
ii. The statements made in para 2 of page 11 regarding the association between changes in guidelines on antibiotic prophylaxis and incidence of IE. This paragraph states that studies from North America have found no association between incidence of IE and the 2007 change in the AHA guidelines on AP, referencing two studies. The Toyoda study, which only covered two states and was probably therefore underpowered to answer this question, and the Mackie study from Canada. Although, the original Mackie paper suggested that there had been no change in the incidence of IE following the 2009 AHA guideline change in Canada, they subsequently published a letter where a re-analysis found that there had been an increase in IE incidence comparing trends from before and after the guideline change that bordered on significance. They concluded that they needed more years of study to draw a final conclusion one way or the other i.e. their study was probably also underpowered to answer this question (Mackie et al. Canadian Journal of Cardiology 2016; 32 (12) page 1578.e11. However, two uncited large studies from the US have shown a significant change in IE incidence following the 2007 AHA guideline change. First the study by S. Pant et al (reference (d) above) and an even larger study, that also included antibiotic prophylaxis prescribing data, that has only just been published (reference (e) above). Furthermore, with regard to the effects of the 2009 ESC guidance on incidence of IE, you only mention your own data based on the population of Finland i.e. ~5.5 million. Yet there are two much larger national data studies from the Netherlands, population ~17 million, (reference (a) above) and Germany, population ~83 million (reference (b) above), that both showed an increase in IE incidence following the 2009 ESC guideline change. The likely effect size for AP in preventing IE is small and is even smaller if AP is only stopped for those at moderate-risk of IE, this means very large population samples are required to demonstrate the impact of any change in AP prescribing guidelines. Just because your data did not show a statistically significant increase in IE incidence after the change in guidelines (although you do not appear to have formally tested for this), it does not mean you can conclude that the change in guidance had no effect. It is just as likely, perhaps more likely, that you simply had too small a sample size to demonstrate the effectas has been the case with many other such studies. This is particularly the case when you have no data to demonstrate how effectively, or not, clinicians changed their antibiotic prophylaxis prescribing habits in response to the guideline change. In view of this, it is inappropriate not to acknowledge that these larger studies found an increase in IE following the introduction of the 2009 ESC guidelines and that the smaller sample size of your own study might explain why you did not find a similar change.
3. The main point of this paper, that distinguishes it from some of those other papers listed above, is the data on the age and sex distribution of individuals who developed IE. This is data, including the data comparing the relative risk of developing IE in different age and sex groups, is of particular interest -as is the 30-day mortality data. However, you do not cite any other studies that have looked at this for comparison, implying that no other such data exists. Yet the European Heart Journal paper cited above (reference (C) above) looked at both the risk of IE in different age and sex groups and the risk of death during the initial hospital admissionso very similar data to this.
Overall, this is an interesting paper with good quality national data on the incidence of IE over time in Finland. However, it needs to be placed more properly into the context of other similar research that has been done and the data should not be over interpretedas is the case with the statement "We found occurrence of IE admissions to be increasing with stable rate between 2005-2014 suggesting no significant role on guideline changes of antibiotic prophylaxis to IE rate."

REVIEWER
Natalia N. Egorova Icahn School of Medicine at Mount Sinai, New York, USA REVIEW RETURNED 21-Nov-2018

