By Betsy Bates
ANAHEIM, Calif. (EGMN) - Three separate PDE-5 inhibitors approved for the treatment of erectile dysfunction showed powerful effects on lower urinary tract symptoms in trials unveiled at the annual meeting of the American Urological Association.
Effects of these drugs seen on standardized measurements were on par with or even surpassed the effects of traditional medications used in treating symptoms secondary to benign prostatic hyperplasia (BPH), including alpha-blockers and 5-alpha-reductase inhibitors, said Dr. Kevin T. McVary, professor of urology at Northwestern University, Chicago.
"These are all pilot studies, preliminary studies," he said of research from his institution, the South Florida Medical Research group in Aventura, and the Ludwig Maximilians University, Munich. "But if this is consistent, we are going to see this class of drugs used for this indication."
A potential pathophysiologic link between erectile dysfunction (ED) and lower urinary tract symptoms (LUTS) was first proposed by a French urologist in 1996.
"Basically, at the AUA, he was laughed off the stage," Dr. McVary recalled.
"We looked at these diseases as totally separate, perhaps occurring in the same people by coincidence. We now realize from different studies that these two diseases, ED and [BPH]/LUTS ... in a sense have a common etiology. In the last couple of years, we have been attempting to link the biology by treating one disease and seeing an impact on the other."
Two of the studies enrolled men with BPH, whether or not they suffered from ED. The third enrolled patients with both conditions. All showed improvement in ED, as expected, but they also had strong, consistent reductions in LUTS.
The German study, presented by Dr. Boris Schlenker, randomized 223 men aged 45-64 years with moderate to severe BPH (based on International Prostate Symptom Score [IPSS]) to receive 10 mg of vardenafil (Levitra) twice daily. Subjects were excluded if they had prostatitis, a history of prostate cancer or certain cardiovascular diseases, acute urinary retention, or previous treatment of their BPH.
By 8 weeks, mean scores on the total IPSS (a 0-35 scale) had declined from a mean 16.8 to 11 in the vardenafil group, compared with a reduction from 16.8 to 13.2 in the placebo group, a highly significant difference (P = .0013).
Even more dramatic were reductions in obstruction and irritation subscores of the IPSS, Dr. Schlenker said at a press briefing during the meeting.
Significant improvements also were seen on a urologic quality-of-life scale, the UROLIFE, among men randomly assigned to receive the active drug.
Paralleling findings from the other two studies, no differences were seen in peak urinary flow rates or postvoid residuals, which pointed to a mechanism of action other than a nitric oxide effect on the prostate, Dr. Schlenker said.
Dr. McVary agreed and suggested a number of other theories, including PDE-5 (phosphodiesterase type 5) activation in the bladder, an impact on neural transmission of altered sensory perceptions at the spinal cord, dilation of small vessels responsible for pelvic ischemia, or a muting of autonomic hyperreactivity in systemic nervous tone.
Regardless of the mechanism, the PDE-5 inhibitors seem to have a class effect on LUTS, investigators at the press briefing agreed.
Dr. McVary, for example, conducted a post hoc analysis of 186 men with severe LUTS and 155 with moderate LUTS in a 12-week study of 369 subjects aged 45 years or older with both ED and BPH. The men were randomized to receive placebo or sildenafil 50 mg titrated to 100 mg daily if tolerated.
He found that those patients with the most severe LUTS had the greatest improvement in IPSS (–8.6, compared with –2.4 among men with severe LUTS assigned to placebo). Men with moderate LUTS saw a 3.6-point decline in IPSS scores, compared with a 1.7-point drop in those with moderate LUTS who received placebo.
In part, the study design favored a larger decline in symptoms among those with the most severe disease, Dr. McVary noted, but he said the findings were nonetheless striking.
"The magnitude of IPSS improvement is really quite comparable to all of the other drugs [for LUTS] we've come to know and love over the last 20 years," he said.
"It's very similar to what we see with alpha-blockers - in fact, better than a lot of alpha-blocker studies."
The third study was presented at the press briefing by Dr. Marc Gittelman of the South Florida Medical Research group.
He found that the impact of tadalafil (Cialis) on ED was not significantly diminished in a subset of 156 men with moderate to severe LUTS in a 12-week study of the PDE-5 inhibitor in men with any degree of LUTS severity. The men were randomly assigned to placebo or tadalafil 5 mg escalating to 20 mg daily, with those on active drug achieving significantly better scores on the International Index of Erectile Function scale, regardless of the severity of their symptoms secondary to BPH.
All three studies were sponsored or supported by pharmaceutical companies: Dr. McVary's by Pfizer Inc., for which he is a consultant and lecturer; Dr. Gittelman's by Lilly ICOS, for which he is a consultant and lecturer; and Dr. Schlenker's by Bayer Health Care Pharmaceuticals.
ED Drugs May Soon Enter Armamentarium for BPH
It may be some time before clinicians begin routinely prescribing PDE-5 inhibitors to treat symptoms of benign prostatic hypertrophy, but eventually they will, investigators predicted at a press briefing during the annual meeting of the American Urological Association.
"Some people are going to be pioneers, early adopters, investigator-minded type people, and physicians who are frustrated with nonresponse in their patients" to traditional classes of drugs used to treat benign prostatic hypertrophy (BPH), Dr. McVary said.
Although many options are available to treat the symptoms of BPH, known as lower urinary tract symptoms (LUTS), these drugs are not without problems.
Roughly 30% of men discontinue using alpha-blockers within the first 12 months because of side effects or nonresponse. One drug in the class, tamsulosin (Flomax), causes ejaculatory dysfunction in 8%-30% of men, depending on the dose.
Meanwhile, 5-alpha-reductase inhibitors can induce sexual dysfunction in a number of ways, impacting ejaculation in 3% of men, diminishing libido in 3%, and causing erectile dysfunction in 3%.
The notion of prescribing a phosphodiesterase type 5 (PDE-5) inhibitor to reduce LUTS in such patients holds a certain appeal, Dr. McVary said.
Drugs in that class are rarely discontinued due to side effects such as headache, dyspepsia, or diarrhea.
"Having a better erection is a pretty nice side effect," he added.
The practical issues involved in prescribing a PDE-5 inhibitor for daily use may pose many challenges, however, Dr. Gittelman said.
A change in indication by the Food and Drug Administration could take 4 years or longer.
"How much [prescribing of PDE-5 inhibitors for BPH] will trickle into our practices depends on how much you want to practice off-label medicine," he said.
The cost and prescription plan coverage of the drug is another concern.
"I would say that in a general sense, if you could have a medication that would do more than one thing, that's a plus from a pharmaco-economic standpoint," Dr. Gittelman said.
Dr. McVary believes PDE-5 inhibitor therapy for BPH is inevitable, but he predicted widespread prescribing is probably unlikely until labeling, packaging, dosing, and cost catch up to the science. "I'm just a doctor; I'm not an economist," he said. "But I can't see us taking, say, sildenafil off the shelf and using it every day for LUTS. I just can't see that working economically."
On the other hand, Dr. McVary said that millions of men may already be unknowingly receiving low-dose therapy for their BPH whenever they pop a pill for ED.
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