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Comparison of Mortality in Women Versus Men With Infections Involving Cardiovascular Implantable Electronic Device
Comparison of Mortality in Women Versus Men With Infections Involving Cardiovascular Implantable Electronic Device M. Rizwan Sohail, MDa,b,*, Charles A. Henrikson, MDc, Mary Jo Braid-Forbes, MPHd, Kevin F. Forbes, PhDe, and Daniel J. Lerner, MDf Device infection is a complication of implantable cardioverter-defibrillator (ICD) therapy that significantly increases mortality. Risk factors associated with death and ICD infection are poorly understood. The purpose of this study was to identify patient characteristics associated with death after cardiovascular implantable electronic device (CIED) infection. This is a retrospective cohort study of 64,903 Medicare fee-for-service patients who received an ICD in 2007, including 1,855 with device infection. Long-term survival was significantly reduced with CIED infection (71.6% vs 85.0%, p <0.001). Regression analysis accounting for age, race, gender, and 28 co-morbidities identified only 2 patient characteristics associated with decreased long-term survival with CIED infection: female gender and human immunodeficiency virus/acquired immunodeficiency syndrome. In patients with CIED infection, women had substantially reduced long-term survival compared with men (67.3% vs 72.9%, p <0.02). The risk-adjusted hazard ratio for long-term mortality with device infection in women compared with that in men increased significantly from 0.86 (95% confidence interval [CI] 0.82 to 0.91) to 1.25 (95% CI 1.02 to 1.53), corresponding to a risk increase of >45%. Importantly, a substantial portion of this excess mortality occurred after the index admission for infection, when the hazard ratio for death in women compared with that in men increased from 0.86 (95% CI 0.82 to 0.91) to 1.20 (95% CI 0.96 to 1.51) with CIED infection, despite little gender difference in admission length of stay, disposition, and cost. In conclusion, women are significantly more likely than men to die with CIED infection. A substantial part of this excess mortality occurs after discharge. It will be important to identify and address the cause(s) of this gender difference in mortality. Ó 2013 Elsevier Inc. All rights reserved. (Am J Cardiol 2013;112:1403e1409) Device infection is a complication of cardiovascular implantable electronic device (CIED) therapy that is associated with significant admission and long-term mortality.1,2 The demographic features and co-morbidities associated with increased mortality with CIED infection are not well understood. In this investigation, we identified patient characteristics associated with decreased survival with CIED infection in a large cohort of Medicare beneficiaries.
Divisions of aInfectious Diseases and bCardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; cDivision of Cardiovascular Medicine, Department of Medicine, Oregon Health & Science University, Portland, Oregon; dBraid-Forbes Health Research, Silver Spring, Maryland; eInstitute for Policy Research & Catholic Studies, Catholic University of America, Washington, DC; and f TYRX Inc., Monmouth Junction, New Jersey. Manuscript received April 1, 2013; revised manuscript received and accepted June 24, 2013. This study was supported, in part, by a Career Development Award to M.R.S. from the department of medicine, Mayo Foundation for Medical Education and Research. TYRX Inc. provided salary support for M.J.B.-F., K.F.F., and David J. Wright, an acknowledged contributor, to assist with data collection (M.J.B.-F.), analyses (M.J.B.-F. and K.F.F.), and review (D.J.W.). M.R.S and C.A.H. have received funding from TYRX Inc. for previous research. D.J.L. is the Chief Medical Officer for TYRX Inc. and, in that role, has been paid a salary and granted stock options by TYRX Inc. No commercial productions are discussed in this manuscript. See page 1408 for disclosure information. *Corresponding author: Tel: (507) 255-7938; fax: (507) 255-7767. E-mail address: [email protected] (M.R. Sohail). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.06.031
Methods The study cohort was derived from the 100% Medicare Standard Analytic File (SAF) Limited Data Set version for inpatient admissions for the 2007 calendar year and consisted of all admissions that included a procedure for implantable cardioverter-defibrillator (ICD) generator implantation, replacement, or revision identified using the corresponding International Classification of Diseases Ninth Revision Clinical Modification (ICD-9-CM) procedure codes for ICDs (37.94, 37.96, and 37.98) or cardiac resynchronization therapy devices with defibrillator (00.51 and 00.54). Admissions that included only electrode implantation, replacement, or revision were not included because most CIED infections are treated with complete system explantation.3,4 Admissions including other major cardiac procedures were excluded to avoid including procedural mortality unrelated to the CIED infection (Supplementary Table 1). The study cohort was divided into admissions with and without a primary or secondary diagnosis of infection, identified using ICD-9-CM diagnosis codes for infection due to a cardiac device (996.61), infection due to a vascular device (996.62), endocarditis (421.0, 421.1, 421.9, 424.90, 424.91, and 424.99), bacteremia (790.7), septicemia (038.0, 038.2, 038.3, 038.10, 038.11, 038.19, 038.40, 038.41, 038.42, 038.43, 038.44, 038.49, 038.8, and 038.9), shock (785.50), cellulitis (682.8 and 682.9), or fever (780.6). Identification of ICD infection cases is discussed in detail in www.ajconline.org
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Table 1 Baseline characteristics with and without device infection Characteristic
Age (yrs) <65 65e69 70e74 75e79 80e84 >84 Women Men White Non-white Congestive heart failure Valvular heart disease Hypertension Peripheral vascular disease Pulmonary circulation disorders Chronic pulmonary disease Renal failure Fluid and electrolyte disorders Diabetes mellitus, without CC Diabetes mellitus, with CC Hypothyroidism Blood loss anemia Deficiency anemia Coagulation deficiency Liver disease HIV infection or AIDS Lymphoma Metastatic cancer Solid tumor without metastasis Rheumatoid arthritis/ CVD Obesity Weight loss Paralysis Other neurologic disorders Alcohol abuse Drug use Psychoses Depression CRT-D
All, n ¼ 64,903 (%)
10,335 12,120 13,128 14,170 10,525 4,625 17,400 47,503 54,429 10,474 28,948 13,805 33,080 4,690
(16) (19) (20) (22) (16) (7) (27) (73) (84) (16) (45) (21) (51) (7)
Infection
p
No, n ¼ 63,048 (%)
Yes, n ¼ 1,855 (%)
9,977 11,807 12,772 13,803 10,223 4,466 16,958 46,090 52,925 10,123 27,938 13,425 32,489 4,269
358 (19) 313 (17) 356 (19) 367 (20) 302 (16) 159 (9) 442 (24) 1,413 (76) 1,504 (81) 351 (19) 1,010 (54) 380 (21) 591 (32) 61 (3)
<0.001 0.04 0.26 0.03 0.94 0.01 0.003 0.003 <0.001 <0.001 <0.001 0.40 <0.001 <0.001
(16) (19) (20) (22) (16) (7) (27) (73) (84) (16) (44) (21) (52) (7)
2,866 (4)
2,827 (5)
39 (2)
<0.001
13,433 (21)
13,004 (21)
429 (23)
0.01
11,684 (18) 5,767 (9)
11,166 (18) 5,411 (9)
518 (28) 356 (19)
<0.001 <0.001
15,915 (25)
15,640 (25)
275 (15)
<0.001
2,009 (3)
1,956 (3)
53 (3)
0.55
3,965 (6) 295 (0.5) 2,523 (4) 1,601 (3) 405 (0.6) NA 375 (0.6) NA 519 (0.8)
3,816 269 2,465 1,483 386 43 363 119 502
800 (1)
(6) (0.4) (4) (2) (0.6) (0.1) (0.6) (0.2) (0.8)
780 (1)
59 (3) <0.001 20 (1) <0.001 58 (3) 0.09 118 (6) <0.001 19 (1) 0.03 * 12 (0.6) 0.69 * 17 (1) 0.57 20 (1)
0.54
2,096 445 399 1,459
(3) (0.7) (0.6) (2)
18 (1) <0.001 68 (4) <0.001 12 (0.6) 0.53 48 (3) 0.44
727 (1) 709 297 (0.5) 283 NA 465 1,296 (2) 1,280 27,261 (42) 26,532
(1) (0.4) (0.7) (2) (42)
18 (1) 0.53 14 (0.8) 0.05 * 16 (1) <0.001 729 (39) 0.02
2,114 513 411 1,507
(3) (0.8) (0.6) (2)
AIDS ¼ acquired immunodeficiency syndrome; CC ¼ chronic complications; CRT-D ¼ cardiac resynchronization therapy devices with defibrillator; CVD ¼ collagen vascular diseases; HIV ¼ human immunodeficiency virus; NA ¼ could not be calculated because value for infected patients could not be reported because <11. * Underlying counts were <11. Proportions cannot be reported because of Centers for Medicare and Medicaid Services privacy regulations.
