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Long-term outcome of infective endocarditis: A study on patients surviving over one year after the initial episode treated in a Finnish teaching hospital during 25 years

  • Maija Heiro1,
  • Hans Helenius2,
  • Saija Hurme2,
  • Timo Savunen3,
  • Kaj Metsärinne1,
  • Erik Engblom1,
  • Jukka Nikoskelainen1 and
  • Pirkko Kotilainen1Email author
BMC Infectious Diseases20088:49

https://doi.org/10.1186/1471-2334-8-49

Received: 17 September 2007

Accepted: 17 April 2008

Published: 17 April 2008

Abstract

Background

Only a few previous studies have focused on the long-term prognosis of the patients with infective endocarditis (IE). Our purpose was to delineate factors potentially associated with the long-term outcome of IE, recurrences of IE and requirement for late valve surgery.

Methods

A total of 326 episodes of IE in 303 patients were treated during 1980–2004 in the Turku University Hospital. We evaluated the long-term outcome and requirement for late valve surgery for 243 of these episodes in 226 patients who survived longer than 1 year after the initial admission. Factors associated with recurrences were analysed both for the 1-year survivors and for all 303 patients.

Results

The mean (SD) follow-up time for the 1-year survivors was 11.5 (7.3) years (range 25 days to 25.5 years). The overall survival was 95%, 82%, 66%, 51% and 45% at 2, 5, 10, 15 and 20 years. In age and sex adjusted multivariate analyses, significant predictors for long-term overall mortality were heart failure within 3 months of admission (HR 1.97, 95% CI 1.27 to 3.06; p = 0.003) and collagen disease (HR 2.54, 95% CI 1.25 to 5.19; p = 0.010) or alcohol abuse (HR 2.39, 95% CI 1.30 to 4.40; p = 0.005) as underlying conditions, while early surgery was significantly associated with lower overall mortality rates (HR 0.31, 95% CI 0.17 to 0.58; p < 0.001). Heart failure was also significantly associated with the long-term cardiac mortality (p = 0.032). Of all 303 patients, 20 had more than 1 disease episode. Chronic dialysis (p = 0.002), intravenous drug use (p = 0.002) and diabetes (p = 0.015) were significant risk factors for recurrent episodes of IE, but when analysed separately for the 1-year survivors, only chronic dialysis remained significant (p = 0.017). Recurrences and late valve surgery did not confer a poor prognosis.

Conclusion

Heart failure during the index episode of IE was the complication, which significantly predicted a poor long-term outcome. Patients who underwent surgery during the initial hospitalisation for IE faired significantly better than those who did not.

Background

The short-term outcome of infective endocarditis (IE) has been examined in several previous studies from the 1990's and 2000's [14], whereas only a small number of studies have addressed the long-term prognosis of the patients with IE. Moreover, most of the studies focusing on the long-term prognosis have involved only certain subgroups of patients, e.g., those with late prosthetic valve IE [5], IE with perivalvular abscess [6], surgically treated IE associated with intravenous drug use (IVDU) [7], or native valve IE in non-addicts [8], as well as of those undergone surgery for defined indications, e.g. aortic valve IE [9], mitral valve IE [10], or native or prosthetic valve IE [11]. Instead, the long-term outcome of IE in large series of unselected patients with IE has been the focus of rather few studies [1215].

We have previously analysed the short-term and 1-year clinical outcome of 303 patients with 326 episodes of IE treated in our hospital during the years 1980–2004 [16]. In the present study, we set out to analyse the long-term clinical outcome of 243 of these episodes in 226 patients who survived longer than 1 year after the initial admission for IE. Our purpose was to delineate the clinical characteristics of the patients during the index hospitalisation for IE, which might be predictive of the long-term outcome of IE. One important issue involved the impact of early surgery on the long-term survival of the patients. We also evaluated risk factors potentially associated with the development of recurrences of IE and the requirement for late valve surgery.

Methods

Between 1980 and 2004, 303 patients with 326 episodes of IE were treated in the Turku University Hospital, Turku, Finland. We evaluated the long-term outcome of 226 of these patients who survived longer than 1 year after the initial admission. The hospital is a 1000-bed teaching facility with a cardiothoracic surgical department, serving as a tertiary referral centre for the southwestern part of the country, and as a primary care facility for infectious diseases for a region of about 200.000 inhabitants.

For each patient, data on age, sex, underlying diseases, causative agents of IE, affected valves, predisposing cardiac conditions and echocardiographic findings, as well as the development of complications and the need for valve surgery were collected by us for our previous study focusing on the changes of the clinical characteristics of IE during the 25-year study period [19]. In addition, serum C-reactive protein (CRP) values, erythrocyte sedimentation rates (ESR) and white blood cell (WBC) counts on admission were registered previously [16, 20], as were the results of the polymerase chain reaction analyses from the removed valve tissue for those patients who underwent surgery during 1994–2005 [21]. In the present study, these data were used to analyse the association between various patient and disease characteristics and the long-term outcome of the patients after an episode of IE. The survival and causes of death were assessed based on data obtained from the National Population Registry, in which all deaths and causes of deaths of the Finnish residents are registered. The patients were also analysed for factors associated with recurrent episodes of IE and with requirement for late valve surgery. Data regarding the recurrences and late valve surgery were obtained from the hospital records of the patients.

The follow-up period for the outcome was from the admission to death, or if alive, up to February 2006.

