Trends in Infective Endocarditis Incidence, Microbiology, and Valve Replacement in the United States From 2000 to 2011

JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY

VOL. 65, NO. 19, 2015

ª 2015 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

ISSN 0735-1097/$36.00

PUBLISHED BY ELSEVIER INC.

http://dx.doi.org/10.1016/j.jacc.2015.03.518

Trends in Infective Endocarditis Incidence, Microbiology, and Valve Replacement in the United States From 2000 to 2011 Sadip Pant, MD,* Nileshkumar J. Patel, MD,y Abhishek Deshmukh, MD,z Harsh Golwala, MD,* Nilay Patel, MD,x Apurva Badheka, MD,k Glenn A. Hirsch, MD, MHS,* Jawahar L. Mehta, MD, PHD{

ABSTRACT BACKGROUND In accordance with the 2007 American College of Cardiology and American Heart Association infective endocarditis (IE) guideline update, antibiotic prophylaxis is now being restricted to a smaller number of cardiac conditions with very high risk for adverse outcomes from IE. However, there is scant data on IE trends since this major practice change in the United States. OBJECTIVES The aim of this study was to compare temporal trends in IE incidence, microbiology, and outcomes before and after the change in the 2007 IE prophylaxis guideline in the United States. METHODS The NIS (Nationwide Inpatient Sample) database was used to investigate IE hospitalization rates in the United States from 2000 through 2011. The mean annual rates of IE before and after the 2007 guideline change were compared using segmented regression analysis. RESULTS There were 457,052 IE-related hospitalizations in the United States from 2000 to 2011, with a steady increase in incidence (p < 0.001). The trend in IE hospitalization rates from 2000 to 2007 and from 2008 to 2011 was not significantly different (p ¼ 0.74). The increases in the number of Staphylococcus IE cases per million population during the study periods 2000 to 2007 and 2008 to 2011 were similar (p ¼ 0.13), but Streptococcus IE hospitalization rates were significantly higher after the release of new guidelines (p ¼ 0.002). Finally, valve replacement rates for IE steadily increased from 2000 to 2007 (p ¼ 0.03) but showed a plateau from 2007 to 2011. Overall, there was no significant difference in the rates of valve replacement for IE before and after the release of new guideline (p ¼ 0.23). CONCLUSIONS These results show that IE incidence has increased in the United States over the past decade. With regard to the microbiology of IE, there has been a significant rise in the incidence of Streptococcus IE since the 2007 guideline revisions. However, the rates of hospitalization and valve surgery for IE have not increased since the change in IE prophylaxis guideline in 2007. (J Am Coll Cardiol 2015;65:2070–6) © 2015 by the American College of Cardiology Foundation.

T

he epidemiology of infective endocarditis

increase in invasive procedures as well as an increase

(IE) has changed over the years because of

in high-risk groups, such as intravenous drug users

changes in the prevalence of risk factors, as

and those with human immunodeficiency virus and

well as improved diagnostic tools and management.

diabetes mellitus (2–5). Furthermore, the increase in

Although there has been a reduction in rheumatic

the survival of IE risk–prone populations, such as

heart disease in United States (1), there has been an

adults with congenital heart disease and prosthetic

From the *Department of Cardiovascular Medicine, University of Louisville, Louisville, Kentucky; yDepartment of Internal Medicine, Staten Island University, Staten Island, New York; zDepartment of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota; xDepartment of Internal Medicine, Saint Peter’s University Hospital, Jersey City, New Jersey; kDepartment of Cardiovascular Medicine, Yale New Haven Medical Center, New Haven, Connecticut; and the {Department of Cardiovascular Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. All authors contributed equally to this work. Manuscript received December 23, 2014; revised manuscript received March 3, 2015, accepted March 9, 2015.

Pant et al.

JACC VOL. 65, NO. 19, 2015 MAY 19, 2015:2070–6

ABBREVIATIONS

device implants, also contributes to increasing IE

codes. With regard to microbiology, 4 groups

incidence. Finally, global trends in infectious disease

were

epidemiology also may affect trends in IE. A revised

coccus, Gram negative (GN), and fungi. We

guideline for antibiotic prophylaxis for the preven-

excluded endocarditis due to syphilis, rheu-

tion of IE was released in 2007 by the American Heart

matic

Association (AHA) and the American College of Cardi-

gonococcal endocarditis, and lupus or other

Association

ology (ACC) (6). According to the new guidelines,

noninfectious causes. We used weights pro-

GN = Gram negative

antibiotic prophylaxis is restricted to only a small

vided with the NIS to generate national

number of cardiac conditions with high risk for

estimates.

