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Effects of changes in management of active infective endocarditis on outcome in a 25-year period
Effects of Changes in Management of Active Infective Endocarditis on Outcome in a 25-Year Period Hans A. Verheul, MD, Renee B. A. van den Brink, MD, Tom van Vreeland, MD, Adrian C. Moulijn, MD, Donald R. Dijren, MD, and Arend J. Dunning, MD
E
ven in 1993, with therapeutic options including modern antibiotic treatmentand early surgical intervention, infective endocarditis remains a lifethreatening disease.Many studies have shown that optimal timing of surgical intervention is of paramount importance to decrease the mortality rate, especially if infective endocarditis is complicated by heart failure.t-9 However, few studies have reported on all patients with active infective endocarditis who received either medical or medical-surgical therapy.3,4We reviewed our experience with treatment of all patients with the diagnosis of active infective endocarditis during a 25year period, using the strict case criteria of von Reyn et aLlo The onset of complications that could not be managed medically resulted in urgent surgical intervention. The purpose of the study was to perform an analysis of factors affecting outcome, and to analyze the short- and long-term results of the managementstrategy described.
and long+nn folloWp of 13Oconsecutivepatients (141episodes)wlthao tive infective endocatditis who were treated be tween1966 and 1991wereanalymd.Therewas a shiitowardahlgherproportlonofre+ferredpa tlents (39 to 75%), patlents aged MO years (11 to 41%) and urgent surgical treatment (11 to 44%). Medical treatment was administered In 95 pa tlents (70%); 30day mortalll was 27%. Surgery was pmfoaed in 43 patients (30%), wlth an m alive mortalll of 26%; 9 of 14 patients (54%) who underwent operation within the first week of a& mission died. Patients with severe heart failure are at the hll rlslc for ealy mortality (relative risk = 21.1; 95% confidence interval 7.4-50.3). Re ferred patients were much mare often treated sup gically than were nonrefelmd patii (45 versus 14%) and had a lower operative mortality (24 vs 30%). Nonrefemed patients were more often treated medically (55 vs 52%) and with lower mortalii (19 vs 39%). The total followup time was 730 pa tbnt-yearq only 1 patient was considered lost to followup. The overall cumulative 5year and 10 year survival after hospital discharge for patients afterurgentsurgerywere84~7%and53~7%, respectively, and for those after medical trea+ merit 64 h 5% and 77 -c 6%, respectively. lhe probability of remaining free of late events (recurrent endocaiditis, late valve replacement or death) during 5 and 10 years for patients after urgentsurgerywas64-t 7%ti53 *15%,respet+ tively, and for those after medical treatment 59 -c 6% and 40 f 7%, respectively. In the tirst year after hospital discharge, the incidence of late events was high, especially in patients who m ceived only medical treatment. Although urgent surgery has improved the outlook for some ps tlent groups, early mortality did not decrease significantly owing to a shii toward more comm mised cases. (Am J Cardiol1993;72:552-557) The clinical a&come
MmHODS
From the Departments of Cardiology and Cardiopulmonary Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Manuscript received October 30, 1992; revised manuscript received May 17, 1993, and accepted May 20. Address for reprints: Hans A. Verheul, MD, Department of Cardiology, Academic Medical Center, F4 109, Meibergdreef 9, 110.5 AZ Amsterdam, the Netherlands.
682
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
study #oup: All consecutivepatientswith a diagnosis of active infective endocarditis treated from 1966 to 1991at the cardiology departmentof a university hospital (with both referral and primary care patient populations) were included in the study. Patients with endocarditis of a valve prosthesiswere excluded. Deflnltions: Detinite, probable and possible episodes of infective endocarditis, according to the criteria of von Reyn et al,1° were analyzed.Definite episodeswere continned by histology from surgery or autopsy material, or by Gram stain or culture of an endocardial vegetationor peripheral embolus. Probable episodeswere defined as: (1) persistently positive blood cultures with growth of the same microorganism and a new/changing murmur, or predisposing heart diseasewith vascular phenomena (e.g., petechiae,splinter hemorrhages,Roth spots,Osler’s nodes, emboli, and so forth); or (2) negative or intermittently positive blood cultures (~70% positive) with fever, a new regurgitant murmur and vascular phenomena. Possible episodes were detined as: (1) persistently positive blood cultures with growth of the same microorganism, and known predisposing heart diseaseor vascular phenomena; or (2) negative or intermittently positive blood cultures(~70% positive) with fever,known predisposing heart diseaseand vascular phenomena.Infective endocarditis was arbitrarily detined as active if the patient had not completed a 4-week standardcourse of antibiotic treatment at the time of admission to the hospital or at the tune of operation.7Medical treatment consisted of organism-specific intravenous antibiotics during 4 to 6 weeks, which were selectedin most cases
SEPTEMBER15.1993
on the basis of in vitro susceptibility tests. In culturenegative endocarditis, empiric regimens were used (vancomycin and streptomycin). Surgical treatment was considered in all patients with refractory congestive heart failure, 22 systemic emboli, uncontrolled infection and development of heart block (except fist-degree atrioventicular block). The degree of congestive heart failure was defined as follows: moderate heart failure was characterized by physical signs of congestion that responded to administration of diuretics or digoxin, or both. Severeheart failure (New York Heart Association class IV) was characterized by similar findings sometimes accompanied by hypotension, which did not respond to intravenous administration of diuretics, digoxin and positive inotropics. Systemic embolization was defined as an acute occlusion of a major artery resulting in a cerebrovascularaccident or loss of peripheral pulses. Uncontrolled infection was characterizedby positive blood cultures or persistent high fever 1 week after beginning proper antibiotic treatment. Urgent surgery was