Figure 1. Relation between CIED infection and survival. Kaplan-Meier estimates of survival during the quarter of the index admission (0 to 1) and the following 4 quarters (1 to 5) without (solid line) and with (dashed line) device infection in 64,903 Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures during the 2007 calendar year. Estimated survival (percentage) at the end of fourth quarter after index admission quarter (right). Comparison made by log-rank test.
the Supplementary Data. Patients identified from these claim files using the encrypted beneficiary identifier were linked to the 2007 and 2008 Medicare Denominator Files to collect beneficiary date of death. Patient demographics were also identified from the Medicare claims file. A total of 70,597 admissions with a qualifying ICD procedure were identified. Of these, 5,694 were excluded: 3,622 had other major cardiac procedures, 2,072 were additional admissions for patients with multiple admissions, were paid for by a Medicare Health Maintenance Organization or not associated with a Medicare payment, or had no Medicare Part A enrollment in the quarter of the index admission. If a patient had an ICD procedure admission with and another one without infection, the admission without infection was excluded. The primary outcome of our study was long-term survival associated with ICD implantation, replacement, or revision procedures, defined as survival through the admission quarter and the subsequent 4 quarters (combination of admission and postadmission periods). Secondary outcomes were admission survival, defined as survival during the index hospitalization for the ICD procedure, and postadmission survival, defined as survival from discharge through the quarter of admission and the 4 quarters after the admission quarter. The unit of analysis for all 3 outcomes was the individual discharge. The prevalence of specific demographic characteristics and co-morbidities in study subgroups were compared using
Arrhythmias and Conduction Disturbances/Gender Differences in ICD Infection Mortality
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Table 2 Baseline characteristics of men and women, with and without infection Characteristic
No Infection Women, n ¼ 16,958 (%)
Age (yrs) <65 65e69 70e74 75e79 80e84 >84 White Non-white Congestive heart failure Valvular heart disease Hypertension Peripheral vascular disease Pulmonary circulation disorders Chronic pulmonary disease Renal failure Fluid and electrolyte disorders Diabetes, without CC Diabetes, with CC Hypothyroidism Blood loss anemia Deficiency anemia Coagulation deficiency Liver disease HIV infection or AIDS Lymphoma Metastatic cancer Solid tumor without metastasis Rheumatoid arthritis/CVD Obesity Weight loss Paralysis Other neurologic disorders Alcohol abuse Drug use Psychoses Depression CRT-D
2,933 3,118 3,420 3,776 2,885 1,268 13,312 3,646 7,786 4,434 8,989 958 964 3,723 2,752 1,918 4,406 589 1,859 105 903 362 83 * 120 37 89 406 704 161 112 441 61 59 177 523 7,428
(17) (18) (20) (22) (17) (8) (79) (22) (46) (26) (53) (6) (6) (22) (16) (11) (26) (4) (11) (0.6) (5) (2) (0.5) (0.7) (0.2) (0.5) (2) (4) (1) (0.7) (3) (0.4) (0.3) (1) (3) (44)
Infection
Men, n ¼ 46,090 (%) 7,402 9,002 9,708 10,394 7,640 3,357 39,262 6,828 21,162 9,371 24,091 3,732 1,902 9,710 8,932 3,849 11,509 1,420 2,106 190 1,620 1,239 322 40 255 88 430 394 1,410 352 299 1,066 666 238 297 773 19,833
(16) (20) (21) (23) (17) (7) (85) (15) (46) (20) (52) (8) (4) (21) (19) (8) (25) (3) (5) (0.4) (4) (3) (0.7) (0.1) (0.6) (0.2) (1) (1) (3) (0.8) (0.6) (2) (1) (0.5) (0.6) (2) (43)
p
Women, n ¼ 442 (%)
Men, n ¼ 1,413 (%)
p
<0.001 0.01 0.03 0.73 0.13 0.34 <0.001 <0.001 0.65 <0.001 0.03 <0.001 <0.001 0.01 <0.001 <0.001 0.01 0.01 <0.001 <0.001 <0.001 <0.001 0.01
89 (20) 66 (15) 84 (19) 94 (21) 70 (16) 39 (9) 325 (74) 117 (27) 224 (51) 114 (26) 151 (34) 11 (3) 14 (3) 100 (23) 121 (27) 107 (24) 55 (12) 19 (4) 28 (6) 11 (3) 15 (3) 21 (5) * * * * * * * 16 (4) * 17 (4) * * * * 161 (36)
269 (19) 247 (18) 272 (19) 273 (19) 232 (16) 120 (9) 1,179 (83) 234 (17) 786 (56) 266 (19) 440 (31) 50 (4) 25 (2) 329 (23) 397 (28) 249 (18) 220 (16) 34 (2) 31 (2) 15 (1) 43 (3) 97 (7) 16 (1) * * * 12 (0.8) 12 (0.8) 11 (0.8) 52 (4) * 31 (2) 17 (1) 12 (0.8) * 11 (0.8) 568 (40)
0.61 0.21 0.91 0.37 0.77 0.83 <0.001 <0.001 0.07 0.002 0.23 0.28 0.07 0.77 0.77 0.002 0.11 0.04 <0.001 0.03 0.71 0.11
0.02 0.48 <0.001 <0.001 <0.001 0.02 0.84 0.03 0.03 0.01 <0.001 <0.001 0.04
0.95 0.06
0.002
AIDS ¼ acquired immunodeficiency syndrome; CC ¼ chronic complications; CRT-D ¼ cardiac resynchronization therapy devices with defibrillator; CVD ¼ collagen vascular diseases; HIV ¼ human immunodeficiency virus. * Underlying counts were <11. Proportions cannot be reported because of Centers for Medicare and Medicaid Services privacy regulations.