adverse outcomes from IE. However, there is a paucity of data on IE trends since this major change in practice guidelines in the United States.

included:

heart

Staphylococcus,

disease

(without

AND ACRONYMS

Strepto-

ACC = American College of Cardiology

infection),

AHA = American Heart

IE = infective endocarditis

STUDY POPULATION. The NIS database is the largest

all-payer database (Medicare, Medicaid, private insurance, and uninsured) of hospital inpatient stays available in United States (excluding the federal,

SEE PAGE 2077

institutional, Through our study, we sought to: 1) identify trends in the incidence of IE before and after the publication of the new guideline for antibiotic prophylaxis for IE in 2007; 2) assess trends in the microbiology of IE over the past decade; and 3) assess the trend in valve replacement before and after the change in the guideline.

and

short-term

rehabilitation

hos-

pitals). Each year, the NIS data are updated to approximately represent a 20% stratified sample of U.S. hospitals. Each individual hospitalization is deidentified and maintained in the NIS as a unique entry with 1 primary discharge diagnosis and #24 secondary diagnoses during that hospitalization. Each entry also contains information on demographic details, including age, sex, race, insurance status,

METHODS

primary and secondary procedures (up to 14), hospi-

DESIGN. We performed a retrospective observational

cohort study, using the Healthcare Cost and Utilization Project NIS (Nationwide Inpatient Sample) database, sponsored by the Agency for Healthcare Research and Quality (7). We used the International Classification of Diseases, Ninth Revision, Clinical Modification code to identify patients discharged with acute and subacute bacterial endocarditis

talization outcome, total charges, and length of stay. Data from the NIS have been previously used to identify, track, and analyze national trends in health care utilization, patterns of major procedures, trends in hospitalizations, charges, quality, and outcomes (8–10). They also have been used to study the epidemiology of IE in the United States in the past (11,12).

between 2000 and 2011 (Online Appendix). Simi-

STATISTICAL ANALYSIS. We used Stata IC version

larly, the microbiology, as well as valve replace-

11.0 (StataCorp LP, College Station, Texas) and SAS

ment, were identified using appropriate procedure

version 9.2 (SAS Institute Inc., Cary, North Carolina)

T A B L E 1 Incidence of IE, Microbiology, and Valve Replacement From 2000 to 2011

Year

Total No. of IE Cases

Incidence of IE per 100,000 Population

2000

29,820

11

2001

31,526

11

Valve Replacement per 1,000 IE Cases

Staphylococcal IE per 1 Million Population

Streptococcal IE per 1 Million Population

Gram-Negative IE per 1 Million Population

Fungal IE per 10 Million Population

14

35

26

6

6

16

38

28

5

11

2002

32,229

11

19

38

29

6

11

2003

35,190

12

18

42

29

7

12

2004

36,660

13

19

46

29

7

11

2005

37,508

13

23

46

31

8

15

2006

40,573

14

23

50

32

8

14

2007

38,207

12

30

46

32

8

17

2008

41,143

14

19

51

35

8

17

2009

43,502

14

27

57

38

12

16

2010

43,560

14

27

55

38

12

17

2011

47,134

15

26

61

42

12

20

IE ¼ infective endocarditis.

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Infective Endocarditis and 2007 Guidelines

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Infective Endocarditis and 2007 Guidelines

for the analyses, which accounted for the com-

F I G U R E 1 Trend in the Incidence of IE Hospitalization in the United States

plex survey design and clustering. To estimate the

(per 100,000 Population) From 2000 to 2011

annual rates of IE hospitalizations, we divided the total number of IE cases in a given year by the

16

U.S. census population for that year, which were

14

represented in tables and graphs per 100,000 or per

12

million population. The proportion of IE hospitalizations due to each organism was expressed in

10 8 6

Change in the incidence of IE for year 2000-2007

[0.54 (0.32 to 0.75), p<0.001]

2 ways: 1) as a proportion of all IE hospitalizations;

Change in the incidence of IE for year 2007-2011

[0.60 (0.23 to 0.97), p=0.005]

and 2) per population for that year. We compared

Change of slope between 2000-2007 & 2007-2011 [0.06 (–0.36 to 0.49), p=0.74]

the estimated mean annual rates of IE for data from before and after the introduction of the 2007 ACC/

4

AHA IE antibiotic prophylaxis guidelines using

2

piecewise regression analysis (also known as seg-

0

mented regression analysis) of the interrupted time 2000

2002

2004

incidence

2006 Year

2008

2010

2012

series (13). The statistical significance level was set at p # 0.05.

