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Rashid Sayyid: Hello, everyone, and thank you for joining us in this UroToday recording. I'm Rashid Sayyid, a urologic oncology fellow at the University of Toronto, and along with Zach Klaassen, associate professor and program director at Wellstar MCG Health. We'll be discussing the recently updated AUA guidelines looking at the management of lower urinary tract symptoms attributed to BPH. In this four-part series, we'll be discussing the medical therapy of such patients. This article has recently been published in the Journal of Urology with Dr. Jaspreet Sandhu leading the latest modification of these guidelines.

In this section, we'll be discussing medical therapy, specifically that pertaining to alpha blockers, 5-alpha reductase inhibitors, PDE-5 inhibitors, and acute urinary retention. In two previous recordings, we've previously gone over the epidemiologic background of BPH as well as the evaluation in the pre- and post-op settings. In the later update, we'll be discussing the surgical therapy and future directions in this space.

Without further ado, let's delve into the alpha blockers and the guidelines pertaining to those in this space. Statement number 10 states that clinicians should offer one of the following alpha blockers as a treatment option for patients with bothersome, moderate, severe lower urinary tract symptoms in BPH.

There are really five options in this setting. These are alfuzosin, doxazosin, silodosin, tamsulosin, and terazosin. This is a moderate recommendation with a grade A level of evidence. Essentially, one important question that comes up in the clinic all the time is, is one better than the other? From a pure efficacy standpoint, it appears that they all have equivalent efficacy, and so they all improve the IPSS scores in the range of five to eight points. As a comparator, placebo usually has a benefit of two to four points. So we see a net three to six-point benefit in this setting.

Based on this, one question that we often are faced with in practice is, is there any benefit in changing from one alpha blocker to another when it fails? Clearly, the answer is no, given that they all work similarly and in similar ways as well.

There's recent data from a network meta-analysis published in 2015 that looked at these different drugs. A network meta-analysis is an advanced form of meta-analysis whereby different treatment options that have a common comparator such as placebo or a common denominator can be compared across trials. This allows for a comparison of efficacy, safety, and different outcomes. Based on this data, it is quite clear that all the alpha blockers have similar efficacy.

Statement number 11 states that when prescribing an alpha blocker for the treatment of lower urinary tract symptoms in BPH, the choice of alpha blockers should be based on patient age and comorbidities and different adverse event profiles, for example, ejaculatory dysfunction or changes in blood pressure. This is a moderate recommendation with a grade A level of evidence.

The two oldest alpha blockers are terazosin and doxazosin. These are also used for the treatment of hypertension, so they lower blood pressure. It's not surprising that these are the two alpha blockers that are associated with the highest risk of orthostatic hypotension. That's because these drugs are nonspecific alpha-1 receptor blockers. And it's also important to highlight that these are the drugs which probably should not be used with a PDE-5 inhibitor such as Cialis or Viagra because the risk of orthostasis is much higher when these drugs are combined, specifically terazosin and doxazosin. This doesn't really apply to the other alpha blockers.

Now, the other three alpha blockers, tamsulosin, alfuzosin, and silodosin, have a lower risk of orthostasis, and that's because they have higher selectivity for the alpha-1A as opposed to the alpha-1B receptor. And these drugs have different selectivity. We see that silodosin, or Rapaflo marketed in the US, has the highest selectivity. It's a 161:1 ratio compared to tamsulosin or Flomax, which is 10:1.

And so, as such, silodosin probably has the lowest risk of orthostasis. But on the flip side, this comes at the price of ejaculatory dysfunction, whereby we see that this adverse effect is highest with the selective alpha-1a blockers, again, tamsulosin and silodosin. This is because of the paralysis of the smooth muscles in the wall of the prostatic ducts and ejaculatory ducts. When we compare these drugs to placebo, we see that the odds ratio of having retrograde ejaculatory dysfunction is 33-fold higher with silodosin and ninefold higher with tamsulosin. So much, much higher risk when compared to doxazosin, which is essentially the same as terazosin, which is slightly increased in alfuzosin as well.

