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JOURNAL READING

ANTIBIOTICS VERSUS APENDICECTOMY FOR THE


TREATMENT OF UNCOMPLICATED ACUTE APPENDICITIS:
AN UPDATED META-ANALYSIS OF RANDOMISED
CONTROLLED TRIALS

Pembimbing: dr. Widi Antono, Sp. B.


Kent Vilandka & Ade Kurniawan
Journal
■ Title:

Antibiotics Versus Appendicectomy for the Treatment of Uncomplicated Acute Appendicitis: An Updated
Meta-Analysis of Randomised Controlled Trials

■ Writers:

Katie E. Rollins1, Krishna K. Varadhan1, Keith R. Neal2, Dileep N. Lobo1

■ Departments:

1. Gastrointestinal Surgery, Nottingham Digestive Diseases Centre, National Institute for Health
Research Biomedical Research Unit, Nottingham University Hospitals, Queen's Medical Centre, E
Floor, West Block, Nottingham, NG7 2UH, UK.

2. Department of Epidemiology and Public Health, Nottingham University Hospitals, City Hospital
Campus, Nottingham, NG5 1PB, UK.

■ Publisher: World Journal of Surgery, October 2016, Volume 40, issue 10, pp 2305–2318

■ Published Online: 19 May 2016


Abstract
■ Background

Uncomplicated acute appendicitis has been managed traditionally by early appendicectomy. However, recently, there has
been increasing interest in the potential for primary treatment with antibiotics, with studies finding this to be associated
with fewer complications than appendicectomy. The aim of this study was to compare outcomes of antibiotic therapy with
appendicectomy for uncomplicated acute appendicitis.

■ Method

This meta-analysis of randomised controlled trials included adult patients presenting with uncomplicated acute
appendicitis treated with antibiotics or appendicectomy. The primary outcome measure was complications. Secondary
outcomes included treatment efficacy, hospital length of stay (LOS), readmission rate and incidence of complicated
appendicitis.

■ Results

Five randomised controlled trials with a total of 1430 participants (727 undergoing antibiotic therapy and 703 undergoing
appendicectomy) were included. There was a 39 % risk reduction in overall complication rates in those treated with
antibiotics compared with those undergoing appendicectomy (RR 0.61, 95 % CI 0.44–0.83, p = 0.002). There was no
significant difference in hospital LOS (mean difference 0.25 days, 95 % CI -0.05 to 0.56, p = 0.10). In the antibiotic cohort,
123 of 587 patients initially treated successfully with antibiotics were readmitted with symptoms suspicious of recurrent
appendicitis. The incidence of complicated appendicitis was not increased in patients who underwent appendicectomy after
‘‘failed’’ antibiotic treatment (10.8 %) versus those who underwent primary appendicectomy (17.9 %).

■ Conclusion

Increasing evidence supports the primary treatment of acute uncomplicated appendicitis with antibiotics, in terms of
complications, hospital LOS and risk of complicated appendicitis. Antibiotics should be prescribed once a diagnosis of
acute appendicitis is made or considered.
Background

■ Uncomplicated acute appendicitis has been managed


traditionally by early appendicectomy.
■ The shift from open to laparoscopic appendicectomy has
resulted in reduced hospital length of stay (LOS), morbidity and
earlier postoperative recovery. However, there are still risks.
■ Appendicitis is a relatively common condition (9% lifetime
incidence). Only 20% of patients present with complicated
appendicitis.
■ With the large number of broad-spectrum antibiotics available
currently which may attenuate or cure the disease process,
primary antibiotic therapy is becoming increasingly attractive.
Background

■ A meta-analysis conducted by our group in 2012 on four


randomised controlled trials found that antibiotics are both
safe and effective as the primary treatment modality for
uncomplicated acute appendicitis and suggested that this
should be considered part of the therapeutic algorithm.
■ The largest RCT to date suggested that the majority of
patients treated with IV antibiotics for uncomplicated acute
appendicitis did not require subsequent appendicectomy for
recurrent appendicitis during 1-year follow-up
■ However, surgical community felt that more convincing
studies and long term results were required
Purpose

■ The aim of this meta-analysis was to update the results of our


previous meta-analysis examining the safety and efficacy
profiles of antibiotics versus appendicectomy for
uncomplicated acute appendicitis and to determine if the
strength of the recommendations of the previous meta-
analysis was improved.
Methods