Fitted values of IE for year 2000-2007 Fitted values of IE for year 2007-2011

RESULTS

Relative change in the incidence of infective endocarditis (IE) cases is shown for 2000 to 2007 and for 2007 to 2011.

A total of 457,052 estimated IE hospitalizations were identified during the study period (2000 to 2011). The annual IE hospitalization rate, microbiology, and valve replacement rates in the United States from 2000 to 2011 are summarized in Table 1. In the entire cohort, there was a steady increase in

F I G U R E 2 Trends in IE Microbiology as a Percent of Total IE Cases From 2000 to 2011

confidence interval: 0.32 to 0.75; p < 0.001). The Staphylococcus aureus

Streptococci

Gram negative

Fungi

change in IE hospitalization rate for 2007 to 2011 was 0.6 per 100,000 population (95% confidence interval:

45

0.23 to 0.97; p ¼ 0.005). The trends in IE hospitalization rates per 100,000 population between the

40 Percent of Total IE Cases

(p < 0.001). The change in IE hospitalization rate for 2000 to 2007 was 0.54 per 100,000 population (95%

55 50

the incidence of IE hospitalizations from 2000 to 2011

study periods 2000 to 2007 and 2008 to 2011 were not

35

significantly different (p ¼ 0.74) in the United States

30

(Figure 1).

25

in number of Staphylococcus IE cases. The proportion

The microbiology data demonstrated a steady rise of IE due to Staphylococcus (expressed as percentage

20

of total IE cases) increased from 33% in 2000 to 40% in 2011, a relative increase of 18.9% (p < 0.001)

15

(Figure 2). The proportion of IE due to Streptococcus

10

also increased from 24.8% in 2000 to 27% in 2011, a relative increase of 10.6% (p < 0.001) (Figure 2).

5

During the study period, the proportion of IE due to 2011

2010

2009

2008

2007

2006

2005

2004

2003

2002

2001

2000

0

Year

Note that the increasing incidence of infective endocarditis (IE) from 2000 to 2011 was seen across all 4 pathogens associated with IE, namely, Staphylococcus, Streptococcus, Gram-negative bacteria, and fungi.

GN bacteria increased from 5.3% to 8.2% (a relative increment of 33.9%; p < 0.001), and IE due to fungi increased from 0.6% to 1.4% (a relative increment of 59.6%; p < 0.001). The increases in the number of Staphylococcus IE cases per million population during the study period 2000 to 2007 and 2008 to 2011 were similar (p ¼ 0.13) (Central

Illustration).

There

was,

however,

a

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CENTRAL I LLU ST RAT ION

Infective Endocarditis and 2007 Guidelines

IE and 2007 Guidelines: Trend in the Incidence of Staphylococcus and Streptococcus IE

Pant, S. et al. J Am Coll Cardiol. 2015; 65(19):2070–6.

The infective endocarditis (IE) trends are assessed (per 1 million population) in the United States from 2000 to 2011. Note that the slope for Streptococcus (Strep) IE is significant between 2000 and 2007 and between 2007 to 2011 but not for Staphylococcus (Staph) IE.

statistically significant increase in Streptococcus IE

significant difference in valve replacement rates for

cases comparing the time periods before (2000 to

IE in the United States after the inception of the

2007) and after (2008 to 2011) the release of new

2007 guideline (p ¼ 0.23) (Figure 3). The trends in

guidelines (p ¼ 0.002) (Central Illustration).

valve replacement for Staphylococcus IE and Strep-

The valve replacement rates for IE steadily

tococcus IE did not change significantly before and

increased from 2000 to 2007 (p ¼ 0.03), followed

after 2007 (p ¼ 0.13 and p ¼ 0.49, respectively)

by a plateau from 2007 to 2011. There was no

(Figure 4).

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Infective Endocarditis and 2007 Guidelines

F I G U R E 3 Valve Replacement Rates for IE (per 1,000 IE Cases) in the United States

From 2000 to 2011

an increase in IE incidence. Despite the overall increase in IE hospitalizations from 2000 to 2011, we did not observe any significant change in hospitalization rates from the pre-guideline era (2000 to

30

2007) to the post-guideline era (2007–2011). Similar findings have been replicated in France, where a

25

guideline change in 2002 did not result in an in20

crease in IE cases (16). However, a recent study from the United Kingdom showed an increase in IE