defined as surgery performed before completion of antibiotic treatment. Death within 30 days after admission (medical treatment) or operation (surgical treatment) was defined as early mortality. In the multivariate analysis, death within 3 months after admission was used as the end point for early mortality. Late mortality was defmed as death after 3 months. Relapsing endocarditis was delined as persistent infection after termination of antibiotic treatment after a complete course (with or without surgery). Recurrent endocarditis was defined as a new episode of endocarditis (not necessarily due to a different organism) after documented curative therapy. Clinical data: All casesidentified as infective endocarditis were reviewed by protocol and processedin a structured data base. Clinical history, signs and symptoms on admission, treatment, clinical course, complications and follow-up were analyzed.Functional class was determined according to the criteria of the New York Heart Association. The site of infection was determined by physical examination and supported by findings at echocardiography,surgery or autopsy.Autopsy was performed in 68% of patients who died in the hospital. Followup: Data on outcome after discharge and the clinical status at the end of follow-up were obtained from outpatient clinical records of the attending cardiologist or general practitioner, or both. The end of the follow-up period was January 1, 1991.Only 1 patient was considered lost to follow-up. The total follow-up time was 790 patient-years; mean follow-up time was 8.7 years (range 0.3 to 23.5). StatIstical analysis: Values are expressedas mean f SD. Differences between proportional variables were tested with &i-square test and between continuous variables with Student’s t test. A logistic regression analysis procedure was used for multivariate analysis of 3month mortality. Cumulative survival and event-free periods were estimated by the Kaplan-Meier method. The covariates (potential risk factors or determinants) were dichotomized and entered in the model as indicator variables for which the value of 0 or 1 was assigned.To adjust for overall change of treatment and patient selection, we divided the study period into “early” (1966 to
TABLE I Characteristics of 130 Consecutive Patients with 141 Episodes of Active Infective Endocarditis Nonreferred Patients Number of cases Men Mean age (years) (range) > 60 years von Reyn classification Definite episode Probable episode Possible episode Prior endocarditis Microorganism Staphylococcus Streptococcus Other Culture negatwe Unknown Sate of infection Aortic valve Mitral valve Aortic and mitral valves Other site* Emboll Systemic Cerebral Heart failure Severe
Referred Patients
All Patients
91(100%) 63 164%) 43 (18-76) 19 (21%)
50 (100%) 41(82%) 48 (19-77) 17 (34%)
141(100%) 104 (74%) 45 (18-77) 36 (25%)
37 (41%) 34 (37%) 20 (22%) 15(16%)
35 (70%) 12 (24%) 3 (6%) 0
72 46 23 15
(51%) (32%) (16%) (11%)
13 67 2 6 3
12 29 4 5 0
(24%) (58%) (8%) (10%)
25 96 6 11 3
(18%) (68%) (4%) (8%) (2%)
36 140%) 26 (29%) 15 (16%) 14(15%)
28 (56%) 15 (30%) 7 114%) 0
64 41 22 14
(45%) (29%) (16%) (10%)
18 17 55 21
13 15 42 23
31 26 99 44
(22%) (18%) (69%) (31%)
(14%) (74%) (2%) (7%) (3%)
(20%) (19%) (60%) (23%)
(31%) (30%) (86%) (46%)
*Includes ventricular septal defect (n = 8). aortic coarctation Fall& (n = 21, and tricuspid valve (n = 2).
(II = 2). tetralogy
of
1978) and “current” (1979 to 1991) periods of treatment. The following indicator variables were tested: gender,age, referral, improper initial antibiotic treatment before admission in our center, preexistent cardiovascular status, recurrent endocarditis, microorganism (staphylococcus or other), site (aortic valve or other), heart failure (severe or moderate/none)and major emboli. A significance level of 0.05 was used in all tests. The multivariate analysis was performed with the BMDP package. RESULTS Patient characteristics From 1966 to 1991, 141 casesof active infective endocarditis were diagnosed in 130patients. Of these cases,91 originated from our hospital, and 50 were referred from other hospitals. Selected clinical characteristicsof the study population are summarized in Table I. In 59% of patients, a murmur or cardiac lesion was known before admission, but only 23% were symptomatic or already consulting a cardiologist. Before hospitalization, 28% of patients had not received antibiotic treatment, and 30% were already using antibiotics without preceding blood cultures; the remaining patients (42%) used antibiotics guided by preceding blood cultures. The aortic valve was more often the site of the infection than was the mitral valve. Severe heart failure occurred more often in aortic valve (45%) than in mitral valve (12%) endocarditis. Transthoracicechocardiographywas performed since 1975in 99 cases.Vegetationswere found in 70% of native aortic valve endocarditis and in 48% of native mitral valve endocarditis. In this population, 32% of cases with echocardiographicaIly demonstratedvegetations on MANAGEMENT OF ACTIVE INFECTIVE ENDOCARDITIS
683
the aortic valve sustained 21 systemic embolus versus 67% with vegetations on the mitral valve. Embolic events occurred in 26% of patients without echocardiographically detectablevegetations.Periannular abscesses were found in 11% of patients. Pericardial effusion was observed in 9% of all cases; there was no association with the presenceor development of conduction disturbances. Rend over time: In comparingthe periods 1966-1971 and 19861991, the proportions of referred patients (39 vs 78%), patients aged %O years (11 vs 41%) and those who underwent urgent surgical treatment (11 vs 44%) increased. TREAT Medical treatment alone was administered in 98 cases (70% of study population). Surgical treatment of active infective endocarditis was introduced
TABLE II Treatment
Patient
Characteristics
of Medical
Versus
Surgical Treatment
Medical Treatment Number of cases Men Mean age (years) (range) > 60 years Microorganism Staphylococcus Streptococcus Others Culture negative Unknown Site of infection Aortic valve Mitral valve Aortic and mitral valve Other site* Severe heart failure
98 66 44 25
Surgical
(70%) (66%) (18-77) (25%)
43 (30%) 38 (86%) 45 (19-71) 11(26%)
4 (4%) 4 (4%) 2 (2%)
8 (19%) 25 (58%) 2 (5%) 7 (16%) 1 (2%)
29 (30%) 35 (36%) 20 (20%)
35 (81%) 6 (14%) 2 (5%)
17 (17%) 71 (72%)
14 (14%)
0
22 (22%)
22 (51%)
‘See Table I.
