APPAC

Published

Salminen P, et al. "Five-Year Follow-up of Antibiotic Therapy for Uncomplicated Acute Appendicitis in the APPAC Randomized Clinical Trial". JAMA. 2018. 320(12):1259-1265.
PubMed • Full text

Clinical Question

Is antibiotic treatment for adult patients with acute appendicitis confirmed by computed tomography (CT) inferior compared to appendectomy?

Bottom Line

In adult patients with CT-proven, uncomplicated appendicitis initial non-surgical, antibiotic treatment the rate of recurrent appendicitis at 1 year was 27.3%, and 39.1% at 5 years. At 5 years the overal complication rate was 24.4% in the surgical arm and 6.4% in the antibiotic arm. It was suggested by the authors that initial treatment with antibiotic therapy may be more feasible than surgical management.

Major Points

Approximately 1 in 10 people undergo an appendectomy for acute appendicitis during their lifetime. Despite the high incidence, the efficacy of an antibiotics-only approach is of unknown efficacy. There has been one Cochrane analysis and several meta-analyses comparing antibiotic treatment to appendectomy. In general, these trials were small and/or had eligibility criteria (e.g., no females) that limited generalizability. These trials showed that antibiotic therapy was inferior to appendectomy for acute appendicitis and the success rates of antibiotic treatment was 70-80% .

Published in 2015, the Appendicitis Acuta (APPAC) trial randomized 530 patients at 6 Finnish hospitals to surgical or medical initial management of acute appendicitis in open-label fashion. Rather than the customary unified primary outcome, each arm had its own outcome. For surgical management, the outcome was the successful completion of an appendectomy. For medical management, it was successful completion of antibiotics that didn't require an appendectomy in the following year. The success rate for surgery in this trial was 99.6%. The investigators prespecified that the non-inferiority margin for the medical management compared to surgical management to be 24% (i.e., participants in the antibiotic arm would not need surgery ~75% of the time). Ultimately, medically-managed patients did not require surgery 72.7% of the time and the non-inferiority margin of antibiotics was not met. The patients were followed for 5 years, and in 2018 the data was published. The 1-year cumulative incidence of appendicitis was 34.0% at 2 years. 85 patients in the antibiotic group (n=257) required an appendectomy after the initial trial, 76 had uncomplicated appendicitis, 2 had complicated appendicitis, and 7 did not have appendicitis. At the end of the follow-up period, the complication rate was 24.4% in the surgical arm and 6.5% in the antibiotic arm, with more days of sick leave required for the surgical group. It was concluded that antibiotic therapy may represent an appropriate first line treatment for appendicitis.

While the authors concluded that while antibiotic treatment did not meet the specified non-inferiority margin, they do not discount antibiotic therapy as a treatment option for acute uncomplicated appendicitis. The 24% non-inferiority margin was based upon the anticipated success rate from prior literature and is not a clinically-meaningful threshold. The majority of patients who received antibiotic treatment did not require an interval appendectomy in the follow-up period, and there was a low rate of complications as compared to the surgical group (6.5% vs. 24.4%).

This trial was not blinded and the decision to pursue surgical intervention was largely driven by professional opinion of the surgical team. It is unclear if the non-inferiority margin would have been met in a blinded study or in an unblinded study with objective criteria to pursue surgical intervention.

Guidelines

As of July 2018, no guidelines have been published that reflect the results of this trial.

Design

The full methodology for this trial was published elsewhere.

• Multicenter, non-inferiority, open label, randomized, controlled trial
• N=530
  • Surgery (n=273)
  • Antibiotics (n=257)
• Setting: 6 hospitals in Finland
• Enrollment: November 2009-June 2012
• Mean follow-up: 5 years
• Analysis: Intention-to-treat
• Primary outcome: Treatment efficacy, which was defined differently for each group.