15 10

cases with a decrease in antibiotic use, after a Na-

Change in no. of valve replacement for 2000-2007 [1.46 (0.14-2.79), p=0.03] Change in number of valve replacement for 2007-2011 [–1.30(–2.21-2.21), p=1.00] Change in the slope between 2000-2007 & 2007-2011 [–1.46(–4.04-1.11), p=0.23]

tional Institute for Health and Care Excellence guideline change in 2008 (17). We speculate that the difference in microbiology of IE among these

5

populations may partly account for such differences. Staphylococcus has remained the predomi-

0 2000

2002

2004

valve_replacement

2006 Year Fitted values

2008

2010

2012

nant pathogen for IE in the United States. Because the antibiotic prophylaxis in the guideline does not

Fitted values

routinely cover Staphylococcus, its growing trend since 2000 would not be affected by the change in

Although the rates for valve replacement increased from 2000 to 2007, rates since then have remained constant. IE ¼ infective endocarditis; Staph ¼ Staphylococcus; Strep ¼ Streptococcus.

the 2007 guideline. Our study shows that Streptococcus IE cases increased significantly after the change in the guideline in 2007. This is in contrast to prior studies, which showed no inflection in hospitalization rates after the 2007 ACC/AHA changes in prophylaxis recom-

DISCUSSION

mendations (11,12). The prior studies, however, had limited follow-up duration (2-year follow-up after the

Our study has several important findings. First, there

guideline change). A similar observation was made

has been a steady increase in the incidence of IE

in the U.K. study, in which a steady incidence of IE

hospitalizations over the past decade in the United

was noted for first 2 years after publication of the

States. However, the incidence of IE pre- and post-

guidelines (18).

inception of new antibiotic prophylaxis guidelines

The increasing incidence of IE from 2000 to 2011

is not significantly different (Central Illustration).

was seen across all 4 pathogens associated with IE,

In parallel to these findings, the rate of valve

namely, Staphylococcus, Streptococcus, GN bacteria,

replacement for IE did not change after the release of

and fungi. Specifically, the number of staphylococcal

new guidelines in 2007. Second, the increase in IE

IE cases increased, with a 20% relative rise during

incidence was seen across all types of pathogens:

the 11-year study period. Staphylococcus has been

Staphylococcus, Streptococcus, GN bacteria, and fungi.

found to be a predominant etiology for health care–

Finally, the rate of Streptococcus IE–related hospital-

associated native valve IE in the United States for

ization increased significantly after the release of new

nosocomial as well as nonnosocomial acquisition

guideline in the United States, while Staphylococcus

(2). Increased contact with health care providers, an

IE hospitalizations, although also on the rise, did not

increase in invasive procedures associated with

differ significantly after the 2007 ACC/AHA guideline

bacteremia, and increases in the sizes of high-risk

update.

population, such as the elderly and patients with

The increase in the U.S. incidence of IE over the

diabetes mellitus or end-stage renal disease, may

past decade has been reported previously and is

well be responsible for growing rates of staphylo-

likely related to an increase in the sizes of at-risk

coccal IE cases (2,3,5,19). In addition, there has been

populations, such as older, diabetic, and hemodialy-

an increasing trend in the use of prosthetic cardiac

sis patients (14,15). In addition, the number of inva-

devices (pacemakers, defibrillators, and prosthetic

sive procedures leading to transient bacteremia has

cardiac valves) in the United States (20), which make

increased markedly over this time period (2). Finally,

patients susceptible to staphylococcal infections.

there has been increase in survival in IE risk–prone

However, the rates of rise in Staphylococcus IE

populations, such as adults with congenital heart

before and after the guideline change did not differ

disease and prosthetic device implants, leading to

significantly.

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We also found that the overall rates of valve replacement for IE in the United States have stabilized since 2007. This was observed for both Strepto-

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Infective Endocarditis and 2007 Guidelines

F I G U R E 4 Trend in Valve Replacement for Staphylococcus Endocarditis

(per 1,000 Total IE Cases) and Streptococcus Endocarditis (per 1,000 Total IE Cases) in the United States From 2000 to 2011

coccus and Staphylococcus IE. This may reflect the 25

nostic tools, leading to earlier detection of IE in the United States. As a result, fewer patients may be developing severe complications from this disease that require surgical intervention. This is supported by our study, in which we noticed that rates of valve replacement for Staphylococcus IE changed significantly before 2007 (p ¼ 0.05). However, the trend stabilized after 2007 (p ¼ 0.78) (Figure 3).