in our center in 1969 and was performed in 43 cases (30%), of which 14 (32%) underwent operation within the tirst week of admission. The mean and median intervals between admission and surgery were 24 and 15 days, respectively.In the total study group, 55% of cases with aortic valve and 15% with mitral valve endocarditis underwent surgical treatment. Urgent surgery was performed in 48% of referred patients, who constituted 77% of the entire group that underwent urgent surgery. Annular abscessesor fistulae (extensive disease), or both, were present in 18% of all operated patients and in 36% of those who underwent operation within the first week after admission. The indications for surgery were: severe heart failure (pulmonary congestion, low output) in 33 cases(77%), systemic emboli in 3 (7%), uncontrolled infection in 2 (5%) and conduction defects in 5 (12%). Table II lists selectedclinical characteristics of medically and surgically treated patients. EARLY MORTALITY: overall early mortality (30 days) was 26%. The mortality of medically treated patients was 27% after 1 month and 29% after 3 months. Causes of death in medically treated patients were: severe heart failure and cardiogenic shock (n = 13), acute intractable rhythm disturbances (n = 6), major cerebral emboli (n = 5) ruptured cerebral mycotic aneurysms (n = 2) disseminated intravascular coagulation (n = l), and bleeding esophageal vat-ices (n = 1). The reasons that the group with severeheart failure was denied surgical treatment were: the limited experience with surgical treatment of active infective endocarditis before 1970 (n = 3), advancedor multivalve endocarditis (n = 3), preexistent paraplegia with decubitus (n = l), recurrent endocarditis in a drug addict (n = l), and sudden hemodynamic deterioration resulting in a moribund state before surgery could be attempted(n = 5). The operative mortality was 26% after 1 month and 30% after 3 months. The operative mortality of patients who underwent operation within the tirst week of ad-
Cl alive/M
q alive/S
subgroup AV MV
q n
60+ 60-
Staph Strep
male female ref nonref 1966-76 1979-91 0%
25%
50%
75%
100%
% of cases 664
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
SEPTEMBER15,1993
dead/S dead/M
FIGURE 1. oetcomeof~ the infective edocadh after3monfbforsoma sub#eupe.AV=amtk valvq HF = heart fake; M=lblddW Mv=mitralvalve;Mnuef= llOMhTdmd= refemdpathmfqsmau~
mission to our hospital was very high (9 of 14; 64%). When surgery was performed in the second week after admission, mortality decreasedto 0 of 5 patients and in the third week to 1 of 6. Causesof operative death were heart failure (n = 7), intractable arrhythmias (n = l), intractable bleeding (n = l), dehiscence of the prosthetic valve (n = l), new fistula (n = l), ischemic bowel infarction (n = l), and ongoing sepsis(n = 1). Mortality in surgically treated patients with extensive disease was 62% compared with 20% in those without annular abscessesor fistulas, or both. Logistic regression analysis marked heart failure as an independent determinant of mortality within 3 months after admission. The early mortality of patients with severe heart failure was 68% (relative risk [RR] 21.1; 95% confidence interval [CI] 7.4-60.3) compared with those without severeheart failure. The outcome for some subgroups 3 months after hospital admission is shown in Figure 1. Patients with heart failure were at high risk for urgent surgery or death, or both (RR 47.6; 95% CI 9.1-249.0), as were referred patients (RR 4.8; 95% CI 1.8-12.8) and those with aortic valve endocarditis (RR 3.0; 95% Cl 1.7-14.3). Late mortalii and survival: In all, 91 patients with 101 cases of active infective endocarditis survived the hospital phase.During follow-up, 29 (29%) of these patients died. A cardiac cause of death was present in 13 patients (heart failure [n = 81 and sudden death with or without prior documented arrhythmias [n = 51); other causes of death were cerebrovascular accident (n = 2), malignancy (n = 2), and unknown (n = 12). The firstyear mortality was 6.6%. The cumulative 5- and lo-year survival for all hospital survivors were estimated at 84 + 4% and 72 f 6%, respectively.Figure 2 shows the cu-
mulative survival after discharge for patients with and without urgent surgery. Late mo&idfQr After hospital dischargeof 60 medically treatedpatients, readmittancefor valve replacement was necessary in 17 (28%), relapsing endocarditis occurred in 1, and recurrent endocarditis occurred in 10. Most of these events (2 recurrent endocarditis and 10 valve replacements)occurred in the first year after hospital admission. After discharge of 31 surgically treated patients, only 1 had recurrent endocarditis and died after surgery,and 1 had a strut fracture of a Bjork Shiley convex-concave aortic prosthesis. The probability of remaining free of late events (recurrent endocarditis, late valve replacement or death) during 5 and 10 years for all patients was 84 + 7% and 53 f 15%, respectively. Figure 3 shows the event-free period after discharge for patients with and without urgent surgery. At the end of follow-up, 64 patients were alive, of whom 45 were without recurrent endocarditis or valve replacement.Only 33 of these 45 patients were without any cardiac complaints.
DISCUSSION The incidence of native valve endocarditis in the Netherlands today is 15 per one million inhabitants annually.’ i This study reviews our experience with both medical and medical-surgical treatment of all consecutive patients with active infective endocarditis in a tertiary referral center with a large outpatient clinic during a 25-year period (1966 to 1991).Only 1 patient was lost to follow-up. In comparing the first and last 5-year periods, there was a shift toward a higher proportion of referred patients, a higher proportion of patients aged >60
% of patients % of patients
80 -
60 -
+ Medical
therapy
* after Surgery
5
10
years after discharge years after discharge
MANAGEMENT OF ACTIVE INFECTIVE ENDOCARDITIS 685
years, and a marked increase in urgent surgery. Similar shifts have been observed in other western populations, which were probably mainly due to the impact of surgical treatment and aging of the population.10J2The number of drug addicts in our series was relatively low; most of these patients are cared for elsewhere,and with a few exceptions,they are not considered candidatesfor surgery. Infective endocarditis has a grim prognosis. Overall mortality in this study was high, and late outcome shows limited prospects for most patients to be free of recurrent endocarditis, valve surgery or death. During the study period, the management strategy was such that complications that could not be managed medically resulted, when possible, in urgent surgical intervention. In the medically treated group, mortality after 1 month was 27% and in the surgically treated group 26%, which is somewhathigher than the case-fatality of 20% reported from a nationwide prospective epidemiologic study performed in the Netherlands during a 2-year period (1986 to 1988).’t This was probably due to selection of severely compromised cases referred to our tertiary referral center. The referred patients in our study population were older, more often had staphylococcus and aortic valve endocarditis, and their clinical course was complicated more frequently by heart failure and emboli. Mortality in medically treated patients with severe heart failure was very high (68% at 1 month, and 93% at 3 months), which is in agreement with the litera~I.E.