■ Search for RCTs comparing appendicectomy with antibiotic


therapy in adult patients (≥ 16 years old) presenting with
uncomplicated acute appendicitis on PubMed, MEDLINE, Web of
Science, GoogleTM Scholar and the Cochrane Controlled Trials
Register  1 January 1966 until 31 July 2015
■ Keywords: antibiotics, surgery, appendicectomy, appendicectomy,
randomised controlled trial, controlled clinical trial, randomised,
drug therapy, randomly and trial in combination with Boolean
operators AND, OR and NOT.
■ The bibliographies of all studies that met the inclusion criteria
were also searched for other relevant articles and conference
abstracts to ensure that study inclusion was as complete as
possible.
Inclusion

■ Adult patients who were diagnosed with uncomplicated acute


appendicitis and randomised to treatment with either
antibiotic therapy or appendicectomy, and If the study
reported at least one relevant post-intervention clinical
outcome.
 Diagnosis of appendicitis could be made by either clinical
suspicion and laboratory analysis or imaging (ultrasound or
computed tomography)
Exclusion

■ Non-randomised controlled trials


■ Studies on paediatric patients
■ Patients with complicated appendicitis (local or contained
perforation with an appendicular mass or abscess)
Measurements

■ Primary outcome measure was post-intervention


complications.
■ Secondary outcome measures considered were primary LOS,
readmission rates and treatment efficacy.
■ Other secondary outcome measures such as pain, analgesia
requirements, incidence of post-intervention perforation and
body temperature.
Statistical Analysis

■ Forest plots using RevMan 5.3 software


■ Risk ratio with 95% confidence intervals (CI) using Mantel-
Haenszel random effects model
■ Continous variables as mean difference and 95% CI similarly
using an inverse-variance random-effects model
■ P<0.05 as significant
■ I2<25%  low heterogeneity
■ I2: 25-50%  moderate heterogeneity
■ I2 >50%  high heterogeneity
■ GRADEpro software to assess the quality of evidence for each
outcome
Results

We found 5 of the 349 studies identified in the screening process eligible for inclusion.
Two studies which met the inclusion criteria were excluded after closer review: one due to
retraction of the study following publication and one due to a lack of evidence of
randomisation.
Results

■ 5 Studies included examined the outcomes of 1430 patients,


of whom 727 received antibiotic therapy and 703 underwent
appendicectomy
Outcomes
Results

■ Complications

 All studies  There was 39% risk reduction (RR 0.61, 95% CI 0.44-0.83, p= 0.002) in
complication rates in patients treated with antibiotics when compared with those
undergoing appendicectomy

 Excluding 1 study with cross-over  risk ratio increased further (RR 0.52, 95% CI 0.36-
0.75, p=0.0005)

■ Length of stay

 All studies  no significant difference (mean difference 0.25 days, 95% CI 0.05-0.56,
p=0.10)

 Excluding 1 study with cross-over  significantly shorter LOS in appendicectomy group


(mean difference 0.39 days, 95% CI 0.18-0.59, p= 0.0003)  result of study protocols
Forest
Plot
Results

■ Treatment efficacy

 Overall treatment efficacy in the antibiotic group at 1-year follow-up was 62.6% versus
88.1% in the appendicectomy group

 Excluding 1 study with cross-over  treatment efficacy associated with antibiotic therapy
ranging from 65-75.8%

 Salminen et al.  70.4% vs 81.0%

 Vons et al. 67.5%

 Styrud et al. 75.8%

 Eriksson et al. 65%

 Hansson et al. 41.1%, possibly related to the high cross-over rates in the study
Results
■ Most recent study stipulated a 24% non inferiority margin between
the therapy modalities.
Results

■ Complicated appendicitis

 Those treated primarily with antibiotics who went on to an appendicectomy for failure of
treatment did not have a higher rate of complicated appendicitis than those who
underwent appendicectomy as the primary treatment modality (10.9% vs 17.9%)

■ Readmissions

 Antibiotics  123 of 602 patients (20.4%) were readmitted with symptoms suspicious
of recurrent appendicitis

 Of these, 120 went on to have an appendicectomy, 3 were treated successfully with a


further course of antibiotics. In those who had surgery during the follow-up period, 9
patients had normal appendix removed and 111 had evidence of recurrent acute
appendicitis.
Treatment
Outcome
Results

■ Duration of sick leave

 Salminen et al. antibiotic treatment to be associated with a significant


reduction in requirement for sick leave when compared with
appendicectomy [median 7 days (IQR 7-12) versus 19 days (14-21),
p<0.001]

 Hansson et al. significant reduction in sick leave in those treated with


antibiotics in both ITT and PP analyses [ITT mean 7 days vs 11, p<0.01;
PP 5 days vs 10, p<0.01]