GENERAL COMMENTS
The trend of infective endocarditis has been explored in multiple studies published in Europe and The USA. The results of these studies are inconclusive due to low incidence rates and serval limitations of the data. Some studies showed increased incidence, others no changes, and some even reported a decrease of incidence. Clinicians and researchers agreed that the incidence of IE is higher among older people, patient who had prosthetic cardiac valves, implantable cardiac devices, and congenital heart diseases.
With an aging population, it is expected that the incidence in IE will increase. This study examined the trend in IE in Finland and showed that it has been increasing over the last 10 years; highlighting that the incidence among younger men is increasing faster than among younger women as well as the elderly population. A potential reason is due to the increasing number of illegal drug users.
There are several issues that should be clarified: 1. Please briefly explain, in the Method section, how the incidence rate ratios were calculated. 2. Endocarditis is a recurrent disease with a mean recurrence time of ~5 years. Please explain how you ensured that the first episode of endocarditis was captured in the calculation of incidence rate. Also, please specify whether or not patients are counted uniquely. 3. Please shortly describe the nationwide Care Register for Health Care database used in this analysis. What variables and how many diagnoses and procedure codes are included in this database? 4. The accuracy of this analysis depends on the accuracy of codes used to identify patients with infective endocarditis. Have you validated ICD 10 codes used for selection of patients with IE against medical charts? Please provide diagnostic characteristics (sensitivity, specificity, positive predictive value) for the selected ICD10 code or reference a paper where the validation was done. 5. The epidemiological profile of patients with IE is changing, the classic risk factors that were examined in this study, such as cardiac surgeries or pacemaker implantations in one year prior to IE, explains only a small proportion of endocarditis. When we study trends of IE, it is important to identify causative organism. If possible, please identify causative organisms. 6. Risk factors such as dialysis or drug abuse potentially can be identified using discharge diagnoses and one year history of hospitalizations. Since the authors were able to calculate Charlson comorbidity scores, I assume they have access to multiple diagnoses for each hospitalization and can explore the trends in other risk factors. These papers are relevant to: i. The statements about the incidence of IE and the incidence trends mentioned in the first 4 lines of the introduction.
ii. The statements made in para 2 of page 11 regarding the association between changes in guidelines on antibiotic prophylaxis and incidence of IE. This paragraph states that studies from North America have found no association between incidence of IE and the 2007 change in the AHA guidelines on AP, referencing two studies. The Toyoda study, which only covered two states and was probably therefore underpowered to answer this question, and the Mackie study from Canada. Although, the original Mackie paper suggested that there had been no change in the incidence of IE following the 2009 AHA guideline change in Canada, they subsequently published a letter where a reanalysis found that there had been an increase in IE incidence comparing trends from before and after the guideline change that bordered on significance. They concluded that they needed more years of study to draw a final conclusion one way or the other i.e. their study was probably also underpowered to answer this question (Mackie et al. Canadian Journal of Cardiology 2016; 32 (12) page 1578.e11. However, two uncited large studies from the US have shown a significant change in IE incidence following the 2007 AHA guideline change. First the study by S. Pant et al (reference (d) above) and an even larger study, that also included antibiotic prophylaxis prescribing data, that has only just been published (reference (e) above).
Furthermore, with regard to the effects of the 2009 ESC guidance on incidence of IE, you only mention your own data based on the population of Finland i.e. ~5.5 million. Yet there are two much larger national data studies from the Netherlands, population ~17 million, (reference (a) above) and Germany, population ~83 million (reference (b) above), that both showed an increase in IE incidence following the 2009 ESC guideline change. The likely effect size for AP in preventing IE is small and is even smaller if AP is only stopped for those at moderate-risk of IE, this means very large population samples are required to demonstrate the impact of any change in AP prescribing guidelines. Just because your data did not show a statistically significant increase in IE incidence after the change in guidelines (although you do not appear to have formally tested for this), it does not mean you can conclude that the change in guidance had no effect. It is just as likely, perhaps more likely, that you simply had too small a sample size to demonstrate the effectas has been the case with many other such studies. This is particularly the case when you have no data to demonstrate how effectively, or not, clinicians changed their antibiotic prophylaxis prescribing habits in response to the guideline change. In view of this, it is inappropriate not to acknowledge that these larger studies found an increase in IE following the introduction of the 2009 ESC guidelines and that the smaller sample size of your own study might explain why you did not find a similar change.
A: We thank the Reviewer for these important additions. Suggested studies have now been added (reference no 9, 10 and 31) and discussion is modified accordingly (p. 12).
3. The main point of this paper, that distinguishes it from some of those other papers listed above, is the data on the age and sex distribution of individuals who developed IE. This is data, including the data comparing the relative risk of developing IE in different age and sex groups, is of particular interest -as is the 30-day mortality data. However, you do not cite any other studies that have looked at this for comparison, implying that no other such data exists. Yet the European Heart Journal paper cited above (reference (C) above) looked at both the risk of IE in different age and sex groups and the risk of death during the initial hospital admissionso very similar data to this.
A: We thank the Reviewer for this important addition. This important paper by Thornhill et al. was not available for reference for the previous version of our paper. It has now been added (reference no 9) and discussion is modified accordingly (p.11-12).