a chi-square test. Long-term survival functions were estimated using Kaplan-Meier survival analysis and compared using a log-rank test. Kaplan-Meier mortality was derived as 1 Kaplan-Meier survival. A significance level of 0.05 was used for all tests. Statistical tests were performed using SAS, version 9.2, 2008 (SAS Institute Inc., Cary, North Carolina) and XLstat (Addinsoft, Montreal, Canada). The rates of admission, postadmission, and long-term mortality were adjusted for age, gender, race or ethnicity, and a set of 28 co-morbidity measures associated with death in Medicare beneficiaries, originally derived by Elixhauser et al5 and validated for risk adjustment using administrative data.6,7 The individual patient status for this set of comorbidities was collected from the administrative data using the Comorbidity Software (versions 3.2 and 3.3)8 from the Agency for Healthcare Research and Quality (Rockville,
Maryland) that specifies ICD-9-CM codes corresponding to each patient co-morbidity. Peptic ulcer disease was omitted because it was rare in our study cohort. The primary condition screens, including for cardiac conditions, were not used because this study was narrowly defined to patients receiving ICD therapy. Admission, postadmission, and long-term mortality were modeled using the binomial complementary log-log regression specification. Terms for an interaction between device infection and age, gender, race/ethnicity, and the 28 co-morbidities were included in the regression models for mortality. A discussion of the rationale for these model choices can be found in the Supplementary Data. For some analyses, certain co-morbidities were not present in either men or women and were dropped for that device. Riskadjusted mortality hazard ratios (HRs), defined as mortality
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rate in women with device infection or mortality rate in men with device infection, for admission, postadmission, and long-term mortality were calculated by exponentiating the ratio of the sum of the parameter estimates for device infection, gender, and the gender-device infection interaction term in the corresponding mortality regression models for women with device infection and men with device infection.9,10 Riskadjusted mortality HR without device infection, defined as mortality rate in women without device infection or mortality rate in men without device infection, were calculated by exponentiating the ratio of the parameter estimates for gender in corresponding mortality regression models for women without device infection and men without device infection.9,10 The regressions were estimated using Stata, version 11 (Stata Corp LP, College Station, Texas). Results were robust to heteroskedasticity. The Goodwyn Institutional Review Board (Cincinnati, Ohio) determined that the study was exempt from full human subjects research review. Results The study cohort consisted of 64,903 Medicare fee-forservice patients who received an ICD in 2007 (Table 1). In the study cohort, 84.1% of patients were aged 65 years, 26.8% were women, 16.1% were non-white, 18.0% had renal failure, 27.6% had diabetes mellitus, and 42% received a cardiac resynchronization therapy device with defibrillator. A total of 1,855 patients (2.9%) in the study cohort had a CIED infection. Patients with CIED infection were more likely to have congestive heart failure (54.4% vs 44.3%, p 0.001), renal failure (27.9% vs 17.7%, p 0.001), fluid and electrolyte disorders (19.2% vs 8.6%, p 0.001), and a coagulopathy (6.4% vs 2.4%, p 0.001) but less likely to have diabetes mellitus (14.8% vs 24.8%, p 0.001) or hypertension (31.9% vs 51.9%, p <0.001) compared with those without CIED infection (Table 1). There were other differences in baseline characteristics that achieved statistical significance, in part because of the large sample size, but they were smaller in magnitude and less likely to be of clinical significance. Long-term survival in patients with CIED infection was significantly less than that in patients without device infection (71.6% vs 85.0%, p <0.001; Figure 1). The corresponding long-term mortality in patients with CIED infection was approximately twofold the long-term mortality in patients without device infection (28.4% vs 15.0%, p <0.001). Admission mortality was also significantly increased for patients with CIED infection compared with those without device infection (5.17% vs 0.72%, p <0.001). To identify patient characteristics associated with decreased long-term survival with CIED infection, we performed a regression analysis for long-term death in patients admitted for an ICD procedure, adjusting for age, gender, race or ethnicity, and a set of 28 co-morbidities associated with death in Medicare beneficiaries, originally derived by Elixhauser et al5 and validated for risk adjustment using administrative data.6,7 This regression analysis identified 2 patient characteristics with a significant interaction with increased long-term death and device infection: female
Figure 2. Relation between gender and survival, with and without CIED infection. Kaplan-Meier estimates of survival during the quarter of the index admission (0 to 1) and the following 4 quarters (1 to 5) in 64,903 women (thick line) and men (thin line) Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures and during the 2007 calendar year, without or with infection. Estimated survival (percentage) at the end of fourth quarter after index admission quarter (right). Comparisons were made by log-rank test.
gender (p <0.001) and human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS; p ¼ 0.035; Supplementary Table 2). HIV/AIDS was rare in this population (<0.1%; Table 1). The administrative database did not permit the distinction between HIV infection and AIDS. Despite the small number of patients with HIV/AIDS in the study cohort, it is noteworthy that the risk-adjusted HR for long-term death with CIED infection in this group was 5.35 (95% confidence interval [CI] 1.16 to 24.69). The study cohort included 17,400 women (26.8%) and 47,503 men (73.2%). Women were more often non-white (21% vs 14.4%, p <0.001) and more likely to have valvular disease (25.5% vs 19.7%, p <0.001) and hypothyroidism (10.7% vs 4.2%, p <0.001). The frequency of cardiac resynchronization therapy devices with defibrillator procedures (42.7% vs 41.8%) was similar for women and men (Table 2). There were other differences in baseline characteristics that achieved statistical significance, in part because of the large sample size, but they were smaller in magnitude and less likely to be of clinical significance. Device infection markedly reduced survival in women compared with men. In patients without a device infection, long-term survival was slightly higher in women compared with men (86.4% vs 84.5%, p <0.001; Figure 2). In contrast, in patients with a device infection, women had significantly reduced long-term survival compared with men (67.3% vs 72.9%, p <0.02; Figure 2).
Arrhythmias and Conduction Disturbances/Gender Differences in ICD Infection Mortality
Figure 3. Risk-adjusted HRs for death in women versus men, with and without CIED infection. Risk-adjusted HRs with 95% CI for mortality in women compared with men, without (gray box) and with (black box) device infection, for admission, postadmission, and long-term mortality in 17,400 women and 47,503 men Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures during the 2007 calendar year. HRs are adjusted for demographic characteristics and 28 co-morbidities associated with death in Medicare beneficiaries.
Table 3 Admission length of stay, disposition, and cost for men and women, with and without infection Women
Men
Admission length of stay (days) No device infection 5.0 5.9 4.2 5.4 Device infection 17.2 22.5 15.2 13.5 Disposition to home or self-care No device infection (%) 12,726 (76) 38,336 (83) Device infection (%) 155 (35) 629 (45) Admission cost ($) No device infection 32,597 18,038 31,561 17,189 Device infection 52,208 38,059 51,098 34,688
p
<0.001 0.02
<0.001 <0.001 <0.001 0.57
Adjusting for differences in demographics and comorbidities revealed an even larger gender difference in long-term mortality. The risk-adjusted HR for long-term mortality in women compared with men increased from 0.86 (95% CI 0.82 to 0.91) without device infection to 1.25 (95% CI 1.02 to 1.53) with device infection (Figure 3). This corresponds to an increase in the adjusted risk of long-term mortality in women compared with men of >45%. The risk-adjusted HR for death during the index admission for women compared with men increased with device infection from 0.81 (95% CI 0.63 to 1.05) to 1.45 (95% CI 0.93 to 2.32; Figure 3), but the difference did not achieve statistical significance. A substantial portion of the excess long-term mortality in women with infection compared with men with infection occurred after the index admission. The risk-adjusted HR for postadmission death in women compared with men
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increased from 0.86 (95% CI 0.82 to 0.91) to 1.20 (95% CI 0.96 to 1.51; Figure 3). There were differences in some aspects of the index admission between men and women, but these differences did not change substantially with device infection. For patients without device infection, admission length of stay was about 1 day longer for women than men (5.0 vs 4.2 days, p <0.001), about 8% fewer women were discharged to home or self-care than men (75.5% vs 83.8%, p <0.001), and the admission cost was about $1,000 higher for women than for men ($32,597 vs $31,561, p <0.001; Table 3). For patients with device infection, these disparities were either similar or less than for patients without device infection. Women with device infection stayed in the hospital 2 days longer than men (17.2 vs 15.2 days, p ¼ 0.02), about 9% fewer women were discharged to home or self-care than men (35.1% vs 44.5%, p <0.001), and the admission cost was not significantly different for women and men ($52,208 vs $51,098, p ¼ 0.57; Table 3). Discussion Our study identified and quantified a substantial gender disparity in mortality associated with device infection in the current era of ICD utilization. It demonstrated that although women without a CIED infection have slightly better survival than men, women with a CIED infection have a significantly increased risk of death compared with men. The risk-adjusted long-term mortality rate was 25% higher in women compared with men. Importantly, the only other patient characteristic associated with increased mortality in infected patients was HIV/AIDS. To date, there are few published data on gender differences in mortality associated with CIED infection. Five recently published series of CIED infections reported that admission mortality for all patients ranged from 3.7% to 8.1%,1,3,11e13 but only 1 study presented gender-specific data. Baman et al11 reported that the unadjusted HR for 6-month mortality, in their cohort of predominantly pacemaker infections, was 1.56 for men compared with that of women, but the difference did not achieve statistical significance. The origin of increased mortality associated with ICD infections is not clear. Mortality associated with CIED infections has been attributed to sepsis and its sequelae, complications related to the explantation procedure, congestive heart failure, cardiac arrest, and renal insufficiency.1,11,12 In our study, the prevalence of congestive heart failure was similar in men and women, whereas women had significantly less renal failure than men. The regression models for mortality used in this study also adjusted for both these co-morbidities. The administrative database does not permit us to reliably compare the severity of device infection, complications related to explantation, or the mechanism of death in the 2 groups. Potential mechanisms that may explain the greater longterm morality in women with device infections include differences in biologic response to infection or sepsis, women with an infected device may present to the healthcare system later than men, fuller breast tissue in women may hinder accurate examination of the CIED generator
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pocket site in the pectoral area, or that health-care systems may treat women with CIED infection differently than men. To our knowledge, there are no published data on differential treatment of ICD infection in women and men. Current guidelines recommend that CIED infection should be treated with complete explantation of all device hardware and administration of appropriate antibiotics for 2 to 6 weeks, depending on the extent of the device infection.4 Previous work demonstrates that other cardiac invasive procedures (angiography and revascularization) have been used less frequently in women compared with men.14,15 Currently, it is not known if complete explantation of the infected device is offered less often or later to women, compared with men, with CIED infection. Other data suggest that women have a greater likelihood of complications associated with ICD implantation than men,16 which may indicate that invasive procedures often used in patients with ICD infection, such as lead extraction, may be associated with increased morbidity and mortality in women compared with men. Unfortunately, the clinical information available in this administrative database does not permit an adequate examination of the origin of the increased mortality associated with CIED infection in women compared with men. It is noteworthy that a substantial portion of this excess long-term mortality in women occurred after the index admission with the device infection, and the difference appears to be increasing at the end of the observation period. This may be because of differences in the severity of infection at presentation, care during or after hospitalization, and other factors. Although there were disparities in some clinical metrics of care between men and women without device infection in this study, these differences were either similar or less in patients with device infection. Understanding these disparities is important, but it makes it less likely that they are responsible for the difference in postadmission or longer-term mortality between women and men with device infection. Overall, these data indicate that risk-adjusted long-term mortality rate after CIED infection is 25% higher in women, despite little change in the gender-based relations for admission length of stay, disposition, and cost. The origin of this excess mortality associated with CIED infection in women remains unclear and merits further investigation. Our analysis has certain limitations. First, infections identified using ICD-9-CM codes for cardiac or vascular device infection, endocarditis, or cardinal manifestations of infection, in the setting of an ICD implantation, were presumed to be CIED infections. It is conceivable that some of these infections may not have been related to the CIED. However, it is quite likely that most of these represent CIED infections because it is unusual to implant an ICD during an admission that includes infection of another organ system because of the concern of device seeding from a distant source of bacteremia, unless infection of that organ system was due to a CIED infection itself or caused a CIED infection. Second, these data were collected from the Medicare Inpatient SAF, which is a claims-based administrative database and therefore may be less accurate than a clinical database for evaluating some aspects of these
admissions that may affect mortality after CIED infection. Finally, the severity of the device infection, which may also be related to outcome, cannot be ascertained from this administrative database. Despite these limitations, we believe that these data provide useful insights into gender differences in the mortality associated with CIED infections. Acknowledgment: David J. Wright, PhD (Westat, Rockville, Maryland) performed a statistical review of the data. TYRX Inc. personnel (D.J.L.) participated in the design of the study, analysis, and interpretation of the data, and in the decision to approve publication of the finished manuscript. Disclosures M.R.S. has received funding from TYRX Inc. for previous research.17 C.A.H. has received funding from TYRX Inc. for research (Clinicaltrials.gov NCT01043705 and NCT01043861). D.J.L. is the Chief Medical Officer for TYRX Inc., and in that role, has been paid a salary and granted stock options by TYRX. Supplementary Data Supplementary data related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.amjcard. 2013.06.031. 1. Tarakji KG, Chan EJ, Cantillon DJ, Doonan AL, Hu T, Schmitt S, Fraser TG, Kim A, Gordon SM, Wilkoff BL. Cardiac implantable electronic device infections: presentation, management, and patient outcomes. Heart Rhythm 2010;7:1043e1047. 2. Sohail MR, Henrikson CA, Braid-Forbes MJ, Forbes KF, Lerner DJ. Mortality and cost associated with cardiovascular implantable electronic device infections. Arch Intern Med 2011;171:1821e1828. 3. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Stoner S, Baddour LM. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851e1859. 4. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB, Masoudi FA, Okum EJ, Wilson WR, Beerman LB, Bolger AF, Estes NAM III, Gewitz M, Newburger JW, Schron EB, Taubert KA, on behalf of the American Heart Association Rheumatic Fever E, Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Y, Council on Cardiovascular S, Anesthesia, Council on Cardiovascular N, Council on Clinical C, the Interdisciplinary Council on Quality of C, Outcomes R. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458e477. 5. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36:8e27. 6. Southern DA, Quan H, Ghali WA. Comparison of the Elixhauser and Charlson/Deyo methods of comorbidity measurement in administrative data. Med Care 2004;42:355e360. 7. Li B, Evans D, Faris P, Dean S, Quan H. Risk adjustment performance of Charlson and Elixhauser comorbidities in ICD-9 and ICD-10 administrative databases. BMC Health Serv Res 2008;8:12. 8. (HCUP) AfHRaQAHCaUP. Comorbidity Software: Healthcare Cost and Utilization Project (HCUP), 2011. 9. Collett D. Modelling Binary Data. Boca Raton: Chapman & Hall/CRC, 2003; 387p. 10. Hilbe J. Negative Binomial Regression. Cambridge; New York: Cambridge University Press, 2007; xii, 251 p. 11. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol 2009;2:129e134.
Arrhythmias and Conduction Disturbances/Gender Differences in ICD Infection Mortality 12. Margey R, McCann H, Blake G, Keelan E, Galvin J, Lynch M, Mahon N, Sugrue D, O’Neill J. Contemporary management of and outcomes from cardiac device related infections. Europace 2010;12: 64e70. 13. Voigt A, Shalaby A, Saba S. Continued rise in rates of cardiovascular implantable electronic device infections in the United States: temporal trends and causative insights. Pacing Clin Electrophysiol 2010;33: 414e419. 14. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991;325:221e225. 15. Vaccarino V, Rathore SS, Wenger NK, Frederick PD, Abramson JL, Barron HV, Manhapra A, Mallik S, Krumholz HM. Sex and racial
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differences in the management of acute myocardial infarction, 1994 through 2002. N Engl J Med 2005;353:671e682. 16. Peterson PN, Daugherty SL, Wang Y, Vidaillet HJ, Heidenreich PA, Curtis JP, Masoudi FA. Gender differences in procedure-related adverse events in patients receiving implantable cardioverter-defibrillator therapy. Circulation 2009;119:1078e1084. 17. Bloom HL, Constantin LD, Daniel DL, David B, El-Chami, M, Ganz LI, Gleed KJ, Hackett FK, Kanuru NK, Lerner DJ, Rasekh AS, Grant RS, Felix O, Sohail MR, for the COMMAND (COoperative Multicenter study Monitoring a CIED ANtimicrobial Device) Investigators. Implantation Success and Infection in Cardiovascular Implantable Electronic Device Procedures Utilizing an Antibacterial Envelope. Pacing Clin Electrophysiol 2011;34:133e142.
