Rebuttal from IR community as AUA continues to not recommend PAE outside of clinical trials

The American Urological Association (AUA) have published guideline amendments in the September issue of The Journal of Urology, but have not changed their stance on prostate artery embolization (PAE). The AUA does not recommend PAE for the treatment of lower urinary tract symptoms/benign prostatic hyperplasia (LUTS/BPH) outside the context of a clinical trial, a recommendation attributed to the expert opinion of a panel of urologists. This news is unwelcome to the interventional radiology (IR) community, which has been advocating for the procedure’s acceptance by the wider medical world. US interventional radiologists were awaiting these guideline amendments hopeful that new recommendations would better reflect the conclusion of multiple IR societies that PAE is a safe, effective, minimally invasive treatment option in select BPH patients.

The guidelines, authored by Harris Foster (American Urological Association Education and Research, Linthicum, USA) and colleagues, cite the following as their rationale:

• “High level evidence remains sparse, and the overall quality of the studies is uniformly low.
• Three randomised controlled trials (n=247) with heterogeneous methods and results.
• Concerns regarding radiation exposure, post-embolization syndrome, vascular access, technical feasibility, and quality control at lower volume centres.
• PAE should only be performed in the context of a clinical trial, comparing to sham will account for placebo effect.”

SIR urges AUA to reconsider their “unnecessarily restrictive” recommendation, and to expand access to available treatment options for men

This has sparked a response from US interventional radiologists. In May this year, the Society of Interventional Radiology (SIR), the Cardiovascular and Interventional Radiological Society of Europe (CIRSE), Société Française de Radiologie (SFR), and the British Society of Interventional Radiology (BSIR) published a position statement in the Journal of Vascular and Interventional Radiology (JVIR) concluding that current evidence supports the use of PAE for the treatment of LUTS for the symptoms of BPH in appropriately selected patients. The AUA has not accommodated this viewpoint in their latest guidelines amendments.

Speaking in her capacity as president of the SIR, Laura Findeiss (Emory University School of Medicine, Atlanta, USA) provides this newspaper with the following statement:

“The AUA’s recent guideline amendment to explicitly not recommend the use of PAE for the treatment of BPH outside of the context of a clinical trial fails to acknowledge the medical evidence supporting the safety and efficacy of this minimally invasive treatment option. It also fails to recognise the US Food and Drug Administration (FDA) approval of embolization devices for this use.

“SIR’s 2019 multi-society position statement on the application of PAE cites multiple randomised controlled trials and comparative studies of PAE versus the gold standard urologic treatment of lower urinary tract symptoms (LUTS) caused by BPH—TURP, or transurethral resection of the prostate. These studies show that symptomatic improvement following PAE approaches are seen after TURP, while maintaining a superior safety profile. The multisociety statement’s authors cite dozens of other prospective and retrospective cohort studies and meta-analyses that also support the safety and efficacy of PAE as a treatment option for LUTS caused by BPH.

“Due to the strong nature of the evidence supporting PAE, the societies endorsed PAE as ‘a definitive treatment option for multiple underserved patient groups, who may not have satisfactory urologic treatment options’. These patient groups include older patients with multiple medical conditions, patients with very large prostates, patients with bleeding from the prostate, patients with long-term bladder catheters, patients who cannot stop anticoagulation therapies and patients who desire to preserve sexual function.

“Furthermore, the National Health Service (NHS) in the United Kingdom has also acknowledged the strength of the evidence and supports the use of PAE to treat BPH symptoms in appropriately selected patients.

“AUA, however, has ignored the peer-reviewed data supporting PAE as appropriate for the sizeable population of men who are poor candidates for surgery and those who seek a nonsurgical, prostate-sparing option to treat their BPH symptoms. While AUA reasonably calls for increasing the level of evidence for the standard patient, the abundance of positive data moves PAE significantly beyond experimental. What is yet to be determined is where this therapy fits in the treatment algorithm. It is our hope that the urology community will partner with IR on behalf of patients in completing such recommended studies. Despite the AUA position, PAE is supportable as an evidence-based treatment modality that will remain available to men with LUTS secondary to BPH who seek this therapy.

“We urge the AUA to reconsider this recommendation, which is unnecessarily restrictive and is not founded in evidence. The SIR and the IR community stand ready to partner with urologists to ensure provision of the treatment that is most appropriate for each patient based on his clinical situation, risk tolerance and priorities.”