Definitions

Long-term outcome was defined as the outcome > 1 year after the admission for the index episode of IE. Early surgery was defined as surgery during the index hospitalisation, and late surgery was defined as surgery > 1 year after the initial admission. A recurrence was defined as a new episode of IE caused by a different microorganism or by a microorganism of the same genus or species of the previous episode of IE after a period of more than 6 months. A relapse was defined as a new episode of IE caused by a microorganism of the same genus and species within 6 months after discharge.

The study was approved by the Institutional Committee on human research.

Statistical analysis

Four different end-points were analysed in the study: long-term overall mortality, long-term cardiac mortality, late valve surgery, and recurrent IE. The associations between the clinical characteristics and end-points were studied separately using survival analysis. The cumulative percentages for survival during different time periods were estimated using the Kaplan-Meier technique. Differences in cumulative percentages between groups were tested using log-rank test. Data regarding the long-term overall outcome, cardiac mortality, and late valve surgery were analysed for the 1-years survivors, and data regarding the repeated episodes of IE both for the 1-year survivors and for all 303 patients.

Early surgery, late surgery and recurrent IE were analysed as time-dependent covariates applying Cox's regression models. Differences between groups were quantified by hazard ratios and ninety-five percent confidence intervals.

Multivariate analyses of end-points were carried out using the Cox regression model with early surgery as a time-dependent covariate. Stepwise method was used for model selection. The results of multivariate analysis were adjusted for age and sex and differences between groups were quantified by hazard ratios and ninety-five percent confidence intervals. Except for the laboratory parameters and indications for surgery, all of the clinical characteristics presented in Table 1 were included in multivariate analyses.
Table 1

Association between characteristics of infective endocarditis (IE) and survival (global and in different subgroups) at 2, 5, 10, 15, and 20 years after the admission in 243 episodes of IE in 226 patients who survived over 1 year after the initial episode of IE

 

Number of IE episodes in patients surviving 1 year

Survival (%) at different points of follow-up

p value

  

2 years

5 years

10 years

15 years

20 years

 

Global survival

243

95

82

66

51

45

 

Gender

       

   Male

174

97

83

68

50

45

0.567

   Female

69

91

80

59

51

46

 

Age

       

   18–64 years

172

99

90

76

60

54

< 0.001

   ≥ 65 years

71

87

65

38

25

25

 

Affected valves

       

   Aortic

85

95

85

63

52

46

0.171*

   Mitral valve

77

95

80

58

40

40

 

   Tricuspid valve

12

100

100

100

NA†

NA

 

   Two native valves

17

100

100

91

76

76

 

   Prosthetic valve(s)

52

94

74

67

52

43

 

Causative agents of IE

       

   Staphylococcus aureus

53

98

86

77

57

57

0.183*

   Coagulase-negative staphylococci

22

86

58

41

41

41

 

   Viridans streptococci

50

96

91

77

56

50

 

   Enterococcus faecalis

18

83

83

67

28

28

 

   Streptococcus pneumoniae

5

100

100

53

53

53

 

   Other

22

95

91

66

60

30

 

   Negative

73

99

78

61

46

46

 

Predisposing cardiac condition

       

   Acquired valvular disease

49

90

70

53

41

36

0.019

   Prosthetic valves

55

95

75

66

52

43

 

   Bicuspid aortic valve

26

100

100

94

81

81

 

   Mitral valve prolapse

30

97

93

74

62

62

 

   Congenital heart disease

8

100

100

33

33

NA

 

   No underlying cardiac condition

75

97

83

63

39

39

 

Echocardiogarphic findings

       

   Major criteria

       

Yes

158

96

85

68

53

49

0.089

No

85

95

78

61

46

39

 

   Vegetation

      

0.162

Yes

139

95

85

68

52

49

 

No

104

96

80

62

49

41

 

Underlying conditions

       

   Diabetes

       

Yes

21

95

95

77

58

29

0.307

No

222

95

81

64

49

45

 

   Dialysis

       

Yes

5

60

40

NA

NA

NA

0.018

No

238

96

83

66

51

46

 

   Collagen disease

       

Yes

14

93

68

24

24

24

0.026

No

229

96

83

68

52

46

 

   Malignancy

       

Yes

11

82

62

31

NA

NA

0.004

No

232

96

83

67

53

47

 

Intravenous drug use

       

Yes

19

100

100

NA

NA

NA

0.049

No

224

95

81

64

50

44

 

Alcohol abuse

       

Yes

22

91

67

47

35

NA

0.029

No

221

96

84

68

53

47

 

Heart failure††

      

0.047

Yes

108

93

75

55

46

44

 

No

135

98

89

75

55

46

 

Neurological complications††

       

Yes

60

95

78

66

52

52

0.766

No

183

96

84

65

50

43

 

Peripheral emboli††

       

Yes

69

97

83

60

50

50

0.570

No

174

95

82

67

51

43

 

Early surgery (in-hospital)

       

Yes

67

99

89

82

76

73

< 0.001

No

176

94

80

59

41

34

 

Mode of treatment††

       

   Surgical

72

99

90

82

74

70

< 0.001

   Conservative

171

94

79

59

41

33

 

Indications for in-hospital surgery

       

   Congestive heart failure

35

97

85

72

61

55

0.002*

   Valvular regurgitation without heart failure

18

100

94

94

94

94

 

   Dehiscence of prosthetic valve without heart failure

8

100

88

88

88

88

 

   Repeated emboli

3

100

100

100

100

100

 

   Intractable infection

3

100

100

100

100

100

 

Erythrocyte sedimentation‡,§

       

   ≥ 50 mm/h

75

93

76

55

40

34

0.018

   < 50 mm/h

74

97

89

77

56

53

 

