Raja Isteri Pengiran Anak Saleha Appendicitis Treatment Without Operation
Raja Isteri Pengiran Anak Saleha Appendicitis Treatment Without Operation
The RIPASA score is a Clinical Prediction Rule (CPR) for the diagnosis of acute appendicitis.
 Since its inception in 2009, the RIPASA score has been validated in various population in
 healthcare institutions around the world and reported significantly higher sensitivity and
 specificity when compared to Alvarado score. RIPASA score ranges from 3 to 16.5 with those
 having a score of less than 7 having a low probability of acute appendicitis and those with a
 score of 7.5 having a high probability of acute appendicitis.

 There has been a trend in the past decade on non-operative management of early-uncomplicated
 acute appendicitis (EuAA) with antibiotic therapy. This antibiotic non-operative management
 strategy (AMS) has been reported to work in children, thus avoiding unnecessary emergency
 operation. In adults presenting with early-uncomplicated acute appendicitis, this management
 pathway is still uncertain and most randomized controlled trials (RCT) and meta-analysis have
 not been able to show significant benefit of AMS over surgery management strategy (SMS),
 partly due to variable treatment efficacy, high recurrence rate within a year and a lack of
 agreement of whom would constitute a group of EuAA.

 The working hypothesis of this study is that RIPASA score as a Clinical Prediction Rule, can
 determine a group of patients with a diagnosis of EuAA, based on the range of scores (RIPASA
 score 7.5 - 11.5), who will benefit from an AMS rather than SMS, leading to improve patients'
 outcomes through a significant reduction in negative appendicectomy rate, shorter length of
 hospital stay, reduce post-operative complications and changing physician behavior in
 managing this group of patients to an AMS rather than SMS and ultimately financial cost
 savings.

 The primary specific aim of this study is to compare AMS with SMS in patients with EuAA in a
 prospective non-inferiority RCT. Secondary specific aims are to determine the range of RIPASA
 score that can define a group of patients with EuAA, step 3 validation of RIPASA score as a
 valid CPR and improve patient outcomes in terms of reducing unnecessary negative
 appendicectomy rate, hospital stay and complications arising from such surgery, and
 ultimately financial cost savings.
Introduction:

 Acute appendicitis is one of the most common surgical emergencies, with a lifetime prevalence
 approximately 1 in 7. The incidence is 1.5-1.9 per 1000 in a male and female population with
 approximately 1.4 times greater in men than in women.

 Despite being a common problem, acute appendicitis remains a difficult diagnosis to
 establish, particularly in the young, elderly and female of reproductive age. Delay in
 surgery may risk appendicular perforation and sepsis. Reduced diagnostic accuracy and early
 surgery risk significantly high negative appendicectomy rate of about 20-40%. Diagnostic
 accuracy can be further improved by using ultrasonography or computed tomography scan.
 However, these modalities are costly and may not easily be available when needed.

 Clinical prediction rule (CPR) such as Alvarado score, the modified Alvarado score, and the
 RIPASA score have been developed to improve the diagnostic accuracy of acute appendicitis.
 Alvarado and Modified Alvarado scores have been reported to have very low sensitivity and
 specificity when applied to an Asian population with a completely different ethnic origin and
 diet. Thus RIPASA score was developed specifically for an Asian population and have been
 reported to have a significantly better sensitivity (98%) and specificity (82%) over the
 former two scores. Since 2009, the RIPASA score has undergone broad validation in different
 population settings with a different prevalence of acute appendicitis across the world and
 reported similarly high sensitivity and specificity.

 The standard management of acute appendicitis has remained largely been unchallenged since
 the late 19th century, largely because of the belief that if left untreated surgically, acute
 uncomplicated appendicitis will progress to perforation and peritonitis with increased
 morbidity and mortality. Furthermore current surgical management of acute appendicitis is
 associated with an unacceptably high negative appendicectomy rate of about 20-40% and
 significant post-operative complications.

 Antibiotic non-operative therapy of intra-abdominal sepsis has been accepted as mainstay
 therapy for a condition such as diverticulitis. Since 2009, antibiotic non-operative therapy
 has been increasingly proposed as an alternative strategy for early uncomplicated acute
 appendicitis (EuAA) and has also been reported to be safe and effective in children with
 acute appendicitis complicated by perforation, abscess or phlegmon formation.