Divisions of aInfectious Diseases and bCardiovascular Diseases, Department of Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota; cDivision of Cardiovascular Medicine, Department of Medicine, Oregon Health & Science University, Portland, Oregon; dBraid-Forbes Health Research, Silver Spring, Maryland; eInstitute for Policy Research & Catholic Studies, Catholic University of America, Washington, DC; and f TYRX Inc., Monmouth Junction, New Jersey. Manuscript received April 1, 2013; revised manuscript received and accepted June 24, 2013. This study was supported, in part, by a Career Development Award to M.R.S. from the department of medicine, Mayo Foundation for Medical Education and Research. TYRX Inc. provided salary support for M.J.B.-F., K.F.F., and David J. Wright, an acknowledged contributor, to assist with data collection (M.J.B.-F.), analyses (M.J.B.-F. and K.F.F.), and review (D.J.W.). M.R.S and C.A.H. have received funding from TYRX Inc. for previous research. D.J.L. is the Chief Medical Officer for TYRX Inc. and, in that role, has been paid a salary and granted stock options by TYRX Inc. No commercial productions are discussed in this manuscript. See page 1408 for disclosure information. *Corresponding author: Tel: (507) 255-7938; fax: (507) 255-7767. E-mail address: [email protected] (M.R. Sohail). 0002-9149/13/$ - see front matter Ó 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.06.031
Methods The study cohort was derived from the 100% Medicare Standard Analytic File (SAF) Limited Data Set version for inpatient admissions for the 2007 calendar year and consisted of all admissions that included a procedure for implantable cardioverter-defibrillator (ICD) generator implantation, replacement, or revision identified using the corresponding International Classification of Diseases Ninth Revision Clinical Modification (ICD-9-CM) procedure codes for ICDs (37.94, 37.96, and 37.98) or cardiac resynchronization therapy devices with defibrillator (00.51 and 00.54). Admissions that included only electrode implantation, replacement, or revision were not included because most CIED infections are treated with complete system explantation.3,4 Admissions including other major cardiac procedures were excluded to avoid including procedural mortality unrelated to the CIED infection (Supplementary Table 1). The study cohort was divided into admissions with and without a primary or secondary diagnosis of infection, identified using ICD-9-CM diagnosis codes for infection due to a cardiac device (996.61), infection due to a vascular device (996.62), endocarditis (421.0, 421.1, 421.9, 424.90, 424.91, and 424.99), bacteremia (790.7), septicemia (038.0, 038.2, 038.3, 038.10, 038.11, 038.19, 038.40, 038.41, 038.42, 038.43, 038.44, 038.49, 038.8, and 038.9), shock (785.50), cellulitis (682.8 and 682.9), or fever (780.6). Identification of ICD infection cases is discussed in detail in www.ajconline.org
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Table 1 Baseline characteristics with and without device infection Characteristic
Age (yrs) <65 65e69 70e74 75e79 80e84 >84 Women Men White Non-white Congestive heart failure Valvular heart disease Hypertension Peripheral vascular disease Pulmonary circulation disorders Chronic pulmonary disease Renal failure Fluid and electrolyte disorders Diabetes mellitus, without CC Diabetes mellitus, with CC Hypothyroidism Blood loss anemia Deficiency anemia Coagulation deficiency Liver disease HIV infection or AIDS Lymphoma Metastatic cancer Solid tumor without metastasis Rheumatoid arthritis/ CVD Obesity Weight loss Paralysis Other neurologic disorders Alcohol abuse Drug use Psychoses Depression CRT-D
All, n ¼ 64,903 (%)
10,335 12,120 13,128 14,170 10,525 4,625 17,400 47,503 54,429 10,474 28,948 13,805 33,080 4,690
(16) (19) (20) (22) (16) (7) (27) (73) (84) (16) (45) (21) (51) (7)
Infection
p
No, n ¼ 63,048 (%)
Yes, n ¼ 1,855 (%)
9,977 11,807 12,772 13,803 10,223 4,466 16,958 46,090 52,925 10,123 27,938 13,425 32,489 4,269
358 (19) 313 (17) 356 (19) 367 (20) 302 (16) 159 (9) 442 (24) 1,413 (76) 1,504 (81) 351 (19) 1,010 (54) 380 (21) 591 (32) 61 (3)
<0.001 0.04 0.26 0.03 0.94 0.01 0.003 0.003 <0.001 <0.001 <0.001 0.40 <0.001 <0.001
(16) (19) (20) (22) (16) (7) (27) (73) (84) (16) (44) (21) (52) (7)
2,866 (4)
2,827 (5)
39 (2)
<0.001
13,433 (21)
13,004 (21)
429 (23)
0.01
11,684 (18) 5,767 (9)
11,166 (18) 5,411 (9)
518 (28) 356 (19)
<0.001 <0.001
15,915 (25)
15,640 (25)
275 (15)
<0.001
2,009 (3)
1,956 (3)
53 (3)
0.55
3,965 (6) 295 (0.5) 2,523 (4) 1,601 (3) 405 (0.6) NA 375 (0.6) NA 519 (0.8)
3,816 269 2,465 1,483 386 43 363 119 502
800 (1)
(6) (0.4) (4) (2) (0.6) (0.1) (0.6) (0.2) (0.8)
780 (1)
59 (3) <0.001 20 (1) <0.001 58 (3) 0.09 118 (6) <0.001 19 (1) 0.03 * 12 (0.6) 0.69 * 17 (1) 0.57 20 (1)
0.54
2,096 445 399 1,459
(3) (0.7) (0.6) (2)
18 (1) <0.001 68 (4) <0.001 12 (0.6) 0.53 48 (3) 0.44
727 (1) 709 297 (0.5) 283 NA 465 1,296 (2) 1,280 27,261 (42) 26,532
(1) (0.4) (0.7) (2) (42)
18 (1) 0.53 14 (0.8) 0.05 * 16 (1) <0.001 729 (39) 0.02
2,114 513 411 1,507
(3) (0.8) (0.6) (2)
AIDS ¼ acquired immunodeficiency syndrome; CC ¼ chronic complications; CRT-D ¼ cardiac resynchronization therapy devices with defibrillator; CVD ¼ collagen vascular diseases; HIV ¼ human immunodeficiency virus; NA ¼ could not be calculated because value for infected patients could not be reported because <11. * Underlying counts were <11. Proportions cannot be reported because of Centers for Medicare and Medicaid Services privacy regulations.
