Kari Tikkinen, MD, highlights the APPEAL trial of antibiotic prophylaxis prior to SWL

In this interview, Kari A.O. Tikkinen, MD, PhD, provides an overview of the APPEAL trial (NCT03692715), which is assessing the efficacy of antibiotic prophylaxis prior to shockwave lithotripsy for patients with nephrolithiasis and/or ureterolithiasis. Tikkinen also shares an update on the trial, which was highlighted in the recent publication, “Update on APPEAL, an International Randomized Controlled Trial Evaluating Ciprofloxacin Versus Placebo in Patients Undergoing Shockwave Lithotripsy for Urolithiasis.”¹

Tikkinen is a professor of urology at the University of Helsinki in Finland.

This transcription has been edited for clarity.

Kari A.O. Tikkinen, MD, PhD

Could you describe the background/rationale for this trial?

First of all, thank you for this discussion; [it’s] very nice to do it with you. The background is that there's a discrepancy in recommendations [across] the guidelines. The European Association of Urology (EAU) urolithiasis guideline recommends using antibiotic prophylaxis in patients with an indwelling catheter, infectious stones, or bacteriuria. On the other hand, EAU urological infectious guidelines recommend against antibiotic prophylaxis before shockwave lithotripsy. Similar with the EAU urolithiasis guideline, the Canadian Urological Association guideline recommends considering antibiotic prophylaxis only in patients with a high risk of infectious complications. The American Urological Association best practice policy statement on antibiotic prophylaxis states or recommends antibiotic prophylaxis prior to shockwave lithotripsy if patients have risk factors from infections such as diabetes, tobacco use, immunodeficiency, or use of catheters. So clearly, they are a little bit different.

We also looked at earlier randomized trials. They are several randomized trials, but when you systematically review and meta-analyze them, they have very low certainty. There's a lot of risk of bias in these trials, there's imprecision, they are underpowered, and the results are inconsistent. So, the evidence base is not so certain. There [are also] no practice surveys; I haven't seen any global survey [on] how people do this. But we asked our centers, [comprised of] about a dozen of centers all over the world. Quite interestingly, [we found that] if patients didn't have a stent, half gave and half didn't give antibiotic prophylaxis before shockwave lithotripsy within our 12 centers. But if the patient had a stent, then about 75% of the centers gave [antibiotic prophylaxis] and 25% didn't. There was a practice variation. So, [with] the guidelines, the evidence base, and the practice variation, we thought this would be worth a trial and thought that doing so would be a big trial so that we can get enough events. It's not, hopefully, going to be underpowered, so then we would have a patient reported outcomes and clinically relevant outcomes.

Could you expand on how the study is designed? What are the primary outcome measures?

APPEAL is a multi-center, randomized controlled trial. We're doing it in 5 regions, the Americas, the Middle East, Asia, and Europe. We have completed the patient recruitment now––so we have randomized patients between antibiotic prophylaxis with ciprofloxacin or placebo. So, this is also a blinded trial. Ciprofloxacin was given orally in 2 centers and through [intravenous administration] in other centers, so we allowed both IV and oral, whatever works better. That has to do with our pragmatic approach. Our pragmatic approach also includes that we wanted to not to have too extensive of a list of exclusion criteria, but surely we have some exclusion criteria. In general, the eligible patients were adults who had either nephrolithiasis or ureterolithiasis or both and were about to get shockwave lithotripsy to treat it.

Then we collected the preoperative urine culture according to local standard of care from all patients, and we assessed baseline characteristics and symptoms before SWL. The primary outcome is a composite outcome of positive urine culture, symptomatic cystitis, pyelonephritis or urosepsis at approximately 7 to 14 days post-SWL.

What were some of the details of the recent progress report on the trial?

First of all, thank you to the European Urology Focus [for giving us] the chance to report this. The great news is that we have now completed recruitment. We actually recruited more than 1700 patients, and now we're starting to analyze this. We have a statistical analysis plan.

It's very common in large trials, but also in smaller trials that the recruitment is a challenge, especially in surgery. It's actually the most common reason for discontinuation of trials, and we also had problems. This trial was started in Canada as a single center trial, but it soon was clear that this recruitment was too slow. Then we expanded the trial globally, and we made it a multicenter trial with more than 10 centers in different countries. We renamed this the APPEAL trial, which is antibiotic prophylaxis before shockwave lithotripsy. Then, as we know, the COVID pandemic hit all over the world, and it also hit the APPEAL recruitment. It was also impeded because many units at that time were not able to recruit patients or even treat patients.

Then, the third thing that was a little bit of a challenge [was] that we originally planned to recruit about 1500 patients, but then we looked [at the data]. We didn't open the blinding, but we looked at the data at about 1000 patients, and we noticed that there were less events than what we had planned. That's another common problem in trials is that investigators tend to overestimate the event rate, and we underestimated it a little bit. Then we increased the sample size to a minimum of 1700 patients, and we have now recruited these 1700 patients. We are now ready for analysis and publishing papers.

Based on the findings, what are the potential implications of this trial for the management of urolithiasis?

APPEAL is trying to determine if antimicrobial prophylaxis is effective, and also if it's needed in shockwave lithotripsy procedures. If the trial is positive, we can, of course, then advocate for increasing the use of antibiotic prophylaxis, and then that should lead then to a decrease in infection rates. [After] we do multivariate analysis and all kinds of subgroup analyses, maybe we can find more specific prophylaxis strategies, [where] some patients should and some patients shouldn't [be given] prophylaxis. We will see.

On the other hand, if the results are negative, this would encourage a reduction of use of unnecessary prophylaxis. Many people still use it for these procedures. Hopefully that would also affect global guidelines and global practices in shockwave lithotripsy.

Then, in general, I think one of the major implications is that APPEAL is an international trial, and hopefully it encourages not only us, but also other investigators to do more collaborative research, which has a critical role in addressing challenges in urology. It is one more large pragmatic trial, and [hopefully that] makes those large pragmatic trials more popular. I hope that would also be one of the potential implications of our work.

Could you share some updates on next steps with the trial?

We are working actively now, and I hope we will present the results in full manuscript during the winter or spring. I hope that we will present the results also at the major meetings, such as the AUA and EAU [meetings] in 2025. I would hope in a little bit more than half a year, the publication should be out, and the results should be presented at the AUA/EAU meetings.

Is there anything else that you would like to add?

First of all, I would, I would like to thank Urology Times for having me here. You’re doing great work, so it's a pleasure and honor to be here.

The APPEAL trial is important for us. We have a research group called the Clinical Urology and Epidemiology (CLUE) Working Group. We are trying to establish ourselves as one of the leading trial units for global, pragmatic, randomized trials in urology. Of course, this was one of the trials which contribute to the establishment of a large trial network, which hopefully will support future studies. We just started our next and even larger trial, which we call ARTS, which is avoiding risk of thrombosis and bleeding in surgery. That's a thromboprophylaxis trial in urology, gynecology, and abdominal surgery. APPEAL built up the network, and then we will continue that with ARTS. I think that's important for this trial work.

I would also like to use this opportunity to thank of course, most importantly, the patients who joined the trial, all clinicians and researchers who contributed in different countries, and also our main funders, Research Council of Finland, Sigrid Jusélius Foundation, and Helsinki University Hospital. These kinds of trials need a lot of people and a lot of support. Thanks to you and to European Urology Focus for publishing our trial update.

Reference

1. Tikkinen KAO, Tornberg SV, Ruotsalainen J, et al. Update on APPEAL, an international randomized controlled trial evaluating ciprofloxacin versus placebo in patients undergoing shockwave lithotripsy for urolithiasis. Eur Urol Focus. 2024:S2405-4569(24)00148-2. doi:10.1016/j.euf.2024.07.011