 However, despite multiple randomized controlled trials (RCTs) and meta-analyses, the role of
 antibiotics in the management of EuAA in adults remains controversial. Early RCTs have
 reported treatment efficacy for antibiotic non-operative management strategy (AMS) of EuAA as
 high as 88-91% with a recurrence rate of acute appendicitis at 13-14% at 1-year follow-up.
 More recent RCTs comparing AMS versus surgical management strategy (SMS) have not been able
 to confirm non-inferiority of AMS over SMS. These later findings were also been supported by
 multiple recent meta-analyses. The discrepancies in reported studies are due to a lack of
 agreeable definition of EuAA, which was the common recommendation by all the recent
 meta-analyses. The NOTA study in 2014 reported using clinical prediction rules such as Acute
 Inflammatory Response (AIR) score (mean score of 4.9) and Alvarado score (mean score of 5.2)
 to define their group with EuAA, but this was only a prospective cohort study design and the
 mean score used were well below the threshold for diagnosing acute appendicitis.

 RIPASA Score provides a range of score from 3.0-16.5 for diagnosing acute appendicitis.
 RIPASA score less than 7 are considered having a low probability of acute appendicitis and
 RIPASA score more than 7.5 are considered high probability of acute appendicitis. Thus it may
 be possible to identify a group of patients with EuAA based on their RIPASA score range who
 may benefit from AMS.

 This study-working hypothesis is that RIPASA score as a CPR can determine a group of patients
 with a diagnosis of EuAA, who will benefit from AMS rather than SMS. The primary specific aim
 of this study is to confirm the non-inferiority status of AMS over SMS in EuAA. Secondary
 specific aims are to determine the range of RIPASA score which can be considered as providing
 a firm diagnosis of EuAA which can be management with AMS rather than SMS, step 3 impact
 analysis of RIPASA score as a CPR, and improve patient outcomes in terms of reducing
 unnecessary negative appendicectomy rate, hospital stay and complications arising from such
 surgery, and ultimately financial cost savings.

 Methodology:

 Trial Design:

 This study also known as RIPASA-TWO trial is designed as a single center, open-label,
 non-inferiority, prospective RCT to compare 2 management strategies for suspected EuAA, AMS
 versus SMS, using RIPASA score to identify the group of patients with EuAA and to monitor the
 progression of the disease and guiding surgical decision based on the participants' RIPASA
 score.

 Population and Study Setting:

 The study setting will be based at Raja Isteri Pengiran Anak Saleha (RIPAS) Hospital, a
 tertiary referral center. All staffs of the Department of General Surgery (GS) and Accident &
 Emergency (A&E) Department at RIPAS Hospital will be brief of the trial design and purpose.

 Recruitment:

 Patients presenting to A&E Department at RIPAS Hospital with right iliac fossa pain will be
 triaged and seen by the Casualty Officer. RIPASA score will be derived. Patients with RIPASA
 score between 7.5 to 11.5 and who satisfy the study inclusion and exclusion criteria will be
 referred to the on-call surgical medical officer (MO) for recruitment to RIPASA-TWO trial.
 Antibiotics will be withheld until patients have been seen by the surgical MO on duty and the
 RIPASA score is confirmed. The Surgical MO will inform and explain to the patient and family
 of the study and a study information sheet will be provided. Upon written signed consent to
 be recruited for the RIPASA-TWO trial, patients will be randomized to either arms - AMS or
 SMS.

 Allocation concealment:

 A variable block randomization sequence of 4,6 and 8 will be used to allocate participants to
 either AMS or SMS. A web-based program will be used and accessed via secured username and
 password, to obtain randomization allocation for the recruited participants. Once the
 randomization allocation code has been given, the surgical MO will allocate the treatment
 according to the randomized arm. Recruitment will be stratified to two RIPASA score range,
 7.5-9.5 and 10.0-11.5.

 Study Protocol:

 The surgical MO/SMO will login into the randomization allocation software to acquire the
 randomization allocation arm and code. The patient will then be admitted to GS inpatient
 wards. Patients randomized to AMS arm will receive the allocated antibiotic treatment. Those
 randomized to SMS arm will receive the usual Departmental antibiotic policy of preoperative
 antibiotics prior to appendicectomy.

 For patients in the AMS arm, the RIPASA score will be repeated to monitor the progression of
 the patient's condition after 24 hours. If RIPASA score remains stable or decreasing, the
 patient will continue on the allocated intravenous (iv) antibiotic treatment. If RIPASA score
 is increasing but remain below 11.5, the team looking after the patient can consider ordering
 further investigations such as ultrasound or CT scan, but patients will continue at this
 point on the antibiotic. If the RIPASA score increases to above 12, the surgeon can consider
 appendicectomy.

 For patients in the AMS arm who have not cross over to surgery, they will continue with iv
 antibiotics for 48 hours and if symptoms improved with decreasing RIPASA score to below 7.5,
 the antibiotic will be changed to oral route and the patient monitored regularly. If RIPASA
 score goes below 5, the patient can be considered for discharge and follow-up in 1 week in
 the clinic with an oral antibiotic for a total of 7 days.

 For patient randomized to the SMS arm, patients will undergo appendicectomy, unless their
 repeated RIPASA score decreases to below 7.5 or if their symptoms improved. For these
 patients, they will remain on iv antibiotics and will be changed to oral route after 48
 hours. If RIPASA score goes below 5, the patient can be considered for discharge and
 follow-up in 1 week in the clinic with an oral antibiotic for a total of 7 days.

 Antibiotic:

 Intravenous Amikacin 15mg/kg/day divided over 3 doses for 48 hours will be the antibiotic of
 choice for RIPASA-TWO trial and is based on the microbial antibiotic sensitivity from pus
 swab taken for all appendicectomy from the previous year (2016). After 48 hours, this will be
 converted to oral ciprofloxacin 500mg bd for 7 days. For patients allocated to SMS arm, the
 Department antibiotic policy is for a preoperative antibiotic combination of intravenous
 Cefuroxime 1.5g TDS and 500mg metronidazole TDS.

 Statistical methods:

 Sample size calculation:

 According to Chong et al, the reported negative appendicectomy rate based on the RIPASA score
 was 14.7%. Hence this 14.7% can be considered as surgical treatment failure due to an
 unnecessary operation and the surgical treatment efficacy is about 85.3%.

 The non-inferiority margin for RIPASA-TWO trial will be set based on this surgical treatment
 failure rate of 14.7%. Using the FDA-approved non-inferiority margin of 50% reduction in
 efficacy or 50% increase in failure rate will give AMS an acceptable failure rate of 22%.
 Thus a treatment failure for AMS between 14-22% will be considered as confirmation of
 non-inferiority. A treatment failure of less than 14% will be considered as superiority.
 Hence based on a difference in treatment efficacy rate of 7% (22% vs 14%), with a sample size
 powered at 80% at 5% significance, the sample size needed to show non-inferiority is 91 in
 each group. Assuming a dropout rate of 25%, the total number of patients needed to be
 recruited is 228 patients, based on a 1:1 recruitment.

 All statistical analysis will be performed using SPSS statistical program. Categorical data
 will be presented using frequencies and percentages. Continuous data will be presented as
 mean ± SD. All analysis will be conducted based on intention-to-treat principle and
 per-protocol analysis. Statistical analysis for categorical data will be carried out using
 Chi Square exact test. Differences between groups with normally distributed variables will be
 tested using independent sample t-test. Variables with no normal distribution will be tested
 using Wann-Whitney test. Non-inferiority for AMS will be tested using one-sided Wald tests
 with an α level of 0.05.

 Duration of Study:

 Based on the previous study, the recruitment of 200 consecutive patients with acute
 appendicitis, took over 8 months. Half of this group had RIPASA score from 7.5 to 11.5. Thus
 for a sample size of 228 for the RIPASA-TWO trial, the expected recruitment time is about 19
 months. Hence the study will be expected to complete within 2 years.

 Interim Analysis:

 An interim analysis will be conducted at 2-time points. For changes to antimicrobial
 sensitivity, the interim analysis will be conducted at every 6 months and any changes will be
 discussed with the Data Safety Monitoring Board for proposed changes to the antibiotic
 regime. The main study interim analysis will be conducted at 1-year post recruitment to
 assess safety efficacy of the trial to ensure that not too many patients are developing
 complicated acute appendicitis in the AMS arm.

 Ethical Consideration:

 Ethics approval for the study has been granted by the Medical and Health Research and Ethics
 Committee based in RIPAS Hospital.
Inclusion Criteria:

 -  More than 12 years of age

 -  High probability of early-uncomplicated acute appendicitis with confirmed RIPASA score
 of 7.5 to 11.5

 Exclusion Criteria:

 -  12 years of age or less

 -  RIPASA score 7 or less, or greater than 12

 -  Clinical diagnosis of acute complicated appendicitis with perforation or signs of
 generalized peritonitis.