White blood cell count‡,§S

       

   ≥ 10 × 109/l

119

97

83

63

41

41

0.142

   < 10 × 109/l

98

94

82

67

61

53

 

Serum C-reactive protein‡

       

   ≥ 100 mg/l

100

96

83

62

48

48

0.927

   < 100 mg/l

105

94

80

68

51

43

 

Serum creatinine valueদ

      

< 0.001

   ≥ 100 μmol/l

76

95

77

53

27

14

 

   < 100 μmol/l

142

97

87

71

61

59

 

*p values for overall group differences; †NA = non-applicable, the follow-up did not reach the time point for any patient of the group; ††within 3 months of admission; ‡on admission; §data available for 149 episodes; §Sdata available for 217 episodes; ¶data available for 205 episodes; ¶¶ data available for 218 episodes

P-values less than 0.05 were considered as statistically significant. Statistical computations were carried out using SAS® release 9.1/2005.

Results

The mean (SD) follow-up time for the 303 patients with 326 episodes of IE treated between 1980–2004 was 12.2 (7.4) years (range 1.0 to 25.5 years). The median survival was 5.0 years for all patients, and the range of survival for those who died during the follow-up was 4 days to 23 years. The overall survival for all 303 patients was 75%, 72%, 62%, 49%, 38% and 34 % at 1, 2, 5, 10, 15, and 20 years. We included in this study the 226 patients, who survived longer than 1 year after the initial admission for IE. These patients had altogether 243 episodes of IE, of which 155 were designated as definite IE and the rest as possible IE by the Duke diagnostic criteria [17]. A detailed diagnostic classification has been previously published by us for 142 of these episodes [18].

There were 174 episodes in men and 69 episodes in women. The mean age (SD) of the patients was 52.4 (17.1) years (range 18 to 87 years). The mean (SD) follow-up time for the l-year survivors was 11.5 (7.3) years (range 25 days to 25.5 years), and the 25% percentile of the follow-up time was 4.8 years and the 75% percentile of the follow-up time was 17.8 years. The median survival was 7.1 years, and the range of survival for those who died during the follow-up was 4 days to 22.3 years. Of these patients, 67 underwent in-hospital valve surgery and 72 were treated both surgically and conservatively within 3 months of the admission. The proportions of various clinical characteristics (e.g. causative agents of IE, affected valves, predisposing cardiac conditions, development of complications) are presented in Tables 1 and 2. A total of 94 patients died during the follow-up. The causes of death were: recurrent IE (n = 1), sequelae of IE (n = 27), coronary heart disease (n = 18), malignancy (n = 16), infection other than IE (n = 14), stroke (n = 6), other or unknown cause (n = 12). Of the 27 patients who died of sequelae of IE, the cause of death was established to be heart failure in 18 patients and sudden death due to arrhythmia in 9 patients.
Table 2

Association between characteristics of infective endocarditis (IE) and cardiac mortality at 2, 5, 10, 15, and 20 years after the admission in 243 episodes of IE in 226 patients who survived over 1 year after the initial episode of IE

 

Number of IE episodes in patients surviving 1 year

Survival (%) at different points of follow-up

p value

  

2 years

5 years

10 years

15 years

20 years

 

Cardiac mortality

243

3

10

16

25

29

 

Gender

       

   Male

174

2

9

15

26

31

0.801

   Female

69

6

11

20

24

24

 

Age

       

   18–64 years

172

1

5

11

22

26

0.002

   ≥ 65 years

71

10

21

32

32

32

 

Affected valves

       

   Aortic

85

4

9

18

24

29

0.416*

   Mitral valve

77

4

9

20

34

34

 

   Tricuspid valve

12

0

0

0

NA

NA

 

   Two native valves

17

0

0

0

17

17

 

   Prosthetic valve(s)

52

4

17

17

24

29

 

Causative agents of IE

       

   Staphylococcus aureus

53

2

4

4

4

4

0.032*

   Coagulase-negative staphylococci

22

10

20

30

30

30

 

   Viridans streptococci

50

2

2

9

34

40

 

   Enterococcus faecalis

18

17

17

25

63

63

 

   Streptococcus pneumoniae

5

0

0

0

0

0

 

   Other

22

0

0

16

16

28

 

   Negative

73

1

17

22

25

25

 

Predisposing cardiac condition

       

   Acquired valvular disease

49

8

19

29

41

41

0.015*

   Prosthetic valves

55

4

16

16

23

28

 

   Bicuspid aortic valve

26

0

0

0

0

0

 

   Mitral valve prolapse

30

3

3

15

29

29

 

   Congenital heart disease

8

0

0

38

38

NA

 

   No underlying cardiac condition

75

1

6

12

27

27

 

Echocardiogarphic findings

       

   Major criteria

       

Yes

158

3

7

14

22

25

0.013

No

85

4

15

22

32

36

 

   Vegetation

      

0.007

Yes

139

4

6

12

22

22

 

No

104

3

15

22

30

36

 

Underlying conditions

       

   Diabetes

       

Yes

21

5

5

5

29

29

0.325

No

222

3

10

18

26

30

 

   Dialysis

      

0.340

Yes

5

25

25

NA

NA

NA

 

No

238

3

9

16

25

29

 

   Collagen disease

      

0.160

Yes

14

7

24

49

49

49

 

No

229

3

9

15

24

28

 

   Malignancy

       

Yes

11

10

10

40

NA

NA

0.383

No

232

3

10

16

25

28

 

Intravenous drug use

       

Yes

19

0

0

NA

NA

NA

0.164

No

224

4

10

17

26

30

 

Alcohol abuse

       

Yes

22

9

15

15

25

NA

0.660

No

221

3

9

16

25

29

 

Heart failure††

       

Yes

108

6

15

23

28

31

0.110

No

135

2

5

11

23

27

 

Neurological complications††

       

Yes

60

3

11

18

27

27

0.930

No

183

3

9

16

25

30

 

Peripheral emboli††

      

0.175

Yes

69

3

8

14

20

20

 

No

174

3

10

17

27

32

 

Early surgery (in-hospital)

       

Yes

67

0

5

7

14

18

0.029

No

176

5

12

20

30

34

 

Mode of treatment††

      

0.026

   Surgical

72

0

4

9

15

19

 

   Conservative

171

5

12

20

30

34

 

Indications for in-hospital surgery

       

   Congestive heart failure

35

0

3

7

22

29

0.269*

   Valvular regurgitation without heart failure

18

0

6

6

6

6

 

   Dehiscence of prosthetic valve without heart failure

8

0

13

13

13

13

 

   Repeated emboli

3

0

0

0

0

0

 

   Intractable infection

3

0

0

0

0

0

 

Erythrocyte sedimentation‡,§

       

   ≥ 50 mm/h

75

4

14

23

29

33

0.527

   < 50 mm/h

74

1

6

13

30

34

 

White blood cell count‡,§S

       

   ≥ 10 × 109/l

119

3

10

17

30

30

0.781

   < 10 × 109/l

98

4

9

17

24

31

 

Serum C-reactive protein‡,¶

       

   ≥ 100 mg/l

100

3

7

10

13

13

0.080

   < 100 mg/l

105

4

12

16

28

39

 

Serum creatinine value‡,¶P

       

   ≥ 100 μmol/l

76

5

12

24

42

60

0.001

   < 100 μmol/l

142

1

7

13

18

18

 

*p values for overall group differences; †NA = non-applicable, the follow-up did not reach the time point for any patient of the group; ††within 3 months of admission; ‡on admission; §data available for 149 episodes; §Sdata available for 217 episodes; ¶data available for 205 episodes; ¶¶ data available for 218 episodes

Long-term overall outcome

Among the 1-year survivors, the long-term overall survival was 95%, 82%, 66%, 51%, and 45% at 2, 5, 10, 15, and 20 years (Figure 1). The association between the survival and various clinical characteristics during the initial episode of IE is presented in Table 1. In univariate analysis, an age ≥ 65 years when contracting the disease was significantly associated with higher mortality, as was malignancy, collagen disease, chronic dialysis, or alcohol abuse as underlying conditions. Mortality was significantly higher for the patients who developed heart failure within 3 months of the initial admission than for those with no heart failure (Figure 2a). Significant differences in mortality were observed between the patients with different predisposing cardiac conditions, the mortality being highest for the patients with congenital heart disease and lowest for the patients with bicuspid aortic valve. Mortality was significantly lower for the patients with IVDU than for those with no IVDU. The long-term survival was significantly better for the patients who underwent early (in-hospital) surgery than for those who did not (Figure 2b). Survival was significantly better for the patients who were treated both surgically and conservatively within 3 months than for those who were treated only conservatively. There were significant differences in survival between the patients who underwent surgery on different indications, the survival being lowest for those operated on for heart failure.
Figure 1

Kaplan-Meier curves of the overall mortality and cardiac mortality for 243 episodes of infective endocarditis in 226 patients, who survived longer than 1 year after the initial episode. The numbers at different time points refer to the number of patients being followed up and at risk for event at the beginning of the time period. Zero on the time access indicates 1 year.

Figure 2

Long-term outcome was analysed for 243 episodes of infective endocarditis in 226 patients, who survived longer than 1 year after the initial episode. Kaplan-Meier curves of the overall survival for patients with and without heart failure during 3 months of admission (a), and for those undergoing and not undergoing early (in-hospital) surgery (b). The numbers at different time points refer to the number of patients being followed up and at risk for event at the beginning of the following time period. Zero on the time access indicates 1 year.

Data on the serum CRP value, ESR, WBC count, and serum creatinine value on admission was available in 205, 149, 217, and 218 episodes of endocarditis, respectively. Higher survival rates were significantly associated with ESR value < 50 mm/h, or serum creatinine value < 100 μmol/l on admission.

In age and sex adjusted multivariate analysis, significant predictors for mortality were heart failure within 3 months of admission (HR 1.97, 95% CI 1.27 to 3.06; p = 0.003) and collagen disease (HR 2.54, 95% CI 1.25 to 5.19; p = 0.010) or alcohol abuse (HR 2.39, 95% CI 1.30 to 4.40; p = 0.005) as underlying conditions. Early surgery was significantly associated with lower overall mortality rates (HR 0.31, 95% CI 0.17 to 0.58; p < 0.001). Also when recurrent episodes of IE were excluded from the analyses, heart failure (HR 1.73, 95% CI 1.10 to 2.72; p = 0.018), collagen disease (HR 2.67, 95% CI 1.30 to 5.49; p = 0.008), and alcohol abuse (HR 2.80, 95% CI 1.51 to 5.19; p = 0.001) remained significant risk factors for mortality, and early surgery was significantly associated with lower overall mortality rates (HR 0.32, 95% CI 0.17 to 0.59; p < 0.001).