 Vons et al. found no significant difference

 Styrud et al. found no significant difference


Results
■ Pain and temperature
 Salminen et al.  significantly higher median VAS pain score in appendicectomy
group at both discharge from hospital [3.0 (2-4) versus 2.0 (1-2), p<0.001] and one-
week follow-up [2.0 (1-3) versus 1.0 (1-1), p<0.001]. However, this difference had
disappeared at two-month follow-up [1.0 (1–1) versus 1.0 (1–1), p = 0.40]
 Erikkson et al.  significant decrease in pain and analgesic requirement at days 6
and 10 in antibiotic group
 Vons et al.  no significant difference in pain score between the groups [mean 2.70
(1.07) following appendicectomy versus 1.63 (1.35) in the antibiotic group]
 Hansson et al.  significantly shorter duration of pain following commencement of
intervention (6 vs. 9 days in the surgical group, <0.05)
 In the year following intervention, there was no significant difference in the number of
patients who experienced subjective abdominal pain (39 in the antibiotic group vs. 30
in the appendicectomy group)
Results
■ Pain and temperature

 Eriksson et al.  significant decrease in patient temperature


following antibiotic treatment versus appendicectomy.
Strengths of study

■ Compared with previous meta-analyses, this meta-analysis


includes one additional trial which contains the largest number
of patients (n=530) and addresses some of the major
weaknesses of previous trials.
■ Recruited patients with CT-proven uncomplicated appendicitis 
Salminen et al. and Vons et al.
■ It should however be considered that imaging modalities,
including CT, ultrasound and MRI, are poorly predictive in the
differentiation of simple and perforated appendicitis  may bias
the potential success of primary treatment with antibiotics.
■ Hospital LOS in the antibiotic group was dictated by the study
protocol which determined the patient must remain in hospital
for 72h prior to discharge for safety reasons.
GRADE Analysis
Limitation of study

■ The studies included in this meta-analysis span a 20-year period  greater


array of broad-spectrum antibiotic therapy, increasing use of CT imaging to
diagnose complicated and uncomplicated appendicitis, increasing use of
laparoscopic appendicectomy and greater emphasis on decreasing overall
LOS.
■ Route, type and timing of antibiotic administration were variable
■ Only a small number of patients underwent laparoscopic rather than open
appendicectomy
■ Method for diagnosis of appendicitis was also variable
■ Protocol for antibiotics group  prolonged LOS
■ Probability that acute uncomplicated appendicitis may resolve spontaneously
without intervention.
■ The documentation of evidence for the histological diagnosis of appendicitis
was variable.
Critical Appraisal
Judul makalah Ya/Tidak
1. Tidak terlalu panjang atau terlalu pendek Tidak, 16 kata (>12 kata)

2. Menggambarkan isi utama penelitian Ya

3. Cukup menarik Ya

4. Tanpa singkatan, selain yang baku Ya

Pengarang & Institusi Ya/Tidak


5. Nama–nama dituliskan sesuai dengan aturan jurnal Ya

Abstrak Ya/Tidak
6. Abstrak satu paragraf atau terstruktur Ya
7. Mencakup komponen IMRAD Ya
8. Secara keseluruhan informatif Ya
9. Tanpa singkatan, selain yang baku Ya
10. Kurang dari 250 kata Tidak (258 kata)
Pendahuluan Ya/Tidak

11. Ringkas, terdiri 2-3 paragraf Ya

12. Paragraf pertama mengemukakan alasan dilakukan penelitian Tidak, paragraf 2

13. Paragraf berikut menyatakan hipotesis atau tujuan penelitian Hipotesis tidak ada, tujuan ada
di paragraf 3
14. Didukung oleh pustaka yang relevan Ya

15. Kurang dari 1 halaman Ya

Metode Ya/Tidak

16. Disebutkan desain, tempat, dan waktu penelitian Ya(desain), tidak (tempat dan
waktu)
17. Disebutkan populasi sumber (populasi terjangkau) Tidak

18. Dijelaskan kriteria inklusi dan ekslusi Ya

19. Disebutkan cara pemilihan subyek (teknik sampling) Tidak

20. Disebutkan perkiraan besar sampel dan alasannya Tidak

21. Besar sampel dihitung dengan rumus yang sesuai Tidak

22. Komponen-komponen rumus besar sampel masuk akal Tidak


Metode Ya/Tidak

23. Observasi, pengukuran, serta intervensi dirinci sehingga orang lain dapat Tidak
mengulanginya
24. Ditulis rujukan bila teknik pengukuran tidak dirinci Tidak