Population

Inclusion Criteria

• 18-60 years old
• CT diagnosis of uncomplicated acute appendicitis: Appendix wall greater than 6mm with one of the following:
  • Abnormal contrast enhancement
  • Inflammatory edema
  • Fluid collection around appendix

Exclusion Criteria

• Pregnancy or lactating
• Allergy to contrast media or iodine
• CKD with serum creatinine >150 μmol/l (1.7 mg/dL)
• Metformin medication
• Peritonitis
• Other serious illness
• Complicated acute appendicitis in a CT scan, defined by the presence of an appendicolith, perforating, periappendicular abscess or suspicion of a tumor

Baseline Characteristics

From the surgery group

• Demographics: Male sex 64%, median age 35
• Median VAS pain score: 6
• Labs: CRP 36 mg/L, hgb 14.3 g/dL, leukocyte count 12.0 x10⁹/L, creatinine 72.2 umol/L (0.82 mg/dL)
• Hours of symptom duration:
  • 1-6: 16
  • 6-12: 31
  • 12-18: 64
  • >18: 160

Interventions

• Participants were randomized to group:
  • Surgery - Open appendectomy, though surgeons could opt for laparoscopic (5.5% in this trial). They received cefuroxime 1.5 and metronidazole 500 mg 30 minutes prior to incision and no further antibiotics unless there a wound infection.
  • Antibiotics - Ertapenem 1 g IV daily was administered for 3 days, first dose in the emergency department, then levofloxacin 500 mg po qday x7 days with metronidazole 500 mg PO TID. Patients were reevaluated 12-24 hours following admission the on-call surgeon. If there was evidence of progressive infection, perforated appendicitis or peritonitis the patient underwent appendectomy.

Outcomes

Comparisons surgery vs. antibiotics except where specified.

Primary Outcomes

Treatment efficacy

Successful surgery, surgical group: 99.6% (95% CI, 98.0%-100.0%)

Did not require surgery in the following year, antibiotic group 72.7% (95% CI 66.8%-78.0%)

Intention-to-treat analysis yielded difference of -27.0% (95% CI −31.6% -∞; P=0.89) between groups

This did not meet the non-inferiority margin of 24%.

Secondary Outcomes

Overall complication rate

20.5% (95% CI 15.3-26.4; P<.001) vs. 2.8% (95% CI 1.0-6.0; P<.001)

Cumulative inccidence of recurrence at 1 year

27.3% (95% CI, 22.0%-33.2%)

Cumulative inccidence of recurrence at 5 years

34.0% (95% CI, 28.2%-40.1%)

Patients in antibitoic group requiring interval appendectomy

16.1% (95% CI, 11.2%-22.2%)

Overall complication rate in surgical group

24.4% (95% CI, 19.2%-30.3%)

Overall complication rate in the antibitotic group

6.5% (95% CI, 3.8%-10.4%)

Median length of hospital stay in surgical group

3 days (95% CI, 3-3)

Median length of hospital stay in antibiotic group

3 days (95% CI, 3-3)

Median length of sick leave in surgical group

22 days (95% CI, 19-23, P<0.001)

Median length of sick leave in antibiotic group

11 days (95% CI, 11-12, P<0.001)

Surgical site infections- Organ space, No.

1 vs. NA

Surgical site infections- Deep incisional, No.

4 vs. NA

Surgical site infections- Superficial, No.

19 vs. 1

Incisional hernias No.

2 vs. NA

Abdominal, incisional pain, or obstructive symptoms, No.

23 vs 4

VAS score, median (25th-75th percentile)- At discharge from hospital

3.0 (2-4) vs. 2.0 (1-2) (P<.001)

VAS score, median (25th-75th percentile)- At 1 week post discharge

2.0 (1-3) vs. 1.0 (1-1) (P<.001)

VAS score, median (25th-75th percentile)- At 2 months post discharge

1.0 (1-1) vs. 1.0 (1-1) (P=.40)

Length of sick leave, median (25th-75th percentile), d

19.0 (14-21) vs. 7.0 (7-12) (P<.001)

Adverse Events

Appendicular tumor

4 (3 neuroendocrine, 1 adenoma) vs. 0

Criticism

• Difficulty recruiting patients since appendectomy is considered the standard treatment.
• Most appendectomies were performed using the open approach. Surgical complications may have been lowered with a laparoscopic approach.
• The outcome of the surgical group was not patient-centered. A more appropriate outcome may have been postoperative complications and disability, for which there was a 20% rate in this arm. This would have.
• Triple therapy with antibiotics may be excessive and may lead to more antibiotic resistance. Likewise, requiring CT scans to confirm the diagnoses was likely unnecessary in some cases and contributed to excess radiation exposure.
• Duration of antibiotic therapy may have been excessive.

Funding

The authors declared that they have no competing interests.