Documente Academic
Documente Profesional
Documente Cultură
5, 2003
© 2003 by the American College of Cardiology Foundation ISSN 0735-1097/03/$30.00
Published by Elsevier Inc. doi:10.1016/S0735-1097(03)00829-5
Infective endocarditis (IE) is a serious medical condition resolution of vegetation, thus reducing the embolic rate
that carries high mortality and morbidity (1–3). Although (14,15). A favorable effect of aspirin on clinical outcome was
many patients respond favorably to medical treatment, the also suggested by a small observational study (16). The
course of the disease may be complicated by valvular objective of the present study was to determine the effect of
destruction, abscess formation, embolism, and heart failure. aspirin on the frequency of embolic events in patients who
had native or prosthetic valve endocarditis but no evidence
See page 781 of perivalvular abscess.
Table 1. Clinical Features of Randomized Patients With Left- Table 2. Results of Investigations of Randomized Patients With
Sided Infective Endocarditis Left-Sided Endocarditis
Aspirin Placebo Aspirin Placebo
(n ⴝ 60) (n ⴝ 55) (n ⴝ 60) (n ⴝ 55)
Age (yrs) 54.9 ⫾ 14.7 56.9 ⫾ 16.7 Hemoglobin (g/l) 116.5 ⫾ 22.0* 113.4 ⫾ 20.5†
Women 16 (26.7) 15 (27.3) Platelets (109/l) 234.3 ⫾ 132.0 235.1 ⫾ 145.1†
Prosthetic valve 10 (16.7) 14 (25.5) Positive blood culture 57 (95) 49 (89.1)
Pre-existing native valve disease 38 (63.3) 34 (61.8) Staphylococcus aureus 14 (25) 16 (32.7)
Anticoagulation therapy 13 (21.7) 13 (23.6) Streptococcus viridans 19 (33.9) 18 (36.7)
Previous endocarditis* 4 (20) 6 (26.1) Other streptococci 7 (12.5) 8 (16.3)
Dental procedure within 12 weeks 12 (20) 10 (18.2) Enterococci 9 (16.1) 2 (4.1)
Intravenous drug use 5 (8.3) 9 (16.4) Coagulase-negative staphylococci 2 (3.6) 2 (4.1)
Symptom duration (days) 34.5 ⫾ 48.3 33.5 ⫾ 54.3 Others 5 (8.9) 3 (6.1)
Vegetation by transthoracic
*Based on 20 patients in the aspirin group and 23 patients in the placebo group. Data
are presented as the mean value ⫾ SD or number (%) of patients. echocardiography
Aortic valve 19 (31.7) 13 (23.6)
Mitral valve 10 (16.7) 13 (23.6)
would reduce the embolic rate by 8.58% (33% relative
Vegetation by transesophageal
reduction). To observe this difference, 184 participants had echocardiography
to be randomized to each intervention group (type I error Aortic valve‡ 22 (41.5) 23 (46)
rate of 5% [two-sided]; type II error rate of 20%). The trial Mitral valve§ 30 (57.7) 21 (42)
was designed and statistically powered to incorporate an *Data available for 59 patients. †Data available for 54 patients. ‡Based on 53 patients
interim analysis performed by a Data Safety and Monitoring in the aspirin group and 50 patients in the placebo group. §Based on 52 patients in
the aspirin group and 50 patients in the placebo group. Data are presented as the mean
Committee. In view of the low enrollment, an interim value ⫾ SD or number (%) of patients.
analysis was not performed. The Data Safety and Monitor-
ing Committee was informed of all major adverse events, Outcome events. The overall embolic rate was 29% for the
such as cerebral hemorrhage. entire group, including both randomized and nonrandom-
Data analysis. An intention-to-treat approach was used to ized patients. The primary and secondary outcome events
analyze the data. Odds ratios (ORs) and measures of between the two groups are shown in Table 3. There were
precision (i.e., 95% confidence intervals [CIs]) were com-
no differences between the two groups in the primary
puted on all primary and secondary outcome data (23).
outcomes of clinical embolic events or intracranial hemor-
Statistically significant intervention differences were consid-
rhage. Clinical embolic events occurred in 17 patients
ered at the 5% level (two-sided). Descriptive statistics were
(28.3%) on aspirin and 11 patients (20.0%) on placebo (OR
generated for each intervention group. Differences in clin-
ical embolic event rates and cerebral hemorrhage between 1.62, 95% CI 0.68 to 3.86, p ⫽ 0.29). The central nervous
the two intervention groups were assessed using contin- system was the site of embolization in eight patients on
gency table analyses. A preliminary examination of each aspirin and three patients on placebo. Overall bleeding,
valve stratum, using the Mantel-Haenzel approach, revealed including major or minor episodes, was higher (p ⫽ 0.075)
no statistical differences in any outcome (all p values ⬎0.5). in the group that received aspirin (n ⫽ 17 [28.8%] vs. 8
Secondary outcomes were evaluated in a similar manner, [14.5%]; OR 1.92, 95% CI 0.76 to 4.86). Similar numbers
using the chi-square or Student t test, depending on the of patients in both groups underwent valve surgery. The
scale of measurement. duration of fever on treatment was also similar between the
two groups. Similar findings were obtained when only
RESULTS patients with native valve endocarditis were analyzed.