Long-term cardiac mortality

Among the 1-year survivors, the long-term cardiac mortality was 3%, 10%, 16%, 25%, and 29% at 2, 5, 10, 15, and 20 years (Figure 1). In univariate analysis, cardiac mortality was significantly associated with an age ≥ 65 years when contracting the disease. There were significant differences in the long-term cardiac mortality between various causative agents of IE, the mortality being highest for Enterococcus faecalis, as well as between various predisposing cardiac conditions, the mortality being highest for acquired valvular disease. The long-term cardiac mortality was significantly lower for the patients who underwent early surgery than for those who did not. Mortality was significantly lower for the patients who were treated both surgically and conservatively within 3 months than for those who were treated only conservatively. The long-term cardiac mortality was significantly higher for the patients with serum creatinine value ≥ 100 μmol/l on admission than for those with lower serum creatinine values. The long-term cardiac mortality was significantly lower for the patients who had a major criterion or vegetation on echocardiography than for those who had no such findings on echocardiography.

In age and sex adjusted multivariate analysis, heart failure during 3 months of admission was significantly associated with high long-term cardiac mortality rates (HR 1.99, 95% CI 1.06 to 3.73; p = 0.032), whereas the presence of a vegetation of echocardiography was significantly associated with low long-term cardiac mortality rates (HR 0.40, 95% CI 0.21 to 0.76; p = 0.005). When recurrent episodes were excluded from the analyses, patients with heart failure had higher cardiac mortality rates, but the association did not reach statistical significance (HR 1.81, 95% CI 0.95 to 3.44; p = 0.070). Yet, vegetation remained as a factor significantly associated with lower cardiac mortality rates (HR 0.44, 95% CI 0.23 to 0.84; p = 0.012).

Late valve surgery

Of all 326 episodes of IE in 303 patients treated between 1980 and 2004, valve surgery during the follow-up was performed in 126. Fifteen patients underwent 2 valve operations and 1 patient 3 valve operations. In 17 patients, the first valve operation was performed > 1 year after the initial admission. Eight of them were operated on between 1 and 2 years, 5 patients between 2 and 5 years, 3 patients between 5 and 9 years, and 1 patient 16 years after the index episode of IE. In addition, 3 patients undergoing the first valve surgery during the initial hospitalisation underwent a reoperation more than 1 year (range 4 to 7 years) later. Thus, altogether 20 patients underwent late valve surgery. The indications for late valve surgery were: valvular regurgitation without heart failure (n = 15), dehiscence of prosthetic valve (n = 3), valvular stenosis (n = 1), and heart failure (n = 1).

Patients who underwent late valve surgery had significantly lower overall mortality rates than those who did not (HR 0.36, 95% CI 0.15 to 0.90; p = 0.029), but the cardiac mortality rates were not significantly different (HR 0.50, 95% CI 0.15 to 1.62; p = 0.247).

Based on univariate analyses, patients with neurological complications within 3 months of admission required late valve surgery significantly less common than those with no neurological complications (p= 0.032). In age and sex adjusted multivariate analysis, no clinical factor during the initial hospitalisation was associated with the requirement of late valve surgery.

Patients with recurrences did not require late valve surgery more commonly that those with no recurrences (HR 1.04, 95% CI 0.24 to 4.63; p = 0.955).

Survival free of complications

Among the 1-year survivors, survival free of complications (death, valve replacement, recurrence) after an episode of IE is shown in Figure 3.
Figure 3

Kaplan-Meier curves of survival free of recurrent endocarditis, valve replacement, and death after an episode of infective endocarditis. The numbers at different time points refer to the number of patients being followed up and at risk for event at the beginning of the following time period. Zero on the time access indicates 1 year.

Repeated episodes of IE

Of all 303 patients treated between 1980 and 2004, 20 had more than 1 episode of IE including 17 patients with 1 recurrence of IE, 2 patients with 2 recurrences of IE, and 1 patient with 1 recurrence and 1 relapse of IE. The relapse was a PVE caused by a Staphylococcus aureus strain genotypically identical with the strain causing native valve IE in the same patient 3 months earlier. Of the 23 repeated episodes of IE, prosthetic valves were involved in 16.

1-year survivors

A total of 16 recurrences occurred among the 1-year survivors. In univariate analysis, the only factor during the index episode of IE significantly associated with recurrences in these patients was chronic dialysis (p < 0.001). This association remained significant also in multivariate analysis (HR 20.73, 95% CI 4.08 to 105.40; p < 0.001). Patients with recurrent episodes of IE had significantly lower overall mortality rates than those with no recurrences (HR 0.09, 95% CI 0.01 to 0.64; p = 0.017).

All patients

In univariate analysis, the factors during the index episode of IE significantly associated with recurrences in all 303 patients with 23 recurrences were age < 65 years (p = 0.016) and diabetes (p = 0.022), chronic dialysis (p = 0.002) or IVDU (p < 0.001) as underlying conditions. Also in age and sex adjusted multivariate analysis, chronic dialysis (HR 12.56, 95% CI 2.54. to 62.24; p = 0.002), IVDU (HR 5.49, 95% CI 1.84 to 16.43; p = 0.002) and diabetes (HR 3.71, 95% CI 1.30 to 10.62; p = 0.015) remained significant. Patients with recurrent episodes of IE had significantly lower overall mortality rates than those with no recurrences (HR 0.05, 95% CI 0.01 to 0.33; p = 0.002).

Discussion

In this study, we analysed the long-term outcome of the patients treated for IE in a Finnish teaching hospital during a period of 25 years. Among the 1-year survivors, the overall survival was 66% at 10 years, 51% at 15 years and 45% at 20 years. These figures are comparable with the results of previous studies [12, 15], although we are not aware of any earlier study in which the long-term survival has been analysed in an identical manner. Collectively, these data illustrate that despite major diagnostic and therapeutic advances, the mortality associated with IE remains high. At 10 years of follow-up, as many 51% of our whole patient population and 34% of the 1-year survivors had died. Admittedly, a few studies have been published reporting somewhat higher survival rates [13].