~J~~~The reasons that patients with severe heart failure were denied surgical treatment were: treatment before 1970, a severely compromisedphysical or hemodynamic condition before onset of infective endocarditis, and sudden hemodynamic deterioration. The IO-year survival after medical treatment was good (77 + 6%), which is in accordancewith the lindings of other investigators.GW However, these patients had many adverse events. Valve replacement was performed mainly witbin the tirst year after hospital discharge, whereasrecurrent endocarditis occurred later. At the end of follow-up, only 13 medically treated patients (13%) were alive without late valve replacement,recurrent endocarditis or physical restraints (New York Heart Association class I or II). Patients most likely to be cured and to remain event-tree by medical treatment alone for 25 years were those with streptococcalendocarditis of the native mitral valve or ventricular septal defect. In the past 25 years, cardiac surgery has become increasingly important in the treatment of endocarditis. In the present series, the percentage of surgically treated patients with active infective endocarditis increasedfrom 11to 44%. In reports on surgical treatment of active infective endocarditis, there are considerabledifferencesin early mortality (0 to 47%).1-10~13-15J7 This may be due to differencesin casedefinitions (only a few studiesused the strict criteria of von Reyn et allo), and in the preoperative hemodynamic statusand age of patients. In addition, differences in mortality in surgical treatment of active infective endocarditis may be due to the inability to remove all infected tissuesand restorevalve function? Many investigators found a trend of early surgical in666
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
tervention to be superior to medical treatment, especially in patients with congestive heart failure, persistent sepsis and major emboli. However, a randomized controlled trial of consecutive patients to resolve the issue of early surgery versus medical therapy of active infective endocarditis has not been performed. Therefore, optimal timing of surgical intervention remains a therapeutic dilemma. If surgery is performed too early, some patients, who would have recovered with antibiotics only and without any complications, will be subjected to the risks of surgery and to the morbidity associated with a valve prosthesis. However, the occurrence and progression of complications such as congestive heart failure, major systemic emboli and uncontrolled infection (which may have been preventedby early surgery) are difficult, if not impossible, to predict, and will increasethe risk of surgery,or in the worst case, the patient may die before surgery can be perfom-ted.In the present series,there was a very high mortality in patients who underwent operation within the first week of admission (64%) as compared with the second and third weeks. The main causeof death in patients who underwent operation in the first week after admission was severe heart failure. There was a remarkable difference in the treatment modalities and outcomesof referred and nonreferred patients. Referred patients were treated surgically much more often than were nonreferred ones (48 vs 14%) and had a lower operative mortality (24 vs 30%). Nonreferred patients were treated medically more often than were referred ones (86 vs 52%) and had a lower mortality (19 vs 39%). Referred patients represent the typical case selection known from the literature, originating from tertiary referral centers with cardiac surgery facilities. In previous studies, results were biased by the often severely compromised referred patients who benefit most from urgent surgery. The experience of the cardiologist (before referral), which incorporates many lowrisk cases,appearsto be quite the opposite. Therefore, studies reporting on treatment of infective endocarditis, which are performed in tertiary referral centers with an outpatient clinic should mention the proportion of referred patients, becausethis may have a profound effect on outcome. Study limhtions The results should be interpreted in regard to the retrospective nature of the study. In many cases,we had to rely on clinical information obtained by physicians other than those directly involved in the study. Comparison of subgroupsin a retrospective study is hazardousbecauseof the potential dissimilarity of patient characteristicsand treatment modalities between groups. In the past 25 years, important advances have been made in medical treatment, diagnosis (echocardiography) and cardiac surgery (increasedexperience with complex surgical procedures, and improved myocardial preservation), which have intIuenced outcome. Conclusionr In the past 25 years, the appearanceof infective endocarditis has profoundly changed due to aging of the population and to the introduction of heart valve surgery. However, mortality of infective endocarditis did not decreaseas much as would be expected with improved treatment owing to an increasing propor-
SEPTEMBER15,1993
tion of seriously ill patients who were considered beyond any possible cure in the past, but are now referred to centers with cardiac surgery facilities. After hospital discharge the incidence of late events is high, especially in patients who received only medical treatment.
1. D’Agostino RS, Miller C. Stinson EB, Mitchell RS, Oyer PE, Jam&on SW, Baldwin JC, Shumway NE. Valve replacement in patients with native valve endocarditis, what really determines operative outcome? Ann Thorar Surg 1985;40: 429-438. 2. Middlemost S, Wisenbaueh T. Meverowitz C. Teeeer S. ESSODR. Skoularieis J, Cromje S, Saudi P. A case for early surgery in nativeleft sided ehdo&ditis cc& plicated by heart failure: results in 203 patients. JAm Coil Cardiol 1991;18:663-667. 2. Croft CH, Woodward W, Elliot A, Commerfoni PJ, Barnard CN, Beck W. Analysis of surgical versus medical therapy in active complicated native infective endocarditis. Am J Cardiol 1983;51:165&1655. 4. Richardson IV, Karp RB, Kirklin JW, Dismukes WE. Treatment of infective endcaniitis: a 10 years comparative analysis. Circulation 1978;58:58%599. 5. St&on EB. Surgical treatment of infective endocarditis. Prog Cardiovasc Dis 1979;22: 145-168. 8. Witchitz S, Reguier B, Wolff M, Rouveix E, Laisue MJ. Surgery in infective endocaniitis. Eur Hearr J 1984;5(suppl C):87-91. 7. David TE, Bos J, Cbristakis GT, Brofman PR, Wang D, Feindel CM. Heart
valve operations in patients with active infective endocarditis. Ann Thorac Surg 1990;49:701-705. 6. Kiiose HH, Lund 0, Kromann-Hansen 0. Risk factors for early and late outcane after surgical treatment of native infective endccarditis. Stand J Thor Cardiovasc Surg 1990,24: 11 l-120. 9. Wilson WR, Danielson GK, Giuliani ER, Washington JA, Jaumin PM, Geraci JE. Cardiac valve replacement in congestive heart failure due to infective endocarditis. Mayo Clin Proc 1979;54:22>226. 10. van Reyn CF. Ley BS, Arbeit RD. Friedland G, Cmmpacker CS. Infective endocarditis: an analysis based on strict case definitions. Ann Intern Med 1981;94: 505-518. 11. van der Mea JTM, van Wijk W, Thompson J, Vandenbrottcke JP, Valkenburg HA Epidemiology of bacterial endocarditis in the Netherlands. Patients characteristics. Arch Intern Med 1992;152:1863-1868. 12. Kaye D. Changing pattern of infective endcaditis. Am J Med 1985;78(suppl 6B):157-162. 12. Ma&t&i V, Samdarian W, Etienne J, Milan H, Del&aye JP. Prognosis of native valve infective endocarditis: a review of 253 cases. Eur Heart J 1984,5(suppl C): 1l-20. 14. Mill I, Utley J, Abbot I. Heart failure in infective endocarditis: predisposing factors, caxse and treatment. Chesf 1974;66:151-157. 15. Dinuble MJ. Surgery in active endocaditis. Ann Infern Med 1982;96:650-659. 16. Tomes MF’, Permanyer-Miida G, Olona M, Gil M, G&e E, Almimtue B, Soler Soler J. Longterm complications of native valve infective endocarditis in non addicts. A 15 year follow up study. Ann Intern Med 1992;117:567-572. 17. Okies El, Bradshaw MW, Williams TW. Valve replacement in bacterial endocarditis. Chesr 1973;63:898-904.
MANAGEMENTOF ACTIVE INFECTIVEENDOCARDITIS 687
E
ven in 1993, with therapeutic options including modern antibiotic treatmentand early surgical intervention, infective endocarditis remains a lifethreatening disease.Many studies have shown that optimal timing of surgical intervention is of paramount importance to decrease the mortality rate, especially if infective endocarditis is complicated by heart failure.t-9 However, few studies have reported on all patients with active infective endocarditis who received either medical or medical-surgical therapy.3,4We reviewed our experience with treatment of all patients with the diagnosis of active infective endocarditis during a 25year period, using the strict case criteria of von Reyn et aLlo The onset of complications that could not be managed medically resulted in urgent surgical intervention. The purpose of the study was to perform an analysis of factors affecting outcome, and to analyze the short- and long-term results of the managementstrategy described.
and long+nn folloWp of 13Oconsecutivepatients (141episodes)wlthao tive infective endocatditis who were treated be tween1966 and 1991wereanalymd.Therewas a shiitowardahlgherproportlonofre+ferredpa tlents (39 to 75%), patlents aged MO years (11 to 41%) and urgent surgical treatment (11 to 44%). Medical treatment was administered In 95 pa tlents (70%); 30day mortalll was 27%. Surgery was pmfoaed in 43 patients (30%), wlth an m alive mortalll of 26%; 9 of 14 patients (54%) who underwent operation within the first week of a& mission died. Patients with severe heart failure are at the hll rlslc for ealy mortality (relative risk = 21.1; 95% confidence interval 7.4-50.3). Re ferred patients were much mare often treated sup gically than were nonrefelmd patii (45 versus 14%) and had a lower operative mortality (24 vs 30%). Nonrefemed patients were more often treated medically (55 vs 52%) and with lower mortalii (19 vs 39%). The total followup time was 730 pa tbnt-yearq only 1 patient was considered lost to followup. The overall cumulative 5year and 10 year survival after hospital discharge for patients afterurgentsurgerywere84~7%and53~7%, respectively, and for those after medical trea+ merit 64 h 5% and 77 -c 6%, respectively. lhe probability of remaining free of late events (recurrent endocaiditis, late valve replacement or death) during 5 and 10 years for patients after urgentsurgerywas64-t 7%ti53 *15%,respet+ tively, and for those after medical treatment 59 -c 6% and 40 f 7%, respectively. In the tirst year after hospital discharge, the incidence of late events was high, especially in patients who m ceived only medical treatment. Although urgent surgery has improved the outlook for some ps tlent groups, early mortality did not decrease significantly owing to a shii toward more comm mised cases. (Am J Cardiol1993;72:552-557) The clinical a&come
MmHODS
From the Departments of Cardiology and Cardiopulmonary Surgery, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. Manuscript received October 30, 1992; revised manuscript received May 17, 1993, and accepted May 20. Address for reprints: Hans A. Verheul, MD, Department of Cardiology, Academic Medical Center, F4 109, Meibergdreef 9, 110.5 AZ Amsterdam, the Netherlands.
682
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
study #oup: All consecutivepatientswith a diagnosis of active infective endocarditis treated from 1966 to 1991at the cardiology departmentof a university hospital (with both referral and primary care patient populations) were included in the study. Patients with endocarditis of a valve prosthesiswere excluded. Deflnltions: Detinite, probable and possible episodes of infective endocarditis, according to the criteria of von Reyn et al,1° were analyzed.Definite episodeswere continned by histology from surgery or autopsy material, or by Gram stain or culture of an endocardial vegetationor peripheral embolus. Probable episodeswere defined as: (1) persistently positive blood cultures with growth of the same microorganism and a new/changing murmur, or predisposing heart diseasewith vascular phenomena (e.g., petechiae,splinter hemorrhages,Roth spots,Osler’s nodes, emboli, and so forth); or (2) negative or intermittently positive blood cultures (~70% positive) with fever, a new regurgitant murmur and vascular phenomena. Possible episodes were detined as: (1) persistently positive blood cultures with growth of the same microorganism, and known predisposing heart diseaseor vascular phenomena; or (2) negative or intermittently positive blood cultures(~70% positive) with fever,known predisposing heart diseaseand vascular phenomena.Infective endocarditis was arbitrarily detined as active if the patient had not completed a 4-week standardcourse of antibiotic treatment at the time of admission to the hospital or at the tune of operation.7Medical treatment consisted of organism-specific intravenous antibiotics during 4 to 6 weeks, which were selectedin most cases
SEPTEMBER15.1993
on the basis of in vitro susceptibility tests. In culturenegative endocarditis, empiric regimens were used (vancomycin and streptomycin). Surgical treatment was considered in all patients with refractory congestive heart failure, 22 systemic emboli, uncontrolled infection and development of heart block (except fist-degree atrioventicular block). The degree of congestive heart failure was defined as follows: moderate heart failure was characterized by physical signs of congestion that responded to administration of diuretics or digoxin, or both. Severeheart failure (New York Heart Association class IV) was characterized by similar findings sometimes accompanied by hypotension, which did not respond to intravenous administration of diuretics, digoxin and positive inotropics. Systemic embolization was defined as an acute occlusion of a major artery resulting in a cerebrovascularaccident or loss of peripheral pulses. Uncontrolled infection was characterizedby positive blood cultures or persistent high fever 1 week after beginning proper antibiotic treatment. Urgent surgery was defined as surgery performed before completion of antibiotic treatment. Death within 30 days after admission (medical treatment) or operation (surgical treatment) was