Figure 1. Relation between CIED infection and survival. Kaplan-Meier estimates of survival during the quarter of the index admission (0 to 1) and the following 4 quarters (1 to 5) without (solid line) and with (dashed line) device infection in 64,903 Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures during the 2007 calendar year. Estimated survival (percentage) at the end of fourth quarter after index admission quarter (right). Comparison made by log-rank test.
the Supplementary Data. Patients identified from these claim files using the encrypted beneficiary identifier were linked to the 2007 and 2008 Medicare Denominator Files to collect beneficiary date of death. Patient demographics were also identified from the Medicare claims file. A total of 70,597 admissions with a qualifying ICD procedure were identified. Of these, 5,694 were excluded: 3,622 had other major cardiac procedures, 2,072 were additional admissions for patients with multiple admissions, were paid for by a Medicare Health Maintenance Organization or not associated with a Medicare payment, or had no Medicare Part A enrollment in the quarter of the index admission. If a patient had an ICD procedure admission with and another one without infection, the admission without infection was excluded. The primary outcome of our study was long-term survival associated with ICD implantation, replacement, or revision procedures, defined as survival through the admission quarter and the subsequent 4 quarters (combination of admission and postadmission periods). Secondary outcomes were admission survival, defined as survival during the index hospitalization for the ICD procedure, and postadmission survival, defined as survival from discharge through the quarter of admission and the 4 quarters after the admission quarter. The unit of analysis for all 3 outcomes was the individual discharge. The prevalence of specific demographic characteristics and co-morbidities in study subgroups were compared using
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Table 2 Baseline characteristics of men and women, with and without infection Characteristic
No Infection Women, n ¼ 16,958 (%)
Age (yrs) <65 65e69 70e74 75e79 80e84 >84 White Non-white Congestive heart failure Valvular heart disease Hypertension Peripheral vascular disease Pulmonary circulation disorders Chronic pulmonary disease Renal failure Fluid and electrolyte disorders Diabetes, without CC Diabetes, with CC Hypothyroidism Blood loss anemia Deficiency anemia Coagulation deficiency Liver disease HIV infection or AIDS Lymphoma Metastatic cancer Solid tumor without metastasis Rheumatoid arthritis/CVD Obesity Weight loss Paralysis Other neurologic disorders Alcohol abuse Drug use Psychoses Depression CRT-D
2,933 3,118 3,420 3,776 2,885 1,268 13,312 3,646 7,786 4,434 8,989 958 964 3,723 2,752 1,918 4,406 589 1,859 105 903 362 83 * 120 37 89 406 704 161 112 441 61 59 177 523 7,428
(17) (18) (20) (22) (17) (8) (79) (22) (46) (26) (53) (6) (6) (22) (16) (11) (26) (4) (11) (0.6) (5) (2) (0.5) (0.7) (0.2) (0.5) (2) (4) (1) (0.7) (3) (0.4) (0.3) (1) (3) (44)
Infection
Men, n ¼ 46,090 (%) 7,402 9,002 9,708 10,394 7,640 3,357 39,262 6,828 21,162 9,371 24,091 3,732 1,902 9,710 8,932 3,849 11,509 1,420 2,106 190 1,620 1,239 322 40 255 88 430 394 1,410 352 299 1,066 666 238 297 773 19,833
(16) (20) (21) (23) (17) (7) (85) (15) (46) (20) (52) (8) (4) (21) (19) (8) (25) (3) (5) (0.4) (4) (3) (0.7) (0.1) (0.6) (0.2) (1) (1) (3) (0.8) (0.6) (2) (1) (0.5) (0.6) (2) (43)
p
Women, n ¼ 442 (%)
Men, n ¼ 1,413 (%)
p
<0.001 0.01 0.03 0.73 0.13 0.34 <0.001 <0.001 0.65 <0.001 0.03 <0.001 <0.001 0.01 <0.001 <0.001 0.01 0.01 <0.001 <0.001 <0.001 <0.001 0.01
89 (20) 66 (15) 84 (19) 94 (21) 70 (16) 39 (9) 325 (74) 117 (27) 224 (51) 114 (26) 151 (34) 11 (3) 14 (3) 100 (23) 121 (27) 107 (24) 55 (12) 19 (4) 28 (6) 11 (3) 15 (3) 21 (5) * * * * * * * 16 (4) * 17 (4) * * * * 161 (36)
269 (19) 247 (18) 272 (19) 273 (19) 232 (16) 120 (9) 1,179 (83) 234 (17) 786 (56) 266 (19) 440 (31) 50 (4) 25 (2) 329 (23) 397 (28) 249 (18) 220 (16) 34 (2) 31 (2) 15 (1) 43 (3) 97 (7) 16 (1) * * * 12 (0.8) 12 (0.8) 11 (0.8) 52 (4) * 31 (2) 17 (1) 12 (0.8) * 11 (0.8) 568 (40)
0.61 0.21 0.91 0.37 0.77 0.83 <0.001 <0.001 0.07 0.002 0.23 0.28 0.07 0.77 0.77 0.002 0.11 0.04 <0.001 0.03 0.71 0.11
0.02 0.48 <0.001 <0.001 <0.001 0.02 0.84 0.03 0.03 0.01 <0.001 <0.001 0.04
0.95 0.06
0.002
AIDS ¼ acquired immunodeficiency syndrome; CC ¼ chronic complications; CRT-D ¼ cardiac resynchronization therapy devices with defibrillator; CVD ¼ collagen vascular diseases; HIV ¼ human immunodeficiency virus. * Underlying counts were <11. Proportions cannot be reported because of Centers for Medicare and Medicaid Services privacy regulations.
a chi-square test. Long-term survival functions were estimated using Kaplan-Meier survival analysis and compared using a log-rank test. Kaplan-Meier mortality was derived as 1 Kaplan-Meier survival. A significance level of 0.05 was used for all tests. Statistical tests were performed using SAS, version 9.2, 2008 (SAS Institute Inc., Cary, North Carolina) and XLstat (Addinsoft, Montreal, Canada). The rates of admission, postadmission, and long-term mortality were adjusted for age, gender, race or ethnicity, and a set of 28 co-morbidity measures associated with death in Medicare beneficiaries, originally derived by Elixhauser et al5 and validated for risk adjustment using administrative data.6,7 The individual patient status for this set of comorbidities was collected from the administrative data using the Comorbidity Software (versions 3.2 and 3.3)8 from the Agency for Healthcare Research and Quality (Rockville,
Maryland) that specifies ICD-9-CM codes corresponding to each patient co-morbidity. Peptic ulcer disease was omitted because it was rare in our study cohort. The primary condition screens, including for cardiac conditions, were not used because this study was narrowly defined to patients receiving ICD therapy. Admission, postadmission, and long-term mortality were modeled using the binomial complementary log-log regression specification. Terms for an interaction between device infection and age, gender, race/ethnicity, and the 28 co-morbidities were included in the regression models for mortality. A discussion of the rationale for these model choices can be found in the Supplementary Data. For some analyses, certain co-morbidities were not present in either men or women and were dropped for that device. Riskadjusted mortality hazard ratios (HRs), defined as mortality
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rate in women with device infection or mortality rate in men with device infection, for admission, postadmission, and long-term mortality were calculated by exponentiating the ratio of the sum of the parameter estimates for device infection, gender, and the gender-device infection interaction term in the corresponding mortality regression models for women with device infection and men with device infection.9,10 Riskadjusted mortality HR without device infection, defined as mortality rate in women without device infection or mortality rate in men without device infection, were calculated by exponentiating the ratio of the parameter estimates for gender in corresponding mortality regression models for women without device infection and men without device infection.9,10 The regressions were estimated using Stata, version 11 (Stata Corp LP, College Station, Texas). Results were robust to heteroskedasticity. The Goodwyn Institutional Review Board (Cincinnati, Ohio) determined that the study was exempt from full human subjects research review. Results The study cohort consisted of 64,903 Medicare fee-forservice patients who received an ICD in 2007 (Table 1). In the study cohort, 84.1% of patients were aged 65 years, 26.8% were women, 16.1% were non-white, 18.0% had renal failure, 27.6% had diabetes mellitus, and 42% received a cardiac resynchronization therapy device with defibrillator. A total of 1,855 patients (2.9%) in the study cohort had a CIED infection. Patients with CIED infection were more likely to have congestive heart failure (54.4% vs 44.3%, p 0.001), renal failure (27.9% vs 17.7%, p 0.001), fluid and electrolyte disorders (19.2% vs 8.6%, p 0.001), and a coagulopathy (6.4% vs 2.4%, p 0.001) but less likely to have diabetes mellitus (14.8% vs 24.8%, p 0.001) or hypertension (31.9% vs 51.9%, p <0.001) compared with those without CIED infection (Table 1). There were other differences in baseline characteristics that achieved statistical significance, in part because of the large sample size, but they were smaller in magnitude and less likely to be of clinical significance. Long-term survival in patients with CIED infection was significantly less than that in patients without device infection (71.6% vs 85.0%, p <0.001; Figure 1). The corresponding long-term mortality in patients with CIED infection was approximately twofold the long-term mortality in patients without device infection (28.4% vs 15.0%, p <0.001). Admission mortality was also significantly increased for patients with CIED infection compared with those without device infection (5.17% vs 0.72%, p <0.001). To identify patient characteristics associated with decreased long-term survival with CIED infection, we performed a regression analysis for long-term death in patients admitted for an ICD procedure, adjusting for age, gender, race or ethnicity, and a set of 28 co-morbidities associated with death in Medicare beneficiaries, originally derived by Elixhauser et al5 and validated for risk adjustment using administrative data.6,7 This regression analysis identified 2 patient characteristics with a significant interaction with increased long-term death and device infection: female
Figure 2. Relation between gender and survival, with and without CIED infection. Kaplan-Meier estimates of survival during the quarter of the index admission (0 to 1) and the following 4 quarters (1 to 5) in 64,903 women (thick line) and men (thin line) Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures and during the 2007 calendar year, without or with infection. Estimated survival (percentage) at the end of fourth quarter after index admission quarter (right). Comparisons were made by log-rank test.
gender (p <0.001) and human immunodeficiency virus/ acquired immunodeficiency syndrome (HIV/AIDS; p ¼ 0.035; Supplementary Table 2). HIV/AIDS was rare in this population (<0.1%; Table 1). The administrative database did not permit the distinction between HIV infection and AIDS. Despite the small number of patients with HIV/AIDS in the study cohort, it is noteworthy that the risk-adjusted HR for long-term death with CIED infection in this group was 5.35 (95% confidence interval [CI] 1.16 to 24.69). The study cohort included 17,400 women (26.8%) and 47,503 men (73.2%). Women were more often non-white (21% vs 14.4%, p <0.001) and more likely to have valvular disease (25.5% vs 19.7%, p <0.001) and hypothyroidism (10.7% vs 4.2%, p <0.001). The frequency of cardiac resynchronization therapy devices with defibrillator procedures (42.7% vs 41.8%) was similar for women and men (Table 2). There were other differences in baseline characteristics that achieved statistical significance, in part because of the large sample size, but they were smaller in magnitude and less likely to be of clinical significance. Device infection markedly reduced survival in women compared with men. In patients without a device infection, long-term survival was slightly higher in women compared with men (86.4% vs 84.5%, p <0.001; Figure 2). In contrast, in patients with a device infection, women had significantly reduced long-term survival compared with men (67.3% vs 72.9%, p <0.02; Figure 2).
Arrhythmias and Conduction Disturbances/Gender Differences in ICD Infection Mortality
Figure 3. Risk-adjusted HRs for death in women versus men, with and without CIED infection. Risk-adjusted HRs with 95% CI for mortality in women compared with men, without (gray box) and with (black box) device infection, for admission, postadmission, and long-term mortality in 17,400 women and 47,503 men Medicare beneficiaries who underwent ICD (single- or dual-chamber and cardiac resynchronization therapy devices with defibrillator) generator implantation, replacement, or revision procedures during the 2007 calendar year. HRs are adjusted for demographic characteristics and 28 co-morbidities associated with death in Medicare beneficiaries.
Table 3 Admission length of stay, disposition, and cost for men and women, with and without infection Women
Men
Admission length of stay (days) No device infection 5.0 5.9 4.2 5.4 Device infection 17.2 22.5 15.2 13.5 Disposition to home or self-care No device infection (%) 12,726 (76) 38,336 (83) Device infection (%) 155 (35) 629 (45) Admission cost ($) No device infection 32,597 18,038 31,561 17,189 Device infection 52,208 38,059 51,098 34,688
p
<0.001 0.02
<0.001 <0.001 <0.001 0.57
Adjusting for differences in demographics and comorbidities revealed an even larger gender difference in long-term mortality. The risk-adjusted HR for long-term mortality in women compared with men increased from 0.86 (95% CI 0.82 to 0.91) without device infection to 1.25 (95% CI 1.02 to 1.53) with device infection (Figure 3). This corresponds to an increase in the adjusted risk of long-term mortality in women compared with men of >45%. The risk-adjusted HR for death during the index admission for women compared with men increased with device infection from 0.81 (95% CI 0.63 to 1.05) to 1.45 (95% CI 0.93 to 2.32; Figure 3), but the difference did not achieve statistical significance. A substantial portion of the excess long-term mortality in women with infection compared with men with infection occurred after the index admission. The risk-adjusted HR for postadmission death in women compared with men
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increased from 0.86 (95% CI 0.82 to 0.91) to 1.20 (95% CI 0.96 to 1.51; Figure 3). There were differences in some aspects of the index admission between men and women, but these differences did not change substantially with device infection. For patients without device infection, admission length of stay was about 1 day longer for women than men (5.0 vs 4.2 days, p <0.001), about 8% fewer women were discharged to home or self-care than men (75.5% vs 83.8%, p <0.001), and the admission cost was about $1,000 higher for women than for men ($32,597 vs $31,561, p <0.001; Table 3). For patients with device infection, these disparities were either similar or less than for patients without device infection. Women with device infection stayed in the hospital 2 days longer than men (17.2 vs 15.2 days, p ¼ 0.02), about 9% fewer women were discharged to home or self-care than men (35.1% vs 44.5%, p <0.001), and the admission cost was not significantly different for women and men ($52,208 vs $51,098, p ¼ 0.57; Table 3). Discussion Our study identified and quantified a substantial gender disparity in mortality associated with device infection in the current era of ICD utilization. It demonstrated that although women without a CIED infection have slightly better survival than men, women with a CIED infection have a significantly increased risk of death compared with men. The risk-adjusted long-term mortality rate was 25% higher in women compared with men. Importantly, the only other patient characteristic associated with increased mortality in infected patients was HIV/AIDS. To date, there are few published data on gender differences in mortality associated with CIED infection. Five recently published series of CIED infections reported that admission mortality for all patients ranged from 3.7% to 8.1%,1,3,11e13 but only 1 study presented gender-specific data. Baman et al11 reported that the unadjusted HR for 6-month mortality, in their cohort of predominantly pacemaker infections, was 1.56 for men compared with that of women, but the difference did not achieve statistical significance. The origin of increased mortality associated with ICD infections is not clear. Mortality associated with CIED infections has been attributed to sepsis and its sequelae, complications related to the explantation procedure, congestive heart failure, cardiac arrest, and renal insufficiency.1,11,12 In our study, the prevalence of congestive heart failure was similar in men and women, whereas women had significantly less renal failure than men. The regression models for mortality used in this study also adjusted for both these co-morbidities. The administrative database does not permit us to reliably compare the severity of device infection, complications related to explantation, or the mechanism of death in the 2 groups. Potential mechanisms that may explain the greater longterm morality in women with device infections include differences in biologic response to infection or sepsis, women with an infected device may present to the healthcare system later than men, fuller breast tissue in women may hinder accurate examination of the CIED generator
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The American Journal of Cardiology (www.ajconline.org)