One of the main purposes of the present study was to define which clinical characteristics or complications of IE during the initial phase of endocarditis would be associated with an adverse long-term outcome of the patients. Consistent with previous studies [12, 14], older age at the time of contracting the disease predicted an adverse long-term outcome. Chronic dialysis as an underlying condition predicted a poor overall long-term prognosis, as did alcohol abuse and collagen disease. In the patients with collagen disease, the severe nature of the underlying disease may have contributed to high mortality. Of all 9 patients with collagen disease who died during the follow-up, 3 needed chronic dialysis, 1 had nephrotic syndrome and in 3 patients, the cause of death was a malignancy. On the other hand, the survival was significantly better for the patients with IVDU than for those with no IVDU, but all of the patients with IVDU were young and most of them had a tricuspid valve disease with no mortality. Moreover, the follow-up time of these patients was short, since the first IVDU-associated case of IE occurred in our hospital in 1996.

Among the complications of IE, heart failure during the first 3 months of admission was significantly associated with long-term overall mortality and cardiac mortality. This corroborates other studies, which have found that heart failure is a major risk factor for long-term mortality [15]. Also among the surgically treated patients, the overall survival was lowest for those who were operated on for heart failure, underscoring the importance of heart failure as a poor long-term prognostic sign.

Neurological manifestations and peripheral emboli usually develop early in the course of endocarditis [16, 2224]. We have previously shown that in this patient population, the occurrence of neurological complications or peripheral emboli was significantly associated with short-term mortality as well as with mortality for up to 1 year of the admission [16]. In contrast, the results of the present study show that the long-term survival was practically similar for the patients with or without neurological manifestations or peripheral emboli during the acute phase of their illness (Table 1). This finding is not surprising, since once the patient has solved such an acute complication, it seems logical that it no longer influences the long-term prognosis.

In our series, early surgery was performed in 27.3% (89) of all 326 episodes [16]. Evaluation of the role of cardiac surgery on the prognosis of the patients with IE is a complex issue. Although early surgery is evidently life saving for certain groups of patients, it does not necessarily decrease the total mortality, since more and more critically ill patients are being treated surgically. This may be one of the reasons why the results regarding the role of early surgery as a prognostic factor have been conflicting. For example, when studying 280 patients treated in their unit between 1970 and 1982, Malquarty et al. [25] did not find any significant difference in the survival rate at 5 years between the surgical and non-surgical treatment groups. Neither did Tornos et al. [8] find any association between early surgery and a better survival rate during a 15-year follow-up among 140 patients hospitalised between 1975 and 1990. On the other hand, according to Bishara et al. [26], early surgical intenvention compared with medical therapy alone was associated with increased long-term survival rates in patients with IE treated between 1987 though 1996, primarily when IE was caused by S. aureus. Similarly, long-term survival was predicted by early surgical treatment in 212 patients with IE treated between 1980 and 1995 in a series described by Netzer at al. [15]. Moreover, Castillo et al. [13] have reported that a high early surgery rate was related to good long-term results in 138 cases of IE hospitalised between 1987 and 1997. Our results corroborate these findings: early surgery led to significantly lower overall and cardiac mortality rates in these 1-year survivors, although in multivariate analysis, the association was not significant regarding the long-term cardiac mortality. Thus, the results of the present study support the contention that a successful and correctly focused early valve surgery may decrease mortality due to IE. This could be accomplished by a careful selection of appropriate patients to be treated surgically.

The prognosis of the patients surviving the initial phase of endocarditis is considered to be due to 3 main factors: the development of heart failure, the risk of recurrences and the need for later valve replacement. In our patients, repeated episodes of IE were not common, as 20 (6.6%) of all 303 patients had recurrences and only 1 patient (0.3%) had a relapse. The rate of recurrences concurs with other published series, in which the rate of recurrences has varied between 3.9 and 16% [12, 14, 2729], but the rate of relapses was here somewhat lower than the 1.1 to 3.3% relapse rate reported in earlier studies [8, 14, 30]. Chronic dialysis, diabetes and IVDU were shown to be risk factors for the development of recurrences when analysed for all 303 patients treated in our hospital between 1980 and 2004. IVDU has been shown to be a risk factor also in some other [29], but not all [14], previous studies. Although recurrent endocarditis is considered to be a risk factor for death [14], the development of a recurrent episode of IE did not confer a poor prognosis in our patients; in direct contrast, patients with recurrences had a better long-term overall outcome than those with no recurrences. At least a partial explanation for this could be that IVDU was a risk factor for the recurrences of IE. The patients with IVDU had a significantly lower mortality than those with no drug use, evidently due to the fact that they commonly had tricuspid valve IE with low mortality.

Late surgery was required in 17 (7.0%) of the 243 episodes. None of the clinical parameters during the initial episode of IE were found to be associated with the requirement for late valve surgery. The requirement for late surgery was not increased even in the patients with recurrent episodes of IE. Also this could be partly explained by the positive association between the development of recurrences and IVDU.

Survival free of complications decreased with time. Although the estimate for 20-year survival was 45%, the estimate for 20-year survival free of complications, i.e. recurrent endocarditis or valve replacement, was only a little more than 30%.

Conclusion

In our patients, heart failure within 3 months of the admission for the index episode of IE was the complication, which significantly predicted a poor long-term outcome. Patients who underwent surgery during the initial hospitalisation for IE faired significantly better than those who did not. Corroborating earlier findings, these results support the contention that a successful and correctly focused early valve surgery may decrease mortality due to IE. This could be accomplished by a careful selection of appropriate patients to be treated surgically. It must be admitted that the heterogeneity of the patient population included in this study may be one limitation when applying our results in the daily clinical practice. An analysis of long-term prognostic factors in some defined subgroups of our whole study population may provide further valuable information in the future.

Declarations

Acknowledgements

We express our thanks to Ms. Leeni Nurmi for her help in collecting patient data for this study. This study was financially supported by a grant from the Foundation of the Turku University to M.H. and by grants from the Turku University Central Hospital Research Fund to M.H., J.N. and P. K., but the funding body had no role in the study design, collection, analysis or interpretation of data, or in the decision to submit the manuscript for publication.

Authors’ Affiliations

(1)
Department of Medicine, Turku University Hospital
(2)
Department of Biostatistics, University of Turku
(3)
Department of Surgery, Turku University Hospital

References

  1. Netzer ROM, Zollinger E, Seiler C, Cerny A: Infective endocarditis: clinical spectrum, presentation and outcome. An analysis of 212 cases 1980–1995. Heart. 2000, 84: 25-30. 10.1136/heart.84.1.25.View ArticlePubMedPubMed CentralGoogle Scholar
  2. Cabell CH, Jollis JG, Peterson GE, Corey GR, Anderson DJ, Sexton DJ, Woods CW, Reller LB, Ryan T, Fowler VG: Changing patient characteristics and the effect on mortality in endocarditis. Arch Intern Med. 2002, 162: 90-94. 10.1001/archinte.162.1.90.View ArticlePubMedGoogle Scholar
  3. Wallace SM, Walton BI, Kharbanda RK, Hardy R, Wilson AP, Swanton RH: Mortality from infective endocarditis: clinical predictors of outcome. Heart. 2002, 88: 53-60. 10.1136/heart.88.1.53.View ArticlePubMedPubMed CentralGoogle Scholar
  4. Chu VH, Cabell CH, Benjamin DK, Kuniholm EF, Fowler VG, Engemann J, Sexton DJ, Corey GR, Wang A: Early predictors of in-hospital death in infective endocarditis. Circulation. 2004, 109: 1745-1749. 10.1161/01.CIR.0000124719.61827.7F.View ArticlePubMedGoogle Scholar
  5. Tornos P, Almirante B, Olona M, Permanyer G, González T, Carballo J, Pahissa A, Soler-Soler J: Clinical outcome and long-term prognosis of late prosthetic valve endocarditis: a 20-year experience. Clin Infect Dis. 1997, 24: 381-386.View ArticlePubMedGoogle Scholar
  6. Castillo JC, Anguita MP, Ruiz M, Delgado M, Mesa D, Romo E, Arizón JM, Vallés F: Clinical features and outcome of non-drug-addicted patients with infective endocarditis and perivalvular abscess. J Heart Valve Dis. 2005, 14: 801-805.PubMedGoogle Scholar
  7. Carozza A, De Santo LS, Romano G, Della Corte A, Ursomando F, Scardone M, Caianiello G, Cotrufo M: Infective endocarditis in intravenous drug abusers: patterns of presentation and long-term outcomes of surgical treatment. J Heart Valve Dis. 2006, 15: 125-131.PubMedGoogle Scholar
  8. Tornos MP, Permanyer-Miralda G, Olona M, Gil M, Galve E, Almirante B, Soler-Soler J: Long-term complications of native valve infective endocarditis in non-addicts. A 15-year follow-up study. Ann Intern Med. 1992, 117: 567-572.View ArticlePubMedGoogle Scholar
  9. Langley SM, Alexiou C, Stafford HM, Dalrymple-Hay MJR, Haw MP, Livesey SA, Monro JL: Aortic valve replacement for endocarditis: determinants of early and late outcome. J Heart Valve Dis. 2000, 9: 697-704.PubMedGoogle Scholar
  10. Alexiou C, Langley SM, Stafford H, Haw MP, Livesey SA, Monro JL: Surgical treatment of infective mitral valve endocarditis: predictors of early and late outcome. J Heart Valve Dis. 2000, 9: 327-334.PubMedGoogle Scholar
  11. Grûnenfelder J, Akins CW, Hilgenberg AD, Vlahakes GJ, Torchiana DF, Madsen JC, MacGillivray TE: Long-term results and determinants of mortality after surgery for native and prosthetic valve endocarditis. J Heart Valve Dis. 2001, 10: 694-702.PubMedGoogle Scholar
  12. Delahaye F, Ecochard R, de Gevigney G, Barjhoux C, Malquarti V, Saradarian W, Delaye J: The long term prognosis of infective endocarditis. Eur Heart J. 1995, 16 (Suppl B): 48-53.View ArticlePubMedGoogle Scholar
  13. Castillo JC, Anguita MP, Ramírez A, Siles JR, Torres F, Mesa D, Franco M, Muòoz I, Concha M, Vallés F: Long term outcome of infective endocarditis in patients who were not drug addicts: a 10 year study. Heart. 2000, 83: 525-530. 10.1136/heart.83.5.525.View ArticlePubMedPubMed CentralGoogle Scholar