So again, when we see these patients in practice, we have to weigh the risks and benefits. If you're worried about orthostasis, go for tamsulosin or silodosin. If the patient is younger and really worried about ejaculatory dysfunction, then consider the older non-selective drugs like terazosin and doxazosin in this setting.

This really also matters with age, and we see that with silodosin, the Rapaflo, the drug with the highest risk of retrograde ejaculation, this risk is especially high in the youngest patients. As we look at the table here, we see that in those younger than 60 years, the risk is about 46%. As patients get older, 60 to 70, it almost halves at 25%, and then older than 70, again halves to about 11 to 12%.

This is reflected in the discontinuation rate due to ED, which is as high as 5% in those who are in the youngest age group, less than 60, 3% in 60 to 70, and essentially really none of the patients older than 70 discontinued because of this side effect. Again, we see younger sexually active men, this is probably the side effect most bothersome to them. So again, it's important to counsel these patients and make a decision, inform them of that.

Conversely, when treating patients on several antihypertensive medications or with orthostatic hypotension, it is best to select an alpha blocker that exhibits minimal impact on blood pressure. For example, the highly selective alpha-1 blocker, silodosin.

Another thing that comes up often in the clinic is the issue of alpha blockers and intraoperative floppy iris syndrome. Statement number 12 indicates that when initiating alpha blocker therapy, patients with planned cataract surgery should be informed of the associated risks and be advised to discuss these risks with their ophthalmologist, and this is an expert opinion.

Often as urologists or people who treat BPH, we're not familiar with this syndrome. What is floppy iris? It's a triad of three things: progressive intra-op miosis despite pre-op dilation, there's a billowing of a flaccid iris, and there's an iris prolapse towards the incision site during the phacoemulsification for cataracts. This is because of the dilator smooth muscle inhibition in the iris, and this risk appears to be highest with tamsulosin. For example, it's 40 times higher with tamsulosin compared to alfuzosin.

It's essentially the same phenomenon. We have the alpha receptors in the iris, the dilator smooth muscles, and this is inhibited by these drugs. We see these patients in practice, many of them are considering cataract surgery. How far along or how far in advance do we need to stop these drugs? It appears that four to seven days is the sweet spot for these drugs. Obviously, you can discontinue for longer, but we risk seeing lots of even retention in certain patients. It appears that four to seven days is the sweet spot, but it's important to be aware that this does not completely negate or nullify the risk of this complication.

What about 5-ARIs? For the purpose of symptom improvement, 5-ARI monotherapy should be used as a treatment option in patients with LUTS BPH with prostatic enlargement as judged by a prostate volume of greater than 30 grams on imaging, a PSA greater than 1.5, or palpable prostate enlargement on DRE. This is a moderate recommendation with grade B level evidence. We previously hinted that testosterone is converted to DHT by the 5-alpha reductase and then exerts effects including translocation of the nucleus and promotes proliferation.

And so, the 5-ARIs inhibit the conversion of testosterone to DHT, and this leads to prostate shrinkage by approximately 15 to 25% by six months. It's most pronounced in the glandular epithelial prostatic component. Given that these are the cells that produce the PSA, we see a reduction of the serum total and free PSA by about 50%.

Currently, there are two 5-ARIs. We have finasteride at the five milligram dose, and this inhibits the 5-ARI type two iso-enzyme only. And this is the predominant one in the prostate. It has a T half of about six to eight hours. It reduces intraprostatic DHT by about 80% and improves the IPSS score by about three to four points in most patients.

Also, we have dutasteride at the 0.5 milligram dose, which is approved in this setting, and inhibits both type one and type two 5-alpha reductases. This T half is much longer as opposed to finasteride where we saw six to eight hours. It's much longer at five weeks. Given that it inhibits both type one and type two androgen, the alpha reductase, it reduces intraprostatic DHT by 94%.

Based on the results of the phase three CombAT trial, which we'll discuss further later on, it improves the IPSS as well by about four to five points in comparison to placebo by about 2.3 points. In the REDUCE trial, which included men with an IPSS less than eight and a prostate volume between 40 to 80 ccs, dutasteride reduced the risk of clinical progression, meaning an IPSS increase by four or higher, acute retention, UTI, or BPH-related surgery from 36% to 21%.