Cerebral computed tomograms were obtained in 84
During the four-year study period, 115 patients with left-
patients at the end of therapy (43 in the aspirin group and
sided endocarditis were randomized into the trial, compris-
41 in the placebo group). There were no differences in
ing 91 patients with native valve endocarditis and 22
patients with prosthetic valve endocarditis. In the 398 intracerebral abnormalities between the two groups (Table 4).
patients who did not meet the inclusion criteria, the reasons Effect on vegetation. The effects of antibiotic treatment on
were the need for cardiac surgery in the next seven days (n the evolution of vegetation and valvular regurgitation were
⫽ 105), already on aspirin (n ⫽ 90), right-sided endocar- evaluated by serial transesophageal echocardiography at
ditis (n ⫽ 66), recent or acute stroke (n ⫽ 65), perivalvular baseline and after four weeks of treatment in 46 patients (23
abscess (n ⫽ 38), and bleeding diathesis (n ⫽ 34). Sixty patients each on aspirin or placebo) (Table 5). The vegeta-
patients were randomized to receive aspirin and 55 patients tion diminished in size in both groups of patients and to
were randomized to placebo. Their clinical characteristics are similar degrees. Both absolute changes and percent changes
shown in Table 1, and the results of laboratory investigations were no different between the groups. The severity of
are shown in Table 2. Staphylococcus aureus and Streptococcus valvular insufficiency was also similar between the two
viridans were common pathogens in both groups. groups at both time points.
778 Chan et al. JACC Vol. 42, No. 5, 2003
Aspirin on Embolic Events in Endocarditis September 3, 2003:775–80
Table 5. Evolution of Vegetation Size and Valvular Regurgitation in Patients With Endocarditis
After Four Weeks of Treatment
Aspirin (n ⴝ 23) Placebo (n ⴝ 25)
Baseline Follow-Up Baseline Follow-Up
Number of vegetations 1.61 ⫾ 0.58 1.50 ⫾ 0.60 1.65 ⫾ 0.93 1.68 ⫾ 0.99
Size of vegetation*
Width (mm) 5.6 ⫾ 2.4 4.6 ⫾ 2.2‡ 4.5 ⫾ 2.6 3.6 ⫾ 2.2‡
Length (mm) 11.4 ⫾ 6.1 9.6 ⫾ 3.9‡ 9.8 ⫾ 5.2 8.8 ⫾ 5.1‡
Area (mm2) 61.6 ⫾ 44.2 43.3 ⫾ 30.6‡ 45.9 ⫾ 50.2 35.9 ⫾ 37.5‡
Severity of valvular regurgitation† 2.42 ⫾ 1.10 2.42 ⫾ 1.10 2.42 ⫾ 1.21 2.54 ⫾ 1.22
*In patients with multiple vegetations, the dimensions of each vegetation were measured and entered as individual data points.
†The grading system for valvular regurgitation was as follows: 0 ⫽ no regurgitation; 1 ⫽ mild; 2 ⫽ moderate; 3 ⫽ moderately
severe; and 4 ⫽ severe. ‡p ⬍ 0.05 compared with baseline values. Data are presented as the mean value ⫾ SD.
uation of anticoagulation (18), and the risk of excessive rates could be similar in both intervention groups. The lack
bleeding associated with the combined use of anticoagulants of a salutary effect of aspirin in these patients was collabo-
and aspirin in patients with mechanical heart valves has rated by the observations regarding the cerebral abnormal-
been reported to be quite modest (36,37). The increased risk ities on computed tomograms and vegetation resolution on
of bleeding with aspirin was observed in patients with native serial transesophageal echocardiograms, which were similar
and prosthetic valve endocarditis. The sample size does not between the treatment groups.
allow an assessment of the differential effects of aspirin in Conclusions. In stable patients with endocarditis without
native versus prosthetic valve endocarditis. perivalvular abscess, the addition of aspirin (325 mg) to
This study only assessed the effect of aspirin during the antibiotic treatment does not appear to reduce the embolic
acute phase of endocarditis, and the long-term effect on risk, but may increase the risk of bleeding. Aspirin also does
outcomes was not determined. We believe this is appropri- not reduce the development of cerebral lesions nor enhance
ate, as embolic events occurred almost exclusively early in vegetation resolution. Thus, aspirin is not indicated in the
the course of the disease (5). The average duration from early management of patients with IE.
symptom onset to presentation was about one month, and
this may explain why most of the embolic events occurred Acknowledgments
early during hospitalization (5). Whether the use of aspirin We thank the investigators at all the participating sites for
shortly after symptom onset may have different effects patient recruitment and Isabelle Gaboury, MSc, for her
remains to be determined. It is plausible that aspirin may statistical expertise in helping revise the manuscript.
have a salutary effect if used earlier in the course of the
disease. The manifestations of endocarditis are protean, and Reprint requests and correspondence: Dr. Kwan-Leung Chan,
prompt diagnosis is difficult. Most patients with endocar- University of Ottawa Heart Institute, 40 Ruskin Street, Ottawa,
ditis are unlikely to be diagnosed and treated significantly Ontario, Canada K1Y 4W7. E-mail: kchan@ottawaheart.ca.
earlier than the patients in this trial.
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APPENDIX
for complications. J Am Coll Cardiol 1991;18:1191–9. The following centers and local principal investigators
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