defined as early mortality. In the multivariate analysis, death within 3 months after admission was used as the end point for early mortality. Late mortality was defmed as death after 3 months. Relapsing endocarditis was delined as persistent infection after termination of antibiotic treatment after a complete course (with or without surgery). Recurrent endocarditis was defined as a new episode of endocarditis (not necessarily due to a different organism) after documented curative therapy. Clinical data: All casesidentified as infective endocarditis were reviewed by protocol and processedin a structured data base. Clinical history, signs and symptoms on admission, treatment, clinical course, complications and follow-up were analyzed.Functional class was determined according to the criteria of the New York Heart Association. The site of infection was determined by physical examination and supported by findings at echocardiography,surgery or autopsy.Autopsy was performed in 68% of patients who died in the hospital. Followup: Data on outcome after discharge and the clinical status at the end of follow-up were obtained from outpatient clinical records of the attending cardiologist or general practitioner, or both. The end of the follow-up period was January 1, 1991.Only 1 patient was considered lost to follow-up. The total follow-up time was 790 patient-years; mean follow-up time was 8.7 years (range 0.3 to 23.5). StatIstical analysis: Values are expressedas mean f SD. Differences between proportional variables were tested with &i-square test and between continuous variables with Student’s t test. A logistic regression analysis procedure was used for multivariate analysis of 3month mortality. Cumulative survival and event-free periods were estimated by the Kaplan-Meier method. The covariates (potential risk factors or determinants) were dichotomized and entered in the model as indicator variables for which the value of 0 or 1 was assigned.To adjust for overall change of treatment and patient selection, we divided the study period into “early” (1966 to
TABLE I Characteristics of 130 Consecutive Patients with 141 Episodes of Active Infective Endocarditis Nonreferred Patients Number of cases Men Mean age (years) (range) > 60 years von Reyn classification Definite episode Probable episode Possible episode Prior endocarditis Microorganism Staphylococcus Streptococcus Other Culture negatwe Unknown Sate of infection Aortic valve Mitral valve Aortic and mitral valves Other site* Emboll Systemic Cerebral Heart failure Severe
Referred Patients
All Patients
91(100%) 63 164%) 43 (18-76) 19 (21%)
50 (100%) 41(82%) 48 (19-77) 17 (34%)
141(100%) 104 (74%) 45 (18-77) 36 (25%)
37 (41%) 34 (37%) 20 (22%) 15(16%)
35 (70%) 12 (24%) 3 (6%) 0
72 46 23 15
(51%) (32%) (16%) (11%)
13 67 2 6 3
12 29 4 5 0
(24%) (58%) (8%) (10%)
25 96 6 11 3
(18%) (68%) (4%) (8%) (2%)
36 140%) 26 (29%) 15 (16%) 14(15%)
28 (56%) 15 (30%) 7 114%) 0
64 41 22 14
(45%) (29%) (16%) (10%)
18 17 55 21
13 15 42 23
31 26 99 44
(22%) (18%) (69%) (31%)
(14%) (74%) (2%) (7%) (3%)
(20%) (19%) (60%) (23%)
(31%) (30%) (86%) (46%)
*Includes ventricular septal defect (n = 8). aortic coarctation Fall& (n = 21, and tricuspid valve (n = 2).
(II = 2). tetralogy
of
1978) and “current” (1979 to 1991) periods of treatment. The following indicator variables were tested: gender,age, referral, improper initial antibiotic treatment before admission in our center, preexistent cardiovascular status, recurrent endocarditis, microorganism (staphylococcus or other), site (aortic valve or other), heart failure (severe or moderate/none)and major emboli. A significance level of 0.05 was used in all tests. The multivariate analysis was performed with the BMDP package. RESULTS Patient characteristics From 1966 to 1991, 141 casesof active infective endocarditis were diagnosed in 130patients. Of these cases,91 originated from our hospital, and 50 were referred from other hospitals. Selected clinical characteristicsof the study population are summarized in Table I. In 59% of patients, a murmur or cardiac lesion was known before admission, but only 23% were symptomatic or already consulting a cardiologist. Before hospitalization, 28% of patients had not received antibiotic treatment, and 30% were already using antibiotics without preceding blood cultures; the remaining patients (42%) used antibiotics guided by preceding blood cultures. The aortic valve was more often the site of the infection than was the mitral valve. Severe heart failure occurred more often in aortic valve (45%) than in mitral valve (12%) endocarditis. Transthoracicechocardiographywas performed since 1975in 99 cases.Vegetationswere found in 70% of native aortic valve endocarditis and in 48% of native mitral valve endocarditis. In this population, 32% of cases with echocardiographicaIly demonstratedvegetations on MANAGEMENT OF ACTIVE INFECTIVE ENDOCARDITIS
683
the aortic valve sustained 21 systemic embolus versus 67% with vegetations on the mitral valve. Embolic events occurred in 26% of patients without echocardiographically detectablevegetations.Periannular abscesses were found in 11% of patients. Pericardial effusion was observed in 9% of all cases; there was no association with the presenceor development of conduction disturbances. Rend over time: In comparingthe periods 1966-1971 and 19861991, the proportions of referred patients (39 vs 78%), patients aged %O years (11 vs 41%) and those who underwent urgent surgical treatment (11 vs 44%) increased. TREAT Medical treatment alone was administered in 98 cases (70% of study population). Surgical treatment of active infective endocarditis was introduced
TABLE II Treatment
Patient
Characteristics
of Medical
Versus
Surgical Treatment
Medical Treatment Number of cases Men Mean age (years) (range) > 60 years Microorganism Staphylococcus Streptococcus Others Culture negative Unknown Site of infection Aortic valve Mitral valve Aortic and mitral valve Other site* Severe heart failure
98 66 44 25
Surgical
(70%) (66%) (18-77) (25%)
43 (30%) 38 (86%) 45 (19-71) 11(26%)
4 (4%) 4 (4%) 2 (2%)
8 (19%) 25 (58%) 2 (5%) 7 (16%) 1 (2%)
29 (30%) 35 (36%) 20 (20%)
35 (81%) 6 (14%) 2 (5%)
17 (17%) 71 (72%)
14 (14%)
0
22 (22%)
22 (51%)
‘See Table I.
in our center in 1969 and was performed in 43 cases (30%), of which 14 (32%) underwent operation within the tirst week of admission. The mean and median intervals between admission and surgery were 24 and 15 days, respectively.In the total study group, 55% of cases with aortic valve and 15% with mitral valve endocarditis underwent surgical treatment. Urgent surgery was performed in 48% of referred patients, who constituted 77% of the entire group that underwent urgent surgery. Annular abscessesor fistulae (extensive disease), or both, were present in 18% of all operated patients and in 36% of those who underwent operation within the first week after admission. The indications for surgery were: severe heart failure (pulmonary congestion, low output) in 33 cases(77%), systemic emboli in 3 (7%), uncontrolled infection in 2 (5%) and conduction defects in 5 (12%). Table II lists selectedclinical characteristics of medically and surgically treated patients. EARLY MORTALITY: overall early mortality (30 days) was 26%. The mortality of medically treated patients was 27% after 1 month and 29% after 3 months. Causes of death in medically treated patients were: severe heart failure and cardiogenic shock (n = 13), acute intractable rhythm disturbances (n = 6), major cerebral emboli (n = 5) ruptured cerebral mycotic aneurysms (n = 2) disseminated intravascular coagulation (n = l), and bleeding esophageal vat-ices (n = 1). The reasons that the group with severeheart failure was denied surgical treatment were: the limited experience with surgical treatment of active infective endocarditis before 1970 (n = 3), advancedor multivalve endocarditis (n = 3), preexistent paraplegia with decubitus (n = l), recurrent endocarditis in a drug addict (n = l), and sudden hemodynamic deterioration resulting in a moribund state before surgery could be attempted(n = 5). The operative mortality was 26% after 1 month and 30% after 3 months. The operative mortality of patients who underwent operation within the tirst week of ad-
Cl alive/M
q alive/S
subgroup AV MV
q n
60+ 60-
Staph Strep
male female ref nonref 1966-76 1979-91 0%
25%
50%
75%
100%
% of cases 664
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
SEPTEMBER15,1993
dead/S dead/M
FIGURE 1. oetcomeof~ the infective edocadh after3monfbforsoma sub#eupe.AV=amtk valvq HF = heart fake; M=lblddW Mv=mitralvalve;Mnuef= llOMhTdmd= refemdpathmfqsmau~
mission to our hospital was very high (9 of 14; 64%). When surgery was performed in the second week after admission, mortality decreasedto 0 of 5 patients and in the third week to 1 of 6. Causesof operative death were heart failure (n = 7), intractable arrhythmias (n = l), intractable bleeding (n = l), dehiscence of the prosthetic valve (n = l), new fistula (n = l), ischemic bowel infarction (n = l), and ongoing sepsis(n = 1). Mortality in surgically treated patients with extensive disease was 62% compared with 20% in those without annular abscessesor fistulas, or both. Logistic regression analysis marked heart failure as an independent determinant of mortality within 3 months after admission. The early mortality of patients with severe heart failure was 68% (relative risk [RR] 21.1; 95% confidence interval [CI] 7.4-60.3) compared with those without severeheart failure. The outcome for some subgroups 3 months after hospital admission is shown in Figure 1. Patients with heart failure were at high risk for urgent surgery or death, or both (RR 47.6; 95% CI 9.1-249.0), as were referred patients (RR 4.8; 95% CI 1.8-12.8) and those with aortic valve endocarditis (RR 3.0; 95% Cl 1.7-14.3). Late mortalii and survival: In all, 91 patients with 101 cases of active infective endocarditis survived the hospital phase.During follow-up, 29 (29%) of these patients died. A cardiac cause of death was present in 13 patients (heart failure [n = 81 and sudden death with or without prior documented arrhythmias [n = 51); other causes of death were cerebrovascular accident (n = 2), malignancy (n = 2), and unknown (n = 12). The firstyear mortality was 6.6%. The cumulative 5- and lo-year survival for all hospital survivors were estimated at 84 + 4% and 72 f 6%, respectively.Figure 2 shows the cu-
mulative survival after discharge for patients with and without urgent surgery. Late mo&idfQr After hospital dischargeof 60 medically treatedpatients, readmittancefor valve replacement was necessary in 17 (28%), relapsing endocarditis occurred in 1, and recurrent endocarditis occurred in 10. Most of these events (2 recurrent endocarditis and 10 valve replacements)occurred in the first year after hospital admission. After discharge of 31 surgically treated patients, only 1 had recurrent endocarditis and died after surgery,and 1 had a strut fracture of a Bjork Shiley convex-concave aortic prosthesis. The probability of remaining free of late events (recurrent endocarditis, late valve replacement or death) during 5 and 10 years for all patients was 84 + 7% and 53 f 15%, respectively. Figure 3 shows the event-free period after discharge for patients with and without urgent surgery. At the end of follow-up, 64 patients were alive, of whom 45 were without recurrent endocarditis or valve replacement.Only 33 of these 45 patients were without any cardiac complaints.
DISCUSSION The incidence of native valve endocarditis in the Netherlands today is 15 per one million inhabitants annually.’ i This study reviews our experience with both medical and medical-surgical treatment of all consecutive patients with active infective endocarditis in a tertiary referral center with a large outpatient clinic during a 25-year period (1966 to 1991).Only 1 patient was lost to follow-up. In comparing the first and last 5-year periods, there was a shift toward a higher proportion of referred patients, a higher proportion of patients aged >60
% of patients % of patients
80 -
60 -
+ Medical
therapy
* after Surgery
5
10
years after discharge years after discharge
MANAGEMENT OF ACTIVE INFECTIVE ENDOCARDITIS 685
years, and a marked increase in urgent surgery. Similar shifts have been observed in other western populations, which were probably mainly due to the impact of surgical treatment and aging of the population.10J2The number of drug addicts in our series was relatively low; most of these patients are cared for elsewhere,and with a few exceptions,they are not considered candidatesfor surgery. Infective endocarditis has a grim prognosis. Overall mortality in this study was high, and late outcome shows limited prospects for most patients to be free of recurrent endocarditis, valve surgery or death. During the study period, the management strategy was such that complications that could not be managed medically resulted, when possible, in urgent surgical intervention. In the medically treated group, mortality after 1 month was 27% and in the surgically treated group 26%, which is somewhathigher than the case-fatality of 20% reported from a nationwide prospective epidemiologic study performed in the Netherlands during a 2-year period (1986 to 1988).’t This was probably due to selection of severely compromised cases referred to our tertiary referral center. The referred patients in our study population were older, more often had staphylococcus and aortic valve endocarditis, and their clinical course was complicated more frequently by heart failure and emboli. Mortality in medically treated patients with severe heart failure was very high (68% at 1 month, and 93% at 3 months), which is in agreement with the litera~I.E.~J~~~The reasons that patients with severe heart failure were denied surgical treatment were: treatment before 1970, a severely compromisedphysical or hemodynamic condition before onset of infective endocarditis, and sudden hemodynamic deterioration. The IO-year survival after medical treatment was good (77 + 6%), which is in accordancewith the lindings of other investigators.GW However, these patients had many adverse events. Valve replacement was performed mainly witbin the tirst year after hospital discharge, whereasrecurrent endocarditis occurred later. At the end of follow-up, only 13 medically treated patients (13%) were alive without late valve replacement,recurrent endocarditis or physical restraints (New York Heart Association class I or II). Patients most likely to be cured and to remain event-tree by medical treatment alone for 25 years were those with streptococcalendocarditis of the native mitral valve or ventricular septal defect. In the past 25 years, cardiac surgery has become increasingly important in the treatment of endocarditis. In the present series, the percentage of surgically treated patients with active infective endocarditis increasedfrom 11to 44%. In reports on surgical treatment of active infective endocarditis, there are considerabledifferencesin early mortality (0 to 47%).1-10~13-15J7 This may be due to differencesin casedefinitions (only a few studiesused the strict criteria of von Reyn et allo), and in the preoperative hemodynamic statusand age of patients. In addition, differences in mortality in surgical treatment of active infective endocarditis may be due to the inability to remove all infected tissuesand restorevalve function? Many investigators found a trend of early surgical in666
THE AMERICANJOURNALOF CARDIOLOGY VOLUME72
tervention to be superior to medical treatment, especially in patients with congestive heart failure, persistent sepsis and major emboli. However, a randomized controlled trial of consecutive patients to resolve the issue of early surgery versus medical therapy of active infective endocarditis has not been performed. Therefore, optimal timing of surgical intervention remains a therapeutic dilemma. If surgery is performed too early, some patients, who would have recovered with antibiotics only and without any complications, will be subjected to the risks of surgery and to the morbidity associated with a valve prosthesis. However, the occurrence and progression of complications such as congestive heart failure, major systemic emboli and uncontrolled infection (which may have been preventedby early surgery) are difficult, if not impossible, to predict, and will increasethe risk of surgery,or in the worst case, the patient may die before surgery can be perfom-ted.In the present series,there was a very high mortality in patients who underwent operation within the first week of admission (64%) as compared with the second and third weeks. The main causeof death in patients who underwent operation in the first week after admission was severe heart failure. There was a remarkable difference in the treatment modalities and outcomesof referred and nonreferred patients. Referred patients were treated surgically much more often than were nonreferred ones (48 vs 14%) and had a lower operative mortality (24 vs 30%). Nonreferred patients were treated medically more often than were referred ones (86 vs 52%) and had a lower mortality (19 vs 39%). Referred patients represent the typical case selection known from the literature, originating from tertiary referral centers with cardiac surgery facilities. In previous studies, results were biased by the often severely compromised referred patients who benefit most from urgent surgery. The experience of the cardiologist (before referral), which incorporates many lowrisk cases,appearsto be quite the opposite. Therefore, studies reporting on treatment of infective endocarditis, which are performed in tertiary referral centers with an outpatient clinic should mention the proportion of referred patients, becausethis may have a profound effect on outcome. Study limhtions The results should be interpreted in regard to the retrospective nature of the study. In many cases,we had to rely on clinical information obtained by physicians other than those directly involved in the study. Comparison of subgroupsin a retrospective study is hazardousbecauseof the potential dissimilarity of patient characteristicsand treatment modalities between groups. In the past 25 years, important advances have been made in medical treatment, diagnosis (echocardiography) and cardiac surgery (increasedexperience with complex surgical procedures, and improved myocardial preservation), which have intIuenced outcome. Conclusionr In the past 25 years, the appearanceof infective endocarditis has profoundly changed due to aging of the population and to the introduction of heart valve surgery. However, mortality of infective endocarditis did not decreaseas much as would be expected with improved treatment owing to an increasing propor-
SEPTEMBER15,1993
tion of seriously ill patients who were considered beyond any possible cure in the past, but are now referred to centers with cardiac surgery facilities. After hospital discharge the incidence of late events is high, especially in patients who received only medical treatment.
1. D’Agostino RS, Miller C. Stinson EB, Mitchell RS, Oyer PE, Jam&on SW, Baldwin JC, Shumway NE. Valve replacement in patients with native valve endocarditis, what really determines operative outcome? Ann Thorar Surg 1985;40: 429-438. 2. Middlemost S, Wisenbaueh T. Meverowitz C. Teeeer S. ESSODR. Skoularieis J, Cromje S, Saudi P. A case for early surgery in nativeleft sided ehdo&ditis cc& plicated by heart failure: results in 203 patients. JAm Coil Cardiol 1991;18:663-667. 2. Croft CH, Woodward W, Elliot A, Commerfoni PJ, Barnard CN, Beck W. Analysis of surgical versus medical therapy in active complicated native infective endocarditis. Am J Cardiol 1983;51:165&1655. 4. Richardson IV, Karp RB, Kirklin JW, Dismukes WE. Treatment of infective endcaniitis: a 10 years comparative analysis. Circulation 1978;58:58%599. 5. St&on EB. Surgical treatment of infective endocarditis. Prog Cardiovasc Dis 1979;22: 145-168. 8. Witchitz S, Reguier B, Wolff M, Rouveix E, Laisue MJ. Surgery in infective endocaniitis. Eur Hearr J 1984;5(suppl C):87-91. 7. David TE, Bos J, Cbristakis GT, Brofman PR, Wang D, Feindel CM. Heart
valve operations in patients with active infective endocarditis. Ann Thorac Surg 1990;49:701-705. 6. Kiiose HH, Lund 0, Kromann-Hansen 0. Risk factors for early and late outcane after surgical treatment of native infective endccarditis. Stand J Thor Cardiovasc Surg 1990,24: 11 l-120. 9. Wilson WR, Danielson GK, Giuliani ER, Washington JA, Jaumin PM, Geraci JE. Cardiac valve replacement in congestive heart failure due to infective endocarditis. Mayo Clin Proc 1979;54:22>226. 10. van Reyn CF. Ley BS, Arbeit RD. Friedland G, Cmmpacker CS. Infective endocarditis: an analysis based on strict case definitions. Ann Intern Med 1981;94: 505-518. 11. van der Mea JTM, van Wijk W, Thompson J, Vandenbrottcke JP, Valkenburg HA Epidemiology of bacterial endocarditis in the Netherlands. Patients characteristics. Arch Intern Med 1992;152:1863-1868. 12. Kaye D. Changing pattern of infective endcaditis. Am J Med 1985;78(suppl 6B):157-162. 12. Ma&t&i V, Samdarian W, Etienne J, Milan H, Del&aye JP. Prognosis of native valve infective endocarditis: a review of 253 cases. Eur Heart J 1984,5(suppl C): 1l-20. 14. Mill I, Utley J, Abbot I. Heart failure in infective endocarditis: predisposing factors, caxse and treatment. Chesf 1974;66:151-157. 15. Dinuble MJ. Surgery in active endocaditis. Ann Infern Med 1982;96:650-659. 16. Tomes MF’, Permanyer-Miida G, Olona M, Gil M, G&e E, Almimtue B, Soler Soler J. Longterm complications of native valve infective endocarditis in non addicts. A 15 year follow up study. Ann Intern Med 1992;117:567-572. 17. Okies El, Bradshaw MW, Williams TW. Valve replacement in bacterial endocarditis. Chesr 1973;63:898-904.
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