And so, clearly, both drugs work quite well in this setting. There's been a head-to-head trial of finasteride versus dutasteride. Essentially, it demonstrated no differences with regards to the result in prostate volume, the AUA symptom index scores, or the max flow in this setting.

And so, just a brief comment about 5-ARIs in prostate cancer. This drug has been trialed in different settings and there's been some media attention as well as a black box labeling with regards to this drug and the risk of prostate cancer. And so, there are three trials in this setting that have looked at the association between these drugs and the risk of prostate cancer.

One of the first we published was the results of the PCPT trial that was published in the New England Journal of Medicine in 2003. This was an RCT of 18,000 men with a PSA less than three that were randomized to receive either finasteride or placebo. And patients underwent a biopsy if the PSA went to above four, if they had abnormal rectal exam findings. If they didn't have the biopsy, then all the patients in the trial were mandated to undergo an end-of-study per protocol biopsy in all subjects.

We saw in this trial that patients in the finasteride group had a 25% relative reduction in the overall prostate cancer risk, going from 24% to 18%. However, there was a higher incidence of high-grade cancer in the finasteride group, going from 5.1% to 6.4%. That rang some alarm bells in that setting.

Next, we have the REDUCE trial that was published also in the New England Journal of Medicine in 2010. This was a phase three double-blind RCT of dutasteride versus placebo in men with a PSA between 2.5 and 10. All these patients had a negative biopsy within six months of enrollment, about 8,000, and then all underwent a mandated 10-core transrectal ultrasound-guided biopsy at two and four years.

Similar to the PCPT trial, there was a 23% relative risk reduction in the prostate cancer risk from 25% to 20%. However, the incidence of high-grade cancer defined as Gleason 8 or worse also increased from 0.03% to 0.36%. So overall, it's almost a 20-fold increase, but from an absolute standpoint, the incidence increased by only 0.33%. So quite a small effect.

Now, what about the CombAT trial? The CombAT trial was a four-year double-blind RCT of about 5,000 men who had moderate to severe BPH, an IPSS score of 12 or worse, a prostate volume of at least 30 ccs, and a serum PSA of 1.5 to 10. These patients were randomized to dutasteride versus placebo.

Unlike the other two trials, the PCPT and the REDUCE trial, biopsies were performed for cause only. As such, this was considered more of a real-world trial in the setting whereby only specific indications of elevated PSA or rectal exam prompted the biopsy. Similar to the other two trials, the risk of any prostate cancer was lower with dutasteride. It was about 35% compared to 41% with placebo.

But also, it's worth noting that patients in the dutasteride arm were also 40% less likely to undergo a prostate biopsy. Is the incidence truly lower, or are we just finding it less often because a biopsy is performed less often? That's a subject matter for debate.

But unlike the other two trials, there was a corresponding reduction in the incidence of high-grade Gleason score cancer. There's not a lot of clarity when it comes to this subject, but again, it's something important for us to be aware of and something to counsel our patients on when considering initiating this drug.

At this point, I'll turn it over to Zach. We'll go over guideline statement 14 of 5-ARIs.

Zach Klaassen: Thanks so much, Rashid. Guideline statement 14, moving to the 5-ARIs, tells us that 5-ARIs alone or in combination with alpha blockers are recommended as a treatment option to prevent progression of LUTS or BPH and/or reduce the risk of urinary retention and the need for future prostate-related surgery. This has a grade A level of evidence.

Looking at the PLESS trial, this was a multicenter double-blind phase three RCT, finasteride versus placebo in more than 3,000 men with moderate to severe LUTS and an enlarged prostate on DRE. Finasteride five milligrams reduced the four-year risk of BPH surgery from 10.5% to 5%, acute urinary retention from 7% down to 3%. Finasteride also decreased IPSS by threefold, improved urinary flow rates, and reduced prostate volume.

