A total of 226 patients with uncomplicated acute appendicitis were included in the study. Among them, 138 (61%), 8 (3.5%), 18 (7.9%), 13 (5.7%), and 49 (21.6%) patients received OA, LA, beta-lactam, quinolone, and CEP+MET, respectively. Mean (±standard deviation) utility scores at baseline between the five groups were not significantly different with values of 0.4 (0.2), 0.4 (0.1), 0.4 (0.2), 0.5 (0.1), and 0.4 (0.1), see Table 1. The mean age and BMI were also not significantly different between groups, although diabetes mellitus, nausea, vomiting, and median neutrophil/lymphocyte ratio were statistically different (P-value: 0.016, 0.011, 0.007, and <0.001 respectively). Occurrence of complications in OA and LA ranged from 17% to 56% and 20% to 44%, respectively, see Table 4. All patients were available for interview at the 1 month follow-up.
Comparison of utility scores
A counterfactual approach was applied to assess the effects of the five treatments on utility scores. The treatment model was constructed to balance factors associated with treatment allocations, see supplementary document. Three factors (i.e., nausea, neutrophil/lymphocyte ratio, and baseline utility score) were significantly associated with treatment allocation between intervention groups.
The outcome model was generated from the IPWRA estimates from the treatment model. The POMs for the utility scores following treatment during hospitalization were 0.91, 0.89, 0.91, 0.30 and 0.03 for beta-lactam, quinolone, CEP+MET, LA and OA respectively. As a result, the ATEs were significantly higher for the three antibiotics and LA relative to OA with values of 0.88 (0.83, 0.93), 0.86 (0.78, 0.93), 0.87 (0.82, 0.92), 0.26 (0.11, 0.42) respectively, see Table 2.
The utility scores at one month follow-up were much improved for all interventions, i.e., 1.00, 1.00, 0.99, 0.93, and 0.98 for beta-lactam, quinolone, CEP+MET, LA, and OA, respectively, see Table 2. The ATEs (95% CI) were not significant for the interventions with the exception of beta-lactam with values of 0.03 (0.01, 0.05), 0.03 (-0.004, 0.06), and 0.01 (-0.02, 0.04), -0.05 (-0.10, 0.01), respectively.
CUA
The CUA compared cost and utility of antibiotic and operative treatments for uncomplicated acute appendicitis with a societal perspective. Direct medical costs associated with appendectomy drugs and equipment were higher than with antibiotic treatments. Furthermore, direct non-medical and indirect costs associated with operative treatments were also higher compared to antibiotics, see Table 3.
Overall means for utility scores and transition probabilities for one month post antibiotic and operative treatments were estimated and stratified by complication/recurrence, see Table 4. For OA and LA, the utility scores ranged between 0.50 - 0.71 and 0.66 - 0.94 with and without wound complications. Taking into account recurrence of appendicitis, the utility scores for antibiotics with were 0.60, 0.74, and 0.66 for beta-lactam, CEP+MET, and quinolone. Utility scores for all interventions were higher in the absence of complications or recurrence of appendicitis, i.e., 0.58, 0.66, 0.96, 0.97, and 0.98, respectively for beta-lactam, quinolone, CEP+MET, LA and OA.
Data from the decision tree model yielded ratios of cost to effectiveness of 773.62, 654.44, 653.32, 5,373.86, and 6,339.32 USD per utility gained for beta-lactam, quinolone, CEP+MET, LA, and OA, respectively, see Table 5. Comparisons between overall antibiotic and appendectomy (OA+LA) resulted in cost-savings with an ICER of -9,585.66 USD per utility gained. Among the antibiotics investigated, the ICERs for beta-lactam and quinolone relative to CEP+MET were -27,914.66 and 1,164.23 USD respectively per utility gained. The ICER for LA relative to OA was 2,536.06 USD per utility gained. Overall, at 1 month post treatment, beta-lactam was most cost-effective in comparison to the other antibiotics and OA was more cost-effective compared to LA.
A sensitivity analysis included a Tornado diagram and the results are presented in Figure 2. The Tornado diagram ordered the most sensitive interventions as the utility of LA with wound complications (ICER = -15,000.00 to -6,500.00), LA with other complications (-12,500.00 to -7,500.00), transition probability of LA with other complications (-11,250.00, -8000.00), utility of quinolone with recurrence (-11,250.00, -8500.00), and utility of quinolone without recurrence (-11,750.00, -9,500.00).
Incremental cost and effectiveness scatter plots were based on 1,000 Monte-Carlo simulations, see Figure 3. Each plot was divided into 4 areas, i.e., the southeast quadrant (cost-saving, i.e., more effectiveness at less cost), northwest quadrant (i.e., more cost and less effectiveness), northeast quadrant (i.e., more cost and more effectiveness) and southwest (i.e., less cost and less effectiveness); the last two quadrants are required for the comparison of WTP thresholds. Antibiotics offered greater cost-savings in comparison to appendectomy, see Figure 3A. For the 2 different types of appendectomy, the plots were scattered in all quadrants but most of them were in the southeast quadrant, i.e. LA might be more effective than OA, see Figure 3B. Among antibiotic treatments, most values were centrally scattered for all comparisons (see Figure 3C-3E), suggesting the cost-effectiveness of antibiotics as a treatment option might be dependent on WTP.
Cost-effectiveness acceptability curves (CEAC) illustrate the percentage cost-effectiveness (y-axis) in relation to a given WTP (x-axis), see Figure 4. Antibiotics were more cost-effective for all WTP levels compared to overall appendectomy, see Figure 4A. Likewise, LA was more cost-effective in comparison to OA for all WTP thresholds (Figure 4B). For antibiotic comparisons, quinolone was the most cost-effective treatment, followed by beta-lactam at WTP thresholds in excess of 40,000 USD per utility gained.
Cost benefit analysis
As described in Table 3, the overall incremental cost (i.e., direct medical, non-medical and indirect costs) of antibiotic treatments versus surgery was -3,265.26 USD. During 1 year follow up, there were 4 (5.0%) out of 80 patients in antibiotic groups had recurrence of appendicitis whereas 6 (4.1%) out of 146 patients in surgery had complications. The average treatment cost per case for recurrence and complication were 536.28 USD and 282.53 USD, respectively. As a result, the incremental cost of recurrence versus complication was 15.23 USD (i.e., (536.28 x 5.0%)-(282.53 x 4.1%)), which resulted in the net benefit of 3,250.08 USD. This could be interpreted that antibiotics had lower benefit, or in other words, surgery had better benefit than antibiotics.