While AUA calls for more Level 1 evidence, some interventional radiologists claim this is “an impossibility”

In April this year, an SIR Foundation-sponsored research consensus panel for PAE was convened with urologists from the AUA with the aim of positively establishing the procedure in the urology society’s guidelines. The meeting was chaired by Clifford Davis (University of South Florida, Tampa, USA) and Jafar Golzarian (University of Minnesota, Minneapolis, USA). Davis informs Interventional News that since their conversation in the spring, where the AUA made it clear that it wanted additional Level 1 evidence, nothing has changed. He is therefore “unsurprised” by the consistent recommendation of the AUA to not recommend PAE outside of the context of clinical trials, and is planning funding applications for a randomised controlled trial aimed at producing Level 1 data.

There are multiple barriers to an RCT involving PAE, however. Firstly, the research consensus panellists need to decide on a study design: PAE versus a sham, or PAE versus surgery. There are concerns with conducting a trial of PAE against a sham due to crossover issues. Current guidelines from the AUA are based on RCTs with at least 12 months of data, and many had up to five years of follow-up. Patients randomised to a sham procedure or to PAE may move across to the opposite cohort before the 24-month mark, and could therefore cofound the data, but this would be still be considered as low Level 1 evidence.

Furthermore, as RCTs are so expensive, Davis explains that “industry or our national associations [in the USA] cannot afford to fund them”. Instead, interventional radiologists are looking to the National Institutes of Health (NIH) for funding. Four years ago, following an earlier SIR-sponsored research consensus panel meeting, a decision was made to apply for NIH funding for a PAE versus sham study, but this was rejected. With this precedent in mind, Davis favours “building a large, multicentre RCT comparing PAE to a surgical procedure”. A follow-up meeting to the April research consensus panel is to take place later this year to decide on which surgical procedure this may be.

“This sounds very simple”, Davis says, “but it is complicated because the patients that do best with PAE may have comorbidities for surgery. We feel that the patients who do best with PAE have bigger prostates in general, over 80g, which is not the typical patient seeking surgery. We have to compare PAE to a surgical technique that is generally accepted for a similar population. In my opinion, I think we should do an RCT [on either PAE] versus simple prostatectomy, or versus Holmium laser.” This latter option is a transurethral procedure that enucleates the prostate through the urethra, and is usually performed on men with larger prostates.

“I also think”, Davis elaborates, “an RCT trial with PAE should focus on patient satisfaction, including symptoms, quality of life, pain, and morbidity, and should not solely focus on flow rates and post-void residual (PVR) urine volumes, which are considered to be quantitative measures of surgical success. If PAE is found to be durable but less efficacious (regarding flow rates and PVR) but with fewer complications, lowers costs and reduced hospital time compared to surgical options, then I would hope the AUA would reconsider it in its guidelines for certain populations.

“In all other RCTs of surgery versus a control group, there was noted a significant drop in International Prostate Symptom Score (IPSS) even without therapy. This is a major argument of the urology community against our current data with small samples sizes and lack of long term follow-up.” In terms of data regarding the safety of radiation dose during PAE, Davis says that he and his team are currently working on publishing data from their centre in response to this concern raised by the PAE Research Consensus Panel.

Commenting on the status of the development of an RCT involving PAE, Ari Isaacson (Department of Radiology, University of North Carolina, Chapel Hill, USA), a co-author of the multisociety consensus document published in May, says: “The initial design and protocol and attempt to get funding [from the NIH] is underway, but it is a slow process. In the meantime,” he explains, “I think that a lot of urologists are going to feel handcuffed, because they do not feel that they can go against their society’s guidelines, and therefore there are going to be a lot of patients who either are not told about PAE or who are going to be dissuaded from pursuing it due to these guidelines.”

Even with funding, an RCT may not be feasible due to patient-driven issues with enrolment. Riad Salem (Northwestern University, Chicago, USA), another co-author of the multisociety position statement and an outspoken advocate of PAE, explains to this newspaper why this is the case: “An RCT has been tried, and it has been rejected, not by the medical community, but by the patients that would enroll. The BEST trial, while initiated as an RCT, was subsequently revised to a prospective comparison to TURP, because patients are not willing to be randomised to TURP. Patients are looking for minimally invasive treatments—so an RCT randomising TURP versus PAE is effectively an impossibility. It is not feasible and not constructive to wait for this clinical trial that will never happen.”

Nabeel Hamoui, one of three physicians dual-trained in urology and interventional radiology in the USA (Brooksville, USA) agrees with Salem. Hamoui expands, “I have seen this in my own experience at Northwestern. If you sit a patient down and say ‘we can do this therapy called PAE, which has fewer side effects, where you most likely do not need a catheter for more than a day, if that, and your recovery time is essentially zero, and if it fails, you can always have the other treatment option’, it is going to be very difficult to enroll enough patients into the TURP or surgery arm of an RCT. How do you accumulate Level 1 data if the patient becomes the rate-limiting factor?”

However, Isaacson tells Interventional News that the AUA was unmoved by discussions with interventional radiologists concerning past attempts to get US RCT data on PAE. “We tried to suggest alternatives as far as what types of data we could get”, he explains, “but despite our, I think solid, arguments, the reply was that unless there is RCT data, the AUA will not consider PAE as part of their guidelines. I think this methodology is flawed—their unwillingness to look at studies of other types excludes most of the evidence available that shows PAE is safe, so I think their evaluation of the procedure is limited, and they cannot gain a full, accurate picture of the safety and effectiveness of PAE. In my view, this is narrow-minded.” He adds that he is “disappointed” by the lack of change to the AUA guidelines for the surgical management of BPH.

This difficulty with accumulating Level 1 data on PAE, and the insistence of the AUA that interventional radiologists provide evidence from a US RCT investigating the procedure, has led to a “stalemate”, in Salem’s words.

Multidisciplinary cooperation called for to break the stalemate

As the US healthcare system operates on a fee-for-service model, one criticism levelled against either side in a dispute about procedural choice is that, instead of fighting for the best patient outcomes, individuals are fighting to protect their pay checks. Hamoui explains, “This is the reality of the US healthcare system. Unlike the NHS [in the UK], our system is based on the intensivity of care, not outcomes per se. As a urologist, if my practice is largely BPH-based, and I get paid to do surgery and treat them, then I am not going to want to give that up because that will affect my bottom-line. The opposite is also true: if an interventional radiologist aggressively markets PAE as the ultimate procedure, and recommend it over TURP and prostatectomy in a vast majority of cases, then they are doing so because they want money.”

However, Timothy McClure (Department of Urology, Weill Cornell Medicine, Lefrak Center for Robotic Surgery, New York, USA), a second dual-trained urologist/interventional radiologist in the USA and another co-author of the multisociety consensus position statement, says that urologists are acting solely on behalf of the patient: “I think the AUA is just being overly cautious, in part because of a lack of understanding of PAE. PAE is technically challenging, and they do not want problems arising in their patients. The guidelines are established to protect patients, so the bottom line is that they are trying to protect patients from having a procedure done that either will not make a difference or will potentially harm people. In fact, most urologists I have spoken with think PAE is a good option for certain patient populations. I think their concerns stem from a lack of understanding of what PAE is and what interventional radiologists can do. They view this as a technically challenging procedure that requires a certain level of skill which may not be applicable to the entire IR community. PAE is a complex case but skilled interventional radiologists do complex cases on a daily basis. Their concerns over radiation, complications, and side effects suggests a lack of understanding of PAE. These concerns could have been addressed by having an interventional radiologist participate with the guidelines.  It is unfortunate that the AUA did not include a representative from IR.”

Davis likewise sympathises with the AUA guidelines committee, saying: “Some have negative feelings against the AUA; I feel differently. They hold their standards for their recommendations based on Level 1 data. They have held every other surgical procedure to that same level. It is just more difficult to compare a procedure across specialties. There is distrust in the USA, because in an RCT design by definition one specialty will lose patients to the other, which could introduce subspecialty bias during patient selection into the trial.”

The AUA guidelines are not all based on Level 1 evidence, though. For example, they state that “Water vapour thermal therapy may be offered to eligible patients who desire preservation of erectile and ejaculatory function”. This is a conditional recommendation, based on Grade C evidence. Grade C means “Low quality evidence: observational studies that provide conflicting information or design problems (such as very small sample size).” However, Davis notes that, although the evidence is marked as Grace C for this recommendation, it is based on an RCT of a sham versus therapy with three months crossover, and that this trial now has follow-up to two years.

“PAE is not alone in having heterogeneous outcomes”, Salem says. “If you look at a lot of data in urology, that too is heterogeneous. Heterogeneity is unfortunately a reality in medicine. Per the AUA guidelines, urologists should only offer robotic prostatectomy if they possess the necessary skillset. Why could that recommendation also not be made for PAE?”

Hamoui points to the urology procedure transurethral nuclear ablation, TUNA, highlighting its obsolescence. “We ourselves have done procedures that are now in the dustbin of urology”, he comments. “Many of those procedures that people thought were cure-all, and that were advocated for by some of the more prominent names in urology and pushed by industry, were largely financially driven, had poor evidence, and in five to seven years completely failed. The nuclear ablation machine in the practice where I work is now collecting dust in the corner. We no longer use it due to bad outcomes, but when it was recommended, I do not think that was based on Level 1 evidence.”

Salem urges urologists to understand that PAE is not in competition with TURP or prostatectomy. “All interventional radiologists are saying”, he says, “is that PAE should be part of the discussion, and one of the treatment options. Nobody is saying that anything should be replaced. Let the patient participate in the decision-making process. By urologist’s own admission, many of their treatments do not really work in glands over 80g. Most of their trials exclude glands larger than that volume. Glands this size or larger are the ideal candidate for PAE. So we are filling a niche, a treatment gap, that exists. To me, it is short-sighted to acknowledge there is a difficulty in treating larger glands, exclude them from urology studies, and then dismiss PAE.”

That interventional radiologists wish PAE to exist within the current treatment algorithm as one option for patients is something many are eager to highlight. “The key thing that I want to get across is that PAE provides a great addition to the BPH treatment algorithm”, Isaacson articulates. It does not replace the current surgical therapies, but it does provide a nice alternative to certain patients: those with very large prostates, those on anticoagulation medication, or patients with surgical comorbidities.”

“PAE is radically different from any of the urologic treatment modalities”, Hamoui says. However, he explains that this can be a hindrance as well as a positive. “In vascular surgery and IR, there is a huge overlap, so if vascular surgeons were to come up with new guidelines, they would have a lot of legitimacy because they understand IR procedures. For me, having the dual perspective [of urology and IR], I can understand that the treatment options sit alongside each other. I do not think that urologists fully understand the benefits of the procedure.”

Hamoui believes urologist education about PAE is critical. He, alongside McClure, advocates for the involvement of interventional radiologists on the AUA guidelines committee when discussing treatment options for BPH. Speaking at urology conferences is another method used by interventional radiologists to reach out across specialty borders. Salem gave a talk at a recent meeting of the Chicago Urologic Society, which reportedly helped diminish their scepticism of PAE, and aided the attending urologists’ understanding of which patients would and would not benefit from the procedure.

Publishing in urology specific journals would also be an effective communication tool for interventional radiologists to communicate to urologists, suggests Isaacson. However, he reports that this is challenging: “We have attempted to [publish in a urology journal] several times; it is very difficult to get a PAE paper in a urology journal”. Salem, who is one of few US interventional radiologists that has published a PAE paper in a urology journal, supports this assertion, commenting, “In my 20 years of publishing over 330 papers, getting published in a urology journal was the most difficult, challenging, controversial process I have ever been through. The captious reviews were rude, insulting, and, worst of all, replete with emotional bias. We tried several times, and finally got accepted into the fourth urology journal. This was a prospective, phase two, FDA-approved study, so it met all the high level criteria, but it was still dismissed by many urology journals.”

As well as operating on the community level, many interventional radiologists have also expressed the need to start locally. “Where I work”, McClure says, “we have great collaboration with the BPH experts, and we have a good, collaborative, multidisciplinary approach to [treating] men with LUTS. Not every patient is a good candidate for PAE, and not every patient is a good candidate for TURP, so ultimately patients benefit when you have this cross-over between disciplines.”

McClure believes that urologists need to understand that interventional radiologists are clinicians and not just technicians, and that for this there needs to be a “friendly, collegial” relationship between these two specialist groups. Hamoui, who mainly works as a urologist, thinks this is easier for him due to his dual training: “I am able to appreciate what interventional radiologists bring to the table”, he says, “so I can foster that by being friendly and receptive from the get-go, rather than being hostile and looking at them as competition. I think it is unfortunate to have PAE under such hostile attack. My own father, himself also a urologist, declined a TURP and opted for PAE, [performed] by Dr Salem, and was happy with the results.”

Salem is unequivocal in how he believes the debate should move forward: “The only way to break this stalemate is to engage individuals from both sides that can take a reasonable, tempered, non-emotional approach to this therapy. Get patients and get neutral physicians involved. Create a guideline that is tempered, recognises the limitations of the data we have, and incorporates PAE as one of the many treatment options for BPH. Until the loudest, most cynical voices are excluded from the discussion, this sensationalised and vitriolic debate will never end.”