Furthermore, before starting a 5-ARI, clinicians should inform patients of the risks of sexual side effects, certain uncommon physical side effects, and the low risk of prostate cancer, which Rashid just outlined for us. This is grade C evidence. We know that 5-ARIs lead to an increased risk of erectile dysfunction by approximately 10% during follow-up, also lead to decreased semen volume and libido when dutasteride was combined with tamsulosin. Gynecomastia risk is about 2% of patients. There's some weak evidence suggesting a potential risk of dementia, depression. There's inconsistent evidence with this, but we do have it listed here for completeness' sake and as well as post-finasteride syndrome, which is this collection of symptoms from chronic 5-ARI use leading to sexual, physical, and psychological symptoms.

There's no strong evidence for post-finasteride syndrome, but this is based on anecdotal case reports and weak observational studies. However, as Rashid mentioned, there is an FDA label warning of this risk.

Based on expert opinion, clinicians may consider 5-ARIs as a treatment option to reduce intraoperative bleeding in peri or postoperative need for blood transfusions after TURP or other surgical interventions for BPH. There was one RCT and two non-randomized studies that suggested that use of 5-ARIs pre-OP reduced blood loss or transfusion requirements post-TURP. However, three RCTs did not show a benefit for blood loss, excessive severe bleeding, or clot retention or risk. This is based on expert opinion alone.

Let's move and shift gears to the PDE-5 inhibitors. Statement number 17, based on grade B evidence, suggests that for patients with LUTS and BPH, irrespective of comorbid ED, five milligram daily tadalafil should be discussed as a treatment option. We know that this improves the mean IPSS score by 5.4 points. There was similar efficacy compared to tamsulosin, 0.4 milligrams in an RCT, whereby tadalafil improves the IIEF score by six points.

Tadalafil does not improve urodynamic parameters, and sildenafil 50 to 100 milligrams also improves IPSS by 6.3 points after 12 weeks of therapy. This may be considered as an alternative when tadalafil is not available, and alpha blockers are not tolerated.

With regards to combination therapy, statement 18, based on grade A level of evidence, states that a 5-ARI in combination with an alpha blocker should be offered as a treatment option only to patients with LUTS associated with demonstrable prostate enlargement, as judged by a prostate volume of greater than 30 grams on imaging, a PSA greater than 1.5, or a palpable prostate enlargement on DRE.

This is based on the famous MTOPS trial. This included more than 3,000 patients who had finasteride plus doxazosin versus finasteride versus doxazosin plus placebo. This demonstrated that the combination of doxazosin plus finasteride versus doxazosin or finasteride monotherapy was associated with a significant improvement in the following parameters: risk of clinical progression decreased by 66% versus 34 to 39%, risk of retention or need for invasive therapy, reduction in symptom scores, as well as improvement in flow rate. Furthermore, there's the CombAT trial which we've discussed. This included tamsulosin versus dutasteride versus combination in patients with a prostate greater than 30 ccs on TRUS ultrasound and PSA greater than 1.5. They had significantly improved outcomes with combination therapy with regards to symptoms from nine months moving forward, BPH-related health status from 12 months onwards, as well as Qmax from six months onwards.

The four-year follow-up data showed that dutasteride and the combination therapy were equivalent if the baseline prostate volume was greater than 60 mLs and PSA was greater than four. Combination only was superior if prostate volume and PSA were lower than these thresholds. The guideline suggests that patients may start combination therapy and then later discontinue the alpha blocker to allow time to exert the 5-ARI effects. However, this has not been studied rigorously, and there is insufficient data at this point in time.

Statement 19 discusses anticholinergics. These should be used alone or in combination with an alpha blocker and may be offered for patients that have moderate to severe predominant storage-related lower urinary tract symptoms. This is grade C evidence. There is evidence that solifenacin and tolterodine are safe in patients with BPH and moderate to severe LUTS with a low risk of urinary retention at less than 1%, although we should be monitoring their post-void residual when they're on these medications. IPSS improvement when an anticholinergic is added to an alpha blocker is minimal and has been variable with regards to results in these trials.

Statement 20, beta-3 agonists in combination with an alpha blocker, may be offered as a treatment option to patients with moderate to severe predominant storage lower urinary tract symptoms. Again, this is grade C evidence. These studies have shown that mirabegron does not increase the risk of acute urinary retention, with roughly a 2% incidence in patients with a mean IPSS of 20. Combination therapy with an alpha blocker is safe and tolerated and can lead to improvement in symptoms similar to dosing with anticholinergics. This may be considered in older patient populations or others where anticholinergic therapy is not recommended or tolerated.

Statement 21, based on grade C evidence, suggests that clinicians may offer the combination of low dose daily tadalafil, 5 milligrams, with alpha blockers for the treatment of LUTS and BPH. Data from three trials suggest minimal to no improvement in IPSS with a slight increase in the risk of adverse events with a relative risk of 1.26.

We may also consider the combination of low dose sildenafil, 25 milligrams, plus tamsulosin, which leads to an improved IPSS by 7.7 points and IIEF by nine points. It's also been assessed the combination of vardenafil, 10 milligrams, plus tamsulosin, 0.4 milligrams, which also may improve the IPSS score.

Statement 22, again, grade C evidence, suggests that clinicians may offer the combination of low dose daily tadalafil, 5 milligrams, with finasteride for the treatment of LUTS and BPH. There was a six-month follow-up from an international RCT of tadalafil plus finasteride versus finasteride that demonstrated improvement in IPSS was minimal, as well as minimal improvement in quality of life. Of note, there was a slight increase in adverse events in this trial for the combination therapy, 31% versus 27%.

The panel consensus was that the impact of the combination of low dose daily tadalafil with finasteride offers little or no advantages in symptom improvement over finasteride alone in the short-term follow-up.

Let's talk about acute urinary retention. Statement 23 states that physicians should prescribe an alpha blocker prior to a voiding trial to treat patients with acute urinary retention related to BPH. This is based on grade B evidence.

Statement 24 suggests that patients newly treated for acute urinary retention with alpha blockers should complete at least three days of medical therapy prior to attempting a trial without a catheter.

Moving on to statement 25, this is grade C evidence. Clinicians should inform patients who pass a successful trial without a catheter for retention from BPH that they do remain at increased risk for recurrent urinary retention.

There have been several medications looking at this. Alfuzosin increases the chance of a successful trial of void from 39% up to 60%. Tamsulosin increases the chance of a successful trial of void from 29% to 47%. And the 5-ARIs have been successful in reducing the long-term risk of retention, with a 6% risk reduction with dutasteride. The guideline panel recommends that practitioners should also consider delaying a voiding trial in patients with an active UTI until the infection has resolved.

This is the Trial of Medical Therapy Algorithm provided by the AUA. Starting at the top left, an alpha blocker is initiated. If these patients have a lack of or incomplete response, or the alpha blocker cannot be tolerated, and if their prostate is greater than 30 ccs, we may consider the addition of 5-ARI therapy. If there's a lack of response or incomplete quality of life improvement, then we can discuss surgical options here.

Moving down to the bottom left, if there's a lack of or incomplete response to alpha blockers, or the patient cannot tolerate the therapy, we can consider a trial of the addition of PDE-5 inhibitors. Again, if there's a lack of or incomplete response, we then move to the discussion of surgical management.

You can see that based on all of these combinations with several types of medications, if they work, this is fantastic; we can avoid surgical procedures, but if they start to fail and we've switched up the treatment options, everything sort of leads to the discussion of surgical management at some point in the future for these patients if the medications are not working.

In conclusion, alpha blockers have success in improving lower urinary tract symptoms but should be selected based on a patient's comorbidity profile. When prescribing 5-ARIs, patients should be counseled on the side effects, including the likely slight increased risk of prostate cancer. PDE-5 inhibitors may be used when patients have LUTS and erectile dysfunction in combination.

Fourth, a combination of alpha blocker plus 5-ARI may be offered when LUTS is present in the setting of documented prostate enlargement. Finally, patients with acute urinary retention should be counseled that they are at risk of repeat retention and that medical therapy should be able to decrease the risk of repeat acute urinary retention episodes.

We thank you very much for your attention to this AUA guideline discussion of BPH, focusing on medical therapy.