pocket site in the pectoral area, or that health-care systems may treat women with CIED infection differently than men. To our knowledge, there are no published data on differential treatment of ICD infection in women and men. Current guidelines recommend that CIED infection should be treated with complete explantation of all device hardware and administration of appropriate antibiotics for 2 to 6 weeks, depending on the extent of the device infection.4 Previous work demonstrates that other cardiac invasive procedures (angiography and revascularization) have been used less frequently in women compared with men.14,15 Currently, it is not known if complete explantation of the infected device is offered less often or later to women, compared with men, with CIED infection. Other data suggest that women have a greater likelihood of complications associated with ICD implantation than men,16 which may indicate that invasive procedures often used in patients with ICD infection, such as lead extraction, may be associated with increased morbidity and mortality in women compared with men. Unfortunately, the clinical information available in this administrative database does not permit an adequate examination of the origin of the increased mortality associated with CIED infection in women compared with men. It is noteworthy that a substantial portion of this excess long-term mortality in women occurred after the index admission with the device infection, and the difference appears to be increasing at the end of the observation period. This may be because of differences in the severity of infection at presentation, care during or after hospitalization, and other factors. Although there were disparities in some clinical metrics of care between men and women without device infection in this study, these differences were either similar or less in patients with device infection. Understanding these disparities is important, but it makes it less likely that they are responsible for the difference in postadmission or longer-term mortality between women and men with device infection. Overall, these data indicate that risk-adjusted long-term mortality rate after CIED infection is 25% higher in women, despite little change in the gender-based relations for admission length of stay, disposition, and cost. The origin of this excess mortality associated with CIED infection in women remains unclear and merits further investigation. Our analysis has certain limitations. First, infections identified using ICD-9-CM codes for cardiac or vascular device infection, endocarditis, or cardinal manifestations of infection, in the setting of an ICD implantation, were presumed to be CIED infections. It is conceivable that some of these infections may not have been related to the CIED. However, it is quite likely that most of these represent CIED infections because it is unusual to implant an ICD during an admission that includes infection of another organ system because of the concern of device seeding from a distant source of bacteremia, unless infection of that organ system was due to a CIED infection itself or caused a CIED infection. Second, these data were collected from the Medicare Inpatient SAF, which is a claims-based administrative database and therefore may be less accurate than a clinical database for evaluating some aspects of these
admissions that may affect mortality after CIED infection. Finally, the severity of the device infection, which may also be related to outcome, cannot be ascertained from this administrative database. Despite these limitations, we believe that these data provide useful insights into gender differences in the mortality associated with CIED infections. Acknowledgment: David J. Wright, PhD (Westat, Rockville, Maryland) performed a statistical review of the data. TYRX Inc. personnel (D.J.L.) participated in the design of the study, analysis, and interpretation of the data, and in the decision to approve publication of the finished manuscript. Disclosures M.R.S. has received funding from TYRX Inc. for previous research.17 C.A.H. has received funding from TYRX Inc. for research (Clinicaltrials.gov NCT01043705 and NCT01043861). D.J.L. is the Chief Medical Officer for TYRX Inc., and in that role, has been paid a salary and granted stock options by TYRX. Supplementary Data Supplementary data related to this article can be found, in the online version, at http://dx.doi.org/10.1016/j.amjcard. 2013.06.031. 1. Tarakji KG, Chan EJ, Cantillon DJ, Doonan AL, Hu T, Schmitt S, Fraser TG, Kim A, Gordon SM, Wilkoff BL. Cardiac implantable electronic device infections: presentation, management, and patient outcomes. Heart Rhythm 2010;7:1043e1047. 2. Sohail MR, Henrikson CA, Braid-Forbes MJ, Forbes KF, Lerner DJ. Mortality and cost associated with cardiovascular implantable electronic device infections. Arch Intern Med 2011;171:1821e1828. 3. Sohail MR, Uslan DZ, Khan AH, Friedman PA, Hayes DL, Wilson WR, Steckelberg JM, Stoner S, Baddour LM. Management and outcome of permanent pacemaker and implantable cardioverter-defibrillator infections. J Am Coll Cardiol 2007;49:1851e1859. 4. Baddour LM, Epstein AE, Erickson CC, Knight BP, Levison ME, Lockhart PB, Masoudi FA, Okum EJ, Wilson WR, Beerman LB, Bolger AF, Estes NAM III, Gewitz M, Newburger JW, Schron EB, Taubert KA, on behalf of the American Heart Association Rheumatic Fever E, Kawasaki Disease Committee of the Council on Cardiovascular Disease in the Y, Council on Cardiovascular S, Anesthesia, Council on Cardiovascular N, Council on Clinical C, the Interdisciplinary Council on Quality of C, Outcomes R. Update on cardiovascular implantable electronic device infections and their management: a scientific statement from the American Heart Association. Circulation 2010;121:458e477. 5. Elixhauser A, Steiner C, Harris DR, Coffey RM. Comorbidity measures for use with administrative data. Med Care 1998;36:8e27. 6. Southern DA, Quan H, Ghali WA. Comparison of the Elixhauser and Charlson/Deyo methods of comorbidity measurement in administrative data. Med Care 2004;42:355e360. 7. Li B, Evans D, Faris P, Dean S, Quan H. Risk adjustment performance of Charlson and Elixhauser comorbidities in ICD-9 and ICD-10 administrative databases. BMC Health Serv Res 2008;8:12. 8. (HCUP) AfHRaQAHCaUP. Comorbidity Software: Healthcare Cost and Utilization Project (HCUP), 2011. 9. Collett D. Modelling Binary Data. Boca Raton: Chapman & Hall/CRC, 2003; 387p. 10. Hilbe J. Negative Binomial Regression. Cambridge; New York: Cambridge University Press, 2007; xii, 251 p. 11. Baman TS, Gupta SK, Valle JA, Yamada E. Risk factors for mortality in patients with cardiac device-related infection. Circ Arrhythm Electrophysiol 2009;2:129e134.
Arrhythmias and Conduction Disturbances/Gender Differences in ICD Infection Mortality 12. Margey R, McCann H, Blake G, Keelan E, Galvin J, Lynch M, Mahon N, Sugrue D, O’Neill J. Contemporary management of and outcomes from cardiac device related infections. Europace 2010;12: 64e70. 13. Voigt A, Shalaby A, Saba S. Continued rise in rates of cardiovascular implantable electronic device infections in the United States: temporal trends and causative insights. Pacing Clin Electrophysiol 2010;33: 414e419. 14. Ayanian JZ, Epstein AM. Differences in the use of procedures between women and men hospitalized for coronary heart disease. N Engl J Med 1991;325:221e225. 15. Vaccarino V, Rathore SS, Wenger NK, Frederick PD, Abramson JL, Barron HV, Manhapra A, Mallik S, Krumholz HM. Sex and racial
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differences in the management of acute myocardial infarction, 1994 through 2002. N Engl J Med 2005;353:671e682. 16. Peterson PN, Daugherty SL, Wang Y, Vidaillet HJ, Heidenreich PA, Curtis JP, Masoudi FA. Gender differences in procedure-related adverse events in patients receiving implantable cardioverter-defibrillator therapy. Circulation 2009;119:1078e1084. 17. Bloom HL, Constantin LD, Daniel DL, David B, El-Chami, M, Ganz LI, Gleed KJ, Hackett FK, Kanuru NK, Lerner DJ, Rasekh AS, Grant RS, Felix O, Sohail MR, for the COMMAND (COoperative Multicenter study Monitoring a CIED ANtimicrobial Device) Investigators. Implantation Success and Infection in Cardiovascular Implantable Electronic Device Procedures Utilizing an Antibacterial Envelope. Pacing Clin Electrophysiol 2011;34:133e142.