  14. Mansur AJ, Dal Bó CM, Fukushima JT, Issa VS, Grinberg M, Pomerantzeff PM: Relapses, recurrences, valve replacements, and mortality during the long-term follow- up after infective endocarditis. Am Heart J. 2001, 141: 78-86. 10.1067/mhj.2001.111952.View ArticlePubMedGoogle Scholar
  15. Netzer ROM, Altwegg SC, Zollinger E, Täuber M, Carrel T, Seiler C: Infective endocarditis: determinants of long term outcome. Heart. 2002, 88: 61-66. 10.1136/heart.88.1.61.View ArticlePubMedPubMed CentralGoogle Scholar
  16. Heiro M, Helenius H, Hurme S, Savunen T, Engblom E, Nikoskelainen J, Kotilainen P: Short-term and one-year outcome of infective endocarditis in adult patients treated in a Finnish teaching hospital during 1980–2004. BMC Infect Dis. 2007, 7: 17-10.1186/1471-2334-7-78.View ArticleGoogle Scholar
  17. Durack DT, Lukes AS, Bright DK, the Duke Endocarditis Service : New criteria for diagnosis of infective endocarditis: utilization of specific echocardiographic findings. Am J Med. 1994, 96: 200-209. 10.1016/0002-9343(94)90143-0.View ArticlePubMedGoogle Scholar
  18. Heiro M, Nikoskelainen J, Hartiala JJ, Saraste MK, Kotilainen PM: Diagnosis of infective endocarditis. Sensitivity of the Duke vs von Reyn criteria. Arch Intern Med. 1998, 158: 18-24. 10.1001/archinte.158.1.18.View ArticlePubMedGoogle Scholar
  19. Heiro M, Helenius H, Mäkilä S, Savunen T, Engblom E, Nikoskelainen J, Kotilainen P: Infective endocarditis in a Finnish teaching hospital: a study on 326 episodes treated during 1980–2004. Heart. 2006, 92: 1457-1462. 10.1136/hrt.2005.084715.View ArticlePubMedPubMed CentralGoogle Scholar
  20. Heiro M, Helenius H, Sundell J, Koskinen P, Engblom E, Nikoskelainen J, Kotilainen P: Utility of serum C-reactive protein in assessing the outcome of infective endocarditis. Eur Heart J. 2005, 26: 1873-1881. 10.1093/eurheartj/ehi277.View ArticlePubMedGoogle Scholar
  21. Kotilainen P, Heiro M, Jalava J, Rantakokko V, Nikoskelainen J, Nikkari S, Rantakokko-Jalava K: Aetiological diagnosis of infective endocarditis by direct amplification of rRNA genes from surgically removed valve tissue. An 11-year experience in a Finnish teachning hospital. Ann Med. 2006, 38: 263-273. 10.1080/07853890600622119.View ArticlePubMedGoogle Scholar
  22. Hart RG, Foster JW, Luther MF, Kanter MC: Stroke in infective endocarditis. Stroke. 1990, 21: 695-700.View ArticlePubMedGoogle Scholar
  23. Røder BL, Wandall DA, Espersen F, Frimodt-Møller N, Skinhøj P, Rosdahl VT: Neurologic manifestations in Staphylococcus aureus endocarditis: a review of 260 bacteremic cases in nondrug addicts. Am J Med. 1997, 102: 379-386. 10.1016/S0002-9343(97)00090-9.View ArticlePubMedGoogle Scholar
  24. Heiro M, Nikoskelainen J, Engblom E, Kotilainen E, Marttila R, Kotilainen P: Neurologic manifestations of infective endocarditis. A 17-year experience in a teaching hospital in Finland. Arch Intern Med. 2000, 160: 2781-2787. 10.1001/archinte.160.18.2781.View ArticlePubMedGoogle Scholar
  25. Malquarti V, Saradarian W, Etienne J, Milon H, Delahaye JP: Prognosis of native valve infective endocarditis: a review of 253 cases. Eur Heart J. 1984, 11-20.Google Scholar
  26. Bishara J, Leibovici L, Gartman-Israel D, Sagie A, Kazakov A, Miroshnik E, Ashkenazi S, Pitlik S: Long-term outcome of infective endocarditis: the impact of early surgical intervention. Clin Infect Dis. 2001, 33: 1636-1643. 10.1086/323785.View ArticlePubMedGoogle Scholar
  27. Van der Meer JTM, Thompson J, Valkenburg HA, Michel MF: Epidemiology of bacterial endocarditis in the Netherlands. I. Patient characteristics. Arch Intern Med. 1992, 152: 1863-1868. 10.1001/archinte.152.9.1863.View ArticlePubMedGoogle Scholar
  28. Hoen B, Selton-Suty C, Lacassin F, Etienne J, Briançon S, Leport C, Canton P: Infective endocarditis in patients with negative blood cultures: analysis of 88 cases from a one-year nationwide survey in France. Clin Infect Dis. 1995, 20: 501-506.View ArticlePubMedGoogle Scholar
  29. Welton DE, Young JB, Gentry WO, Raizner AE, Alexander JK, Chahine RA, Miller RR: Recurrent infective endocarditis. Analysis of predisposing factors and clinical features. Am J Med. 1979, 66: 932-938. 10.1016/0002-9343(79)90447-9.View ArticlePubMedGoogle Scholar
  30. Verheul HA, van den Brink RB, van Vreeland T, Moulijn AC, Düren DR, Dunning AJ: Effects of changes in management of active infective endocarditis on outcome in a 25-year period. Am J Cardiol. 1993, 72: 682-687. 10.1016/0002-9149(93)90885-G.View ArticlePubMedGoogle Scholar
  31. Pre-publication history

    1. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/8/49/prepub

Copyright

© Heiro et al; licensee BioMed Central Ltd. 2008

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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