25. Pengukuran dilakukan secara tersamar Tidak

26. Dilakukan uji keandalan pengukuran (kappa) Tidak

27. Definisi istilah dan variabel penting dikemukakan Ya

28. Ethical clearance diperoleh Ya

29. Persetujuan subjek diperoleh Tidak

30. Disebut rencana analisis, batas kemaknaan, dan power penelitian Ya

31. Disebutkan program komputer yang dipakai Ya

Hasil Ya/Tidak

32. Disertakan tabel karakteristik subyek penelitian Ya

33. Karakteristik subyek sebelum intervensi dideskripsi Ya

34. Tidak dilakukan uji hipotesis untuk kesetaraan pra-intervensi Ya

35. Disebutkan jumlah subyek yang di teliti Ya


Hasil Ya/Tidak

36. Dijelaskan subyek yang dropout dengan alasannya Tidak

37. Ketepatan numerik dinyatakan dengan benar Ya

38. Penulisan tabel dilakukan dengan tepat Ya

39. Tabel dan ilustrasi informatif dan memang diperlukan Ya

40. Tidak semua hasil di dalam tabel disebutkan Ya

41. Semua outcome yang penting disebutkan dalam hasil Ya

42. Subyek yang drop out diikutkan dalam analisis Tidak

43. Analisis dilakukan dengan uji yang sesuai Ya

44. Ditulis hasil uji statistika, degree of freedom & nilai p Ya

45. Tidak dilakukan analisis yang semula tidak direncanakan Ya

46. Disertakan interval kepercayaan Ya

47. Dalam hasil tidak disertakan komentar atau pendapat Tidak


Diskusi Ya/Tidak

48. Semua hal yang relevan dibahas Ya

49. Tidak sering diulang hal yang dikemukakan pada hasil Ya

50. Dibahas keterbatasan penelitian dan dampaknya terhadap hasil Ya

51. Disebut penyimpangan protokol dan dampaknya terhadap hasil Tidak

52. Diskusi dihubungkan dengan pertanyaan penelitian Ya

53. Dibahas hubungan hasil dengan teori/penelitian terdahulu Ya

54. Dibahas hubungan hasil dengan praktek klinis Tidak

55. Efek samping dikemukakan dan dibahas Tidak

56. Disebutkan hasil tambahan selama observasi Tidak

57. Hasil tambahan tersebut tidak dianalisis secara statistika Tidak

58. Disertakan simpulan utama penelitian Ya

59. Simpulan didasarkan pada data penelitian Ya

60. Simpulan tersebut sahih Ya

61. Disebutkan generalisasi hasil penelitian Ya

62. Disertakan saran penelitian selanjutnya Tidak


Ucapan Terima Kasih Ya/Tidak
63. Ucapan terima kasih ditujukan kepada orang yang tepat Tidak

64. Ucapan terima kasih dinyatakan secara wajar Tidak

Daftar Pustaka Ya/Tidak

65. Daftar pustaka disusun sesuai dengan aturan jurnal Ya

66. Kesesuaian sitasi pada nas dan daftar pustaka Ya

Lain - lain Ya/Tidak

67. Bahasa yang baik dan benar, enak dibaca, informatif, dan efektif Ya

68. Makalah ditulis dengan ejaan yang taat asas Ya


Penilaian Validitas Meta-Analisis

■ Apakah disebutkan dengan jelas dalam latar belakang


mengapa diperlukan kajian meta-analisis? Ya
■ Apakah disebut kriteria inklusi studi yang disertakan
dalam meta-analisis dan cara penelusuran pustaka
yang relevan? Ya
■ Apakah dilakukan telaah validitas setiap studi yang
disertakan dalam meta–analisis? Ya banyak bias
■ Apakah hasil setiap studi lebih kurang konsisten satu
dengan yang lain? Ya
Penilaian Pentingnya Hasil Meta-Analisis

■ Apakah hasil total meta-analisis berarti atau


penting secara klinis sehingga memengaruhi tata
laksana pasien secara keseluruhan? Hal ini dapat
dinilai dari rasio odds gabungan atau beda proporsi
kesembuhan gabungan, masing-masing disertai
dengan interval kepercayaan. Ya
Kemamputerapan Hasil Meta-Analisis

■ Apakah pasien kita mirip dengan karakteristik


pasien studi yang dilakukan meta-analisis? Ya
■ Apakah terapi tersebut tersedia, terjangkau, dapat
diterima pasien? Ya
THANK YOU