Overall, this is an interesting paper with good quality national data on the incidence of IE over time in Finland. However, it needs to be placed more properly into the context of other similar research that has been done and the data should not be over interpreted -as is the case with the statement "We found occurrence of IE admissions to be increasing with stable rate between 2005-2014 suggesting no significant role on guideline changes of antibiotic prophylaxis to IE rate." A: We thank the Reviewer for positive comments. As suggested statement "We found occurrence of IE admissions to be increasing with stable rate between 2005-2014 suggesting no significant role on guideline changes of antibiotic prophylaxis to IE rate." is now changed to more appropriate "we found occurrence of IE admissions to increase with stable rate between 2005-2014 suggesting that guideline changes did not have a major impact to overall occurrence of IE in adult Finnish population" (p.12). Please leave your comments for the authors below The trend of infective endocarditis has been explored in multiple studies published in Europe and The USA. The results of these studies are inconclusive due to low incidence rates and serval limitations of the data. Some studies showed increased incidence, others no changes, and some even reported a decrease of incidence. Clinicians and researchers agreed that the incidence of IE is higher among older people, patient who had prosthetic cardiac valves, implantable cardiac devices, and congenital heart diseases. With an aging population, it is expected that the incidence in IE will increase. This study examined the trend in IE in Finland and showed that it has been increasing over the last 10 years; highlighting that the incidence among younger men is increasing faster than among younger women as well as the elderly population. A potential reason is due to the increasing number of illegal drug users.
There are several issues that should be clarified: 1. Please briefly explain, in the Method section, how the incidence rate ratios were calculated.
A: We thank the Reviewer for this important addition. As suggested, we have now clarified the calculation method of incidence rate ratios in Methods (p.6).
2. Endocarditis is a recurrent disease with a mean recurrence time of ~5 years. Please explain how you ensured that the first episode of endocarditis was captured in the calculation of incidence rate. Also, please specify whether or not patients are counted uniquely.
A: We thank the Reviewer for pointing out the need for clarification. Each patient was counted uniquely. We have now clarified this in Methods (p.5). For calculation of incidence rate we used standard epidemiological methodology of annual incidence rate. Accordingly, one admission / year / person was included. This is now clarified in the Methods (p.6). Unfortunately, the data available to study does not allow reliable distinguishing of relapses from new onset IE. We have however, now included number of individuals (n=2331) with IE admission in the Results (p.7).
3. Please shortly describe the nationwide Care Register for Health Care database used in this analysis. What variables and how many diagnoses and procedure codes are included in this database?
A: We thank the Reviewer for pointing out the need for clarification. All hospitals in Finland are legislatively obligated to report annually every inpatient treatment periods to the Care Registry for Healthcare held by the Center for Health and Welfare. Each healthcare contact is provided with basic baseline data (e.g. age, sex, speciality of healthcare contact), admission date, procedure dates, data on length of stay, performed procedures (with the Nordic Medico-Statistical Committee classification of surgical procedures, up to 8 procedures per admission) and ICD-10 diagnostic codes (up to 8 ICD-10 codes). We have now clarified this in Methods (p.5).
4. The accuracy of this analysis depends on the accuracy of codes used to identify patients with infective endocarditis. Have you validated ICD 10 codes used for selection of patients with IE against medical charts? Please provide diagnostic characteristics (sensitivity, specificity, positive predictive value) for the selected ICD10 code or reference a paper where the validation was done.
A: We thank the Reviewer for raising out this important point. We have now included a subgroup validation of ICD-10 IE codes. We studied 188 randomly selected patients with the same inclusion criteria (≥ 18 years, 2005-2014, ICD-10 codes I33, I38 or I39 as discharge diagnosis) treated in the Turku University Hospital. Patient records (including laboratory, microbiology, pathological and imaging data) were reviewed to determine whether Duke criteria for IE were fulfilled. Duke criteria were fulfilled in 182 studied patients (definitive IE in 122 and possible IE in 60) resulting to specificity of 96.8%. In addition, we have now added reference to previous study by Tan et al. using similar methodology which found 100% specificity and 90% sensitivity of ICD-10 IE codes (reference no 39).
5. The epidemiological profile of patients with IE is changing, the classic risk factors that were examined in this study, such as cardiac surgeries or pacemaker implantations in one year prior to IE, explains only a small proportion of endocarditis. When we study trends of IE, it is important to identify causative organism. If possible, please identify causative organisms.
A: We thank the Reviewer comment. Unfortunately we were unable to reliably identify causative organisms. Etiological specific ICD-10 codes were not widely used, and we did not have access to detailed microbiological data of patients. This limitation is now further clarified in Discussion (p.14).
6. Risk factors such as dialysis or drug abuse potentially can be identified using discharge diagnoses and one year history of hospitalizations. Since the authors were able to calculate Charlson comorbidity scores, I assume they have access to multiple diagnoses for each hospitalization and can explore the trends in other risk factors. To identify patients with drug dependencies, I would recommend to use ICD10 codes that are available at HCUP website for clinical classification software https://www.hcup-us.ahrq.gov/toolssoftware/ccs10/ccs10.jsp#download (CCS 661 -Substancerelated disorders) or drug abuse codes from Elixhauser comorbidity score (https://www.hcupus.ahrq.gov/toolssoftware/comorbidityicd10/comorbidity_icd10.jsp).
A: We agree with the reviewer that drug usage is an important risk factor for IE especially in youngest patients. Indeed, we had access to multiple admissions enabling us to calculate CCI-score. Drug dependency ICD-10 diagnoses are however coded to psychiatric texts and databases. Unfortunately we did not have access to this database. Access to psychiatric information is more restricted due to sensitivity of data. Thus we are unable to reliably identify drug usage in the current study. This limitation is now further clarified in Discussion (p.13).

Martin Thornhill
University of Sheffield, UK REVIEW RETURNED 14-Jan-2019

GENERAL COMMENTS
The authors have addressed the issues raised by myself and the other reviewer to my satisfaction.

REVIEWER
Natalia N. Egorova Icahn School of Medicine at Mount Sinai, New York, USA REVIEW RETURNED 18-Jan-2019

GENERAL COMMENTS
Authors addressed the comments, added ICD 10 code validation and revised the manuscript. Several issues remained. 1. There are two different analyses in this study: trend in incidence and 30-day mortality. Please clarify, if only the first episode of infective endocarditis was included in analysis of incidence. Do you report 30-day mortality after any or only the first hospitalization with diagnoses of infective endocarditis? When authors report incidence, they should include the first episode of IE in the analysis and patients should be counted only once during the entire study. Thus, it remains unclear (see results, 1st paragraph) if the patients characteristics and the analysis of incidence were performed based on the first episode of disease. 2. Please consider revision of this sentence (page 6, line 20): 'Associations of age, sex and study year were studied with interaction variables.'