Valve Replacement Per 1000 Staph IE Cases

increasing awareness of this disease and better diag-

STUDY LIMITATIONS. Despite its national scope and

20 15 10 5

Change in valve replacement in staph IE for year 2000-2007, [1.57 (0.62 to 2.53), p=0.005] Change in valve replacement in Staph IE for year 2007-2012, [0.20 (–1.40 to 1.80), p=0.78] Change in slope between 2000-2007 & 2007-2011, [–1.37 (–3.23 to 0.49), p=0.13]

0

the use of a widely used, well-characterized data-

2000

2002

2004

base, our study had some important limitations. The the International Classification of Diseases codes for IE. However, there has been a pilot study with a broader extraction of these codes for IE, which had a positive predictive value of 81% (21). The trend data also are affected by variations in coding practices among hospitals. Hence, it is not possible to know whether the increase in the incidence of Streptococcus IE is due to more complete recording or a true increase. However, there was no unexpected increase seen in IE due to Staphylococcus, GN bacteria, or fungi, which at least points toward the latter speculation that this observation might be something more than just a coding issue. Furthermore, the NIS, being

2008

2010

2012

50 Valve Replacement Per 1000 Strep IE Cases

main one is the lack of proper validation studies for

2006 Year

40 30 20 10

Change in valve replacement in Strep IE for year 2000-2007, [1.32 (–1.14 to 3.78), p=0.10] Change in valve replacement in Strep IE for year 2007-2012, [–0.20 (–4.32 to 3.92), p=0.12] Change in slope between 2000-2007 & 2007-2011, [–1.52 (–6.32 to 3.27), p=0.49]

0 2000

2002

2004

2006 Year

2008

2010

2012

Incidence of valve replacement in Staph/Strep IE Fitted values for valve replacement in Staph/Strep IE for year 2000-2007 Fitted values for valve replacement in Staph/Strep IE for year 2007-2011

a discharge-level database, cannot distinguish if multiple hospitalizations are from the same patient. This may limit the precision of our estimates. Finally, our database does not capture antibiotic use, and

The rate of valve replacement for Streptococcus endocarditis did not change significantly, but that for Staphylococcus endocarditis increased significantly from 2000 to 2007 and then stabilized. IE ¼ infective endocarditis.

hence, we do not know the impact of the 2007 guideline change on antibiotic prescription for IE prophylaxis. Despite these limitations, the NIS data-

speculate that this could be related to the decrease

base provides data from approximately 20% of all

in the use of IE antibiotic prophylaxis since the

U.S. community hospitals. This large cohort, repre-

guideline change. A prospective study designed to

sentative sample, and longer follow-up duration after

understand the antibiotic prescription pattern after

the 2007 guideline change makes our study reflective

the change in IE guidelines is needed to further test

of changing trends in IE hospitalizations from a na-

the validity of our observations. Furthermore, on-

tional perspective.

going monitoring of the impact of these guideline recommendations is highly warranted, as the new

CONCLUSIONS

guideline in itself is not “evidence based” but rather attempts to demonstrate the lack of evidence un-

The overall incidence of IE showed a steady increase

derlying the previous recommendations for IE pro-

in the United States from 2007 to 2011. However, the

phylactic antibiotics.

annual hospitalization rates and frequency of valve surgery due to IE have not changed significantly

REPRINT REQUESTS AND CORRESPONDENCE: Dr.

since the change in IE prophylaxis guideline in 2007.

Jawahar L. Mehta, Department of Cardiovascular

With regard to the microbiology of IE, there has

Medicine, University of Arkansas for Medical Sci-

been a significant rise in the incidence of Strepto-

ences, 4301 West Markham Street, Little Rock,

coccus IE since the 2007 guideline revisions. We

Arkansas 72205. E-mail: [email protected].

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Infective Endocarditis and 2007 Guidelines

PERSPECTIVES COMPETENCY IN MEDICAL KNOWLEDGE: Unnec-

restricted number of cardiac conditions in which IE is

essary use of antibiotic drugs exposes patients to un-

associated with a high risk for adverse outcomes.

necessary side effects and leads to the development TRANSLATIONAL OUTLOOK: More research is

antibiotic-resistant bacteria.

needed to define the conditions for which antibiotic COMPETENCY IN PATIENT CARE: Since the publica-

prophylaxis is actually effective in preventing IE and to

tion of the 2007 ACC/AHA scientific statement on IE,

assess the impact of changes in the practice of antibiotic

antibiotic prophylaxis is recommended for a more

prophylaxis on the epidemiology of IE.

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KEY WORDS clinical practice, guidelines, infective endocarditis, valve replacement, valvular heart disease

A PPE NDI X For a list of the ICD codes identifying infective endocarditis and causative organisms, please see the online version of this article.