On 2015 Aug 31, Bill Cayley commented:

From the fore-going discussion, it is clear that there remain questions about this approach, but it seems that this is an area where, at least in some cases, "less" may be "more". See also: https://lessismoreebm.wordpress.com/?s=appendicitis

On 2015 Aug 20, Paulina Salminen commented:

In response to colleagues Bertele and Garattini, we agree that it is of great importance to evaluate the optimal treatment for uncomplicated acute appendicitis regarding all pros and cons for both surgery and antibiotic therapy. The aim of the APPAC trial was to test the hypothesis that uncomplicated acute appendicitis can be successfully treated with antibiotics by comparing antibiotic therapy with emergency open appendectomy. Even though more patient-centric outcomes are valuable, we aimed to identify a clear and concise definition of efficacy that would apply to both treatments in order to enable fair comparison – resolution of acute appendicitis. The non-inferiority approach was used as the goal was not to find an approach that is more effective than current standard treatment as appendectomy cures appendicitis. The non-inferiority approach allows us to evaluate other advantages and a novel treatment that is almost as effective as standard treatment might be preferred in practice or for some patients.(1)

Based on our APPAC study results, we now know that the majority (73%) of patients with uncomplicated acute appendicitis were successfully treated with antibiotics.(2) We agree with Bertele and Garattini that major complications in both treatment arms are of vital importance. In the APPAC trial none of the patients treated initially with antibiotics and later with appendectomy had major complications; thus antibiotics are a safe first-line treatment for CT-proven uncomplicated acute appendicitis.

The optimal use of antibiotic therapy regarding both spectrum and duration of the treatment in patients with uncomplicated acute appendicitis needs to be prospectively evaluated in large patient series including the important assessment of relevant patient-centric outcomes.

1.Kaji AH, Lewis RJ. Noninferiority Trials: Is a New Treatment Almost as Effective as Another? Jama. 2015 Jun 16;313(23):2371-2. 2.Salminen P, Paajanen H, Rautio T, et al. Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. Jama. 2015 Jun 16;313(23):2340-8.

On 2015 Jul 29, Vittorio Bertele' commented:

The question of antibiotic therapy as an alternative to surgery for acute appendicitis keeps being addressed by a non-inferiority approach. We have previously challenged this attitude as it is not in the best interest of patients(1). The APPAC trial aimed to prove that fewer than one out of four patients with uncomplicated acute appendicitis would have required surgery within one year if they had been treated with antibiotics. The trial failed to prove this as the arbitrarily selected non-inferiority margin of antibiotics relative to surgery, although huge (24%), was not met. Still, the technically negative outcome of APPAC does not necessarily signify a failure(2). Avoiding surgery may be an advantage but patients also want to know what else could happen if they undergo, avoid or just defer appendicectomy. Unfortunately, the APPAC trial does not specify what patients can gain or lose with the two therapeutic strategies apart from the possibility of avoiding surgery in the antibiotic group. Besides –or even rather than– the greater than expected need for surgery in this group (27% instead of 24%), what matters most to patients is how many cases of peritonitis, other severe infections, complications of surgery, undue interventions, etc. there are in the two study arms. A trial addressing the superior overall benefit-risk profile of either the surgical or the antibiotic approach would have put these alternative strategies in a clearer perspective, enabling physicians and patients to make firmer decisions. A composite outcome measure including clinically relevant efficacy and safety endpoints –to address the sum of benefits and risks– would have answered the question whether failure to avoid surgery in spite of antibiotics still provides an actual advantage to patients, not just an acceptable disadvantage in exchange for unknown benefit. APPAC is one further demonstration that non-inferiority trials are often useless for patients(3): they assume an advantage (avoidance of surgery), allow too large a margin of failures –several patients needed surgery later in spite of the antibiotics– and, most important, do not address the possible overall benefit for patients (fewer complications?).

Vittorio Bertele’ and Silvio Garattini IRCCS-Istituto di Ricerche Farmacologiche Mario Negri email: vittorio.bertele@marionegri.it, silvio.garattini@marionegri.it

References 1. Banzi R, Torri V, Bertele V, Garattini S. Antibiotics versus surgery for appendicitis. Lancet 2011;378:1067-8. 2. Livingston E, Vons C. Treating Appendicitis Without Surgery. JAMA 2015;313:2327-8. 3. Garattini S, Bertele V. Non-inferiority trials are unethical because they disregard patients' interests. Lancet 2007;370:1875-7.

On 2015 Jul 29, Vittorio Bertele' commented:

The question of antibiotic therapy as an alternative to surgery for acute appendicitis keeps being addressed by a non-inferiority approach. We have previously challenged this attitude as it is not in the best interest of patients(1). The APPAC trial aimed to prove that fewer than one out of four patients with uncomplicated acute appendicitis would have required surgery within one year if they had been treated with antibiotics. The trial failed to prove this as the arbitrarily selected non-inferiority margin of antibiotics relative to surgery, although huge (24%), was not met. Still, the technically negative outcome of APPAC does not necessarily signify a failure(2). Avoiding surgery may be an advantage but patients also want to know what else could happen if they undergo, avoid or just defer appendicectomy. Unfortunately, the APPAC trial does not specify what patients can gain or lose with the two therapeutic strategies apart from the possibility of avoiding surgery in the antibiotic group. Besides –or even rather than– the greater than expected need for surgery in this group (27% instead of 24%), what matters most to patients is how many cases of peritonitis, other severe infections, complications of surgery, undue interventions, etc. there are in the two study arms. A trial addressing the superior overall benefit-risk profile of either the surgical or the antibiotic approach would have put these alternative strategies in a clearer perspective, enabling physicians and patients to make firmer decisions. A composite outcome measure including clinically relevant efficacy and safety endpoints –to address the sum of benefits and risks– would have answered the question whether failure to avoid surgery in spite of antibiotics still provides an actual advantage to patients, not just an acceptable disadvantage in exchange for unknown benefit. APPAC is one further demonstration that non-inferiority trials are often useless for patients(3): they assume an advantage (avoidance of surgery), allow too large a margin of failures –several patients needed surgery later in spite of the antibiotics– and, most important, do not address the possible overall benefit for patients (fewer complications?).

Vittorio Bertele’ and Silvio Garattini IRCCS-Istituto di Ricerche Farmacologiche Mario Negri email: vittorio.bertele@marionegri.it, silvio.garattini@marionegri.it

References 1. Banzi R, Torri V, Bertele V, Garattini S. Antibiotics versus surgery for appendicitis. Lancet 2011;378:1067-8. 2. Livingston E, Vons C. Treating Appendicitis Without Surgery. JAMA 2015;313:2327-8. 3. Garattini S, Bertele V. Non-inferiority trials are unethical because they disregard patients' interests. Lancet 2007;370:1875-7.

On 2015 Aug 20, Paulina Salminen commented:

In response to colleagues Bertele and Garattini, we agree that it is of great importance to evaluate the optimal treatment for uncomplicated acute appendicitis regarding all pros and cons for both surgery and antibiotic therapy. The aim of the APPAC trial was to test the hypothesis that uncomplicated acute appendicitis can be successfully treated with antibiotics by comparing antibiotic therapy with emergency open appendectomy. Even though more patient-centric outcomes are valuable, we aimed to identify a clear and concise definition of efficacy that would apply to both treatments in order to enable fair comparison – resolution of acute appendicitis. The non-inferiority approach was used as the goal was not to find an approach that is more effective than current standard treatment as appendectomy cures appendicitis. The non-inferiority approach allows us to evaluate other advantages and a novel treatment that is almost as effective as standard treatment might be preferred in practice or for some patients.(1)

Based on our APPAC study results, we now know that the majority (73%) of patients with uncomplicated acute appendicitis were successfully treated with antibiotics.(2) We agree with Bertele and Garattini that major complications in both treatment arms are of vital importance. In the APPAC trial none of the patients treated initially with antibiotics and later with appendectomy had major complications; thus antibiotics are a safe first-line treatment for CT-proven uncomplicated acute appendicitis.

The optimal use of antibiotic therapy regarding both spectrum and duration of the treatment in patients with uncomplicated acute appendicitis needs to be prospectively evaluated in large patient series including the important assessment of relevant patient-centric outcomes.

1.Kaji AH, Lewis RJ. Noninferiority Trials: Is a New Treatment Almost as Effective as Another? Jama. 2015 Jun 16;313(23):2371-2. 2.Salminen P, Paajanen H, Rautio T, et al. Antibiotic Therapy vs Appendectomy for Treatment of Uncomplicated Acute Appendicitis: The APPAC Randomized Clinical Trial. Jama. 2015 Jun 16;313(23):2340-8.

On 2015 Aug 31, Bill Cayley commented:

From the fore-going discussion, it is clear that there remain questions about this approach, but it seems that this is an area where, at least in some cases, "less" may be "more". See also: https://lessismoreebm.wordpress.com/?s=appendicitis