Tag: LUTS-BPH

Re: Efficacy and safety of PAE for BPH: an observational study and propensity-matched comparison with TUR of the prostate (the UK- ROPE study)

September 27, 2018/by admin Z.9

Letter to the Editor

Efficacy and safety of prostate artery embolization for benign prostatic hyperplasia: an observational study and propensity-matched comparison with transurethral resection of the prostate (the UK- ROPE study)

Sir,

We read the manuscript by Ray and colleagues and congratulate the authors for the effort spent on this remarkable work. To date, this is the first large multicentre study to assess and compare the efficacy and safety of prostate artery embolization (PAE) for lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH) with transurethral resection of the prostate (TURP). We have, however, some concerns regarding the interpretation and reporting of the study that warrant further clarification.

It was suggested that the PAE-related learning curve ranges from 10-20 cases. However, even with training and proctorship, the number of PAE each centre had performed to participate in the UK-ROPE Registry was not mentioned. It would be interesting to see a comparison of outcomes between PAE patients who had their procedures performed before and after the learning curve.
Unfortunately, due to the large number of centres in UK it was not possible to have a homogenous technique used in the PAE arm. Even considering that the PErFecTED was not used, each centre was allowed to use their own embolization technique.
Another technical issue concerns the use of cone-beam CT (CBCT) during the procedures. It is not clear whether CBCT was available and used in every case. For example, it was not mentioned whether penile ulcers were related to embolic agent’s reflux or to anastomoses that were not observed because CBCT was not available or was not used during PAE. All of these issues could be considered bias, however, it has been proven that clinical and imaging success can be achieved with different techniques.
Unfortunately, prostate volume measurement data were not available for TURP cases. This information could be important and supportive of the use of TURP, since men are very concerned about prostate volume before and after any therapy.
The estimated reported operation rate on and off the 12-month follow-up period was 19.9%. Cases of unilateral embolization, small prostate volume and median lobe enlargement were reported. However, the significance of small prostate volume was not defined, the grade of the median lobe enlargement, as well as if some patients had hypocontractile bladder rather than LUTS. Urodynamic studies might have a key role in this type of evaluation.
We understand that transient haematospermia and haematuria should be considered as side effects instead of complications, which could be added to a mail-based questionnaire system used to collect data in the Registry.

The pathophysiology of PAE is probably related to ischemia in the transitional zone of the prostate followed by coagulative necrosis. How was retrograde ejaculation (24.1%) diagnosed in the PAE group? Could it be due to a reduction in ejaculation volume resultant of prostatic tissue death after embolization? Some men stated they had been experiencing retrograde ejaculation prior to PAE due to medication. It seems that ejaculatory status was not captured at baseline. Future investigators should consider the importance of collecting these data preprocedure.

Francisco Cesar Carnevale MD PhD, Andre Moreira de Assis MD and Airton Mota Moreira MD PhD.

Department of Radiology, University of Sao Paulo, Sao Paulo, Brazil.

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Reply by the authors

We thank Carnevale and colleagues for their comments on our study. Regarding the PAE-related learning curve, these data are available and will be published separately. Procedural and screening times and therefore overall radiation dose reduced with increasing experience but there was very little difference in outcome measures in keeping with PAE being a robust technique in many centres and not just the well-known centres of excellence.

Four of the centres were trained and proctored by the Lisbon group and the remaining centres were trained by the University Hospital Southampton IRs using the same technique. The details of catheter and microcatheters used as well as the size and nature of the embolic particles are being published in a subsequent paper. Micro catheters of 2.4Fr and smaller were used in all cases at all centres. The majority of cases were embolized with either particulate PVA (Cook Medical or Boston Scientific) or spherical microspheres (Celonova/Boston Scientific). Cone beam CT was available in almost all centres and was used on the majority of cases. These data are available and are being collated for subsequent publication.

The study protocol and budget allowed normal practice for TURP patients. These did not therefore get formal Urodynamics nor post-surgical imaging and prostate volume measurements. While prostate volume was not formally measured for TURP we recorded resected weights which give some idea of gland volume, though not a reliable measure.

Unilateral embolization, small prostate volume and median lobe enlargement are important co-variates which are being analyzed and will be submitted for publication shortly. All patients having PAE had confirmed obstruction on UDS so hypocontractile bladders were excluded.

We agree that transient haematospermia and haematuria should be considered as side effects instead of complications, and could be added to a mail-based questionnaire system used to collect data in the Registry and we thank Carnevale and colleagues for pointing this out.

Baseline dry or retrograde ejaculation is common in marked prostatic enlargement being treated by alpha blockers such as Tamsulosin. It is a weakness of this study that we did not capture ejaculatory status at baseline. This will be answered in subsequent clinical studies derived from the UK-ROPE dataset.

All of these technical issues were not controlled in our pragmatic study, however, as Carnevale and colleagues note, the study has shown that clinical and imaging success can be achieved with different techniques.

A Ray¹, J Powell², MJ Speakman³, NT Longford⁴, R DasGupta⁵, T Bryant⁶, S Modi⁶, J Dyer⁷, M Harris⁷, G Carolan-Rees¹, N Hacking⁶

¹Cedar, Cardiff University/Cardiff and Vale University Health Board, Cardiff, UK

²Centre for Health Technology Evaluation, National Institute for Health and Care Excellence, London, UK

³Department of Urology, Taunton and Somerset NHS Trust, Taunton, UK

⁴SNTL Statistics Research and Consulting, Department of Medicine, Imperial College London, London, UK

⁵Department of Urology, St. Mary’s Hospital, Imperial College Healthcare NHS Trust, London, UK

⁶Department of Interventional Radiology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK

⁷Department of Urology, Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, UK

Article of the Week: Evaluating the proportion of tadalafil-treated patients with clinical improvement in LUTS associated with BPH

May 27, 2015/by admin Z.9

Every Week the Editor-in-Chief selects the Article of the Week from the current issue of BJUI. The abstract is reproduced below and you can click on the button to read the full article, which is freely available to all readers for at least 30 days from the time of this post.

In addition to the article itself, there is an accompanying editorial written by a prominent member of the urological community. This blog is intended to provoke comment and discussion and we invite you to use the comment tools at the bottom of each post to join the conversation.

Finally, the third post under the Article of the Week heading on the homepage will consist of additional material or media. This week we feature a video from Dr. Jonathan Rees, discussing the paper.

If you only have time to read one article this week, it should be this one.

Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia – integrated data from 1499 study participants

John Curtis Nickel, Gerald B. Brock*, Sender Herschorn†, Ruth Dickson‡, Carsten Henneges§ and Lars Viktrup¶

Department of Urology, Queen’s University, Kingston, *University of Western Ontario, London, †Division of Urology, University of Toronto, ‡Eli Lilly Canada Inc., Toronto, ON, Canada, §Lilly Deutschland GmbH, Bad Homburg, Germany, and ¶Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

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OBJECTIVES

To evaluate the proportion of patients achieving clinically meaningful improvement of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH-LUTS) with tadalafil using two definitions of response.

PATIENTS AND METHODS

Post hoc integrated analysis of four placebo-controlled studies in men (aged ≥45 years; International Prostate Symptom Score [IPSS] of ≥13; maximum urinary flow rate [Q_max] of ≥4 to ≤15 mL/s) with BPH-LUTS randomised to tadalafil 5 mg (752 patients) or placebo (747) for 12 weeks after a 4-week placebo run-in. Responders were defined as having a total IPSS improvement of ≥3 points or ≥25% from randomisation to endpoint (Week 12). Response status was calculated per patient, and relative benefit and odds ratio (OR) with 95% confidence interval (CI) of tadalafil vs placebo was calculated using a logistic Generalised Mixed Model for Repeated Measures.

RESULTS

Tadalafil 5 mg once daily resulted in a significantly greater proportion of patients achieving a ≥3-point IPSS improvement (71.1% and 56.0% for tadalafil and placebo patients, respectively [OR 1.9, 95% CI 1.5, 2.4; P < 0.001]) and achieving a ≥25% improvement in total IPSS randomisation to endpoint (61.7% and 45.5% for tadalafil and placebo patients, respectively [OR 2.0, 95% CI 1.6, 2.5; P < 0.001]).

CONCLUSIONS

About two-thirds of tadalafil-treated patients achieve a clinically meaningful improvement in BPH-LUTS symptoms, based on two different definitions of responder status.

Editorial: Patients not p-values

May 27, 2015/by Jonathan Rees

A well powered study can attain statistical significance at a small effect size, but in real-life clinical practice, we do not routinely judge the success or failure of treatment based on the mean result for the hundreds of patients we have treated previously. Nor do we compare the response to treatment with what would have happened if we gave our patient a placebo; instead, clinical effectiveness is determined by the response of the individual patient seated across the desk in our clinic. In an ideal world, therefore, clinical significance, as well as statistical significance, should be built into study design and influence sample size and methodology in much the same way. In this way, we could attempt to assign objectivity to what is essentially a subjective metric: ‘did this treatment work for you?’

It is 25 years since the concept of ‘minimum clinically important difference’ (MCID) was first postulated [1] and almost 20 years since Barry et al. [2] applied this theory to LUTS and the IPSS in particular. MCID represents the smallest change as a result of treatment that is of clinical importance. In a measure such as blood pressure or diabetic control, this is the difference that makes a meaningful impact on complications, but in a quality-of-life field, such as measurement of urinary symptoms where we are predominantly treating the bother caused by the symptoms, the MCID is the smallest change that is noticeable to the patient. Barry et al. showed that a three-point improvement in IPSS is the minimum change required for a patient to notice a slight improvement in symptoms (five points correlating with a moderate improvement and eight points with marked improvement). For the IPSS quality-of-life item, the MCID is considered to be 0.5 points. This is based on two considerations: in other well studied questions with similar seven-point Likert scales, the MCIDs are usually ∼0.5, with the rule of thumb that the MCID is ∼0.5 of the standard deviation/one standard error of measurement. The 2010 National Institute for Health and Care Excellence LUTS in Men Guideline examined the concept of what constituted the MCID for flow rate changes; the evidence base is weak, but a change of 2 mL/s was taken as the MCID, based on the evidence available and expert opinion [3]. A change of three points in total IPSS, however, whilst noticeable, does not necessarily imply a significant improvement in overall or disease-specific quality of life. Furthermore, in a patient with severe symptoms, an improvement of three points may represent a much smaller change than in a patient with milder symptoms at baseline, and for this reason, an improvement in IPSS of ≥25% from baseline has also been proposed as a threshold for clinically meaningful improvement.

The study by Nickel et al. [4] is a rare example of an attempt to integrate the concept of MCID into LUTS trial reporting, analysing the proportion of men with LUTS/BPH, treated with tadalafil 5 mg once daily, who achieved a meaningful improvement in symptoms based on changes in both actual and percentage IPSS. This analysis again shows the power of placebo in LUTS treatment, with approximately half the patients in placebo arms of the four studies achieving the MCID on the IPSS. For those treated with tadalafil, a greater proportion achieved the MCID, with 71.1% seeing an improvement of ≥3 points on the IPSS, and 61.7% a ≥25% change in total IPSS. This benefit over placebo was greater when more demanding clinical thresholds were used, e.g. 50 or 75% improvement on IPSS.

It is encouraging to see a paper that reports clinical significance, but whilst of interest, the study is a post hoc analysis of four trials designed to test tadalafil vs tamsulosin or placebo, for licensing approval, and not a trial designed specifically to measure the clinical significance of changes in symptoms. It is a useful reminder to urologists, however, of the concept of MCID, which despite being well established is not widely known. MCID should be incorporated into the analysis of any results based on patient-reported outcomes [5] where the clinical significance of the results may not be immediately apparent to the clinician.

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by Jonathan Rees

Backwell & Nailsea Medical Group, Nailsea, North Somerset, UK

References

1 Jaeschke R, Singer J, Guyatt G. Measurement of health status: ascertaining the minimally clinically important difference. Control Clin Trials 1989; 10: 407–41

2 Barry MJ, Williford WO, Chang Y et al. Benign prostatic hyperplasia speciﬁc health 30 status measures in clinical research: how much change in the American Urological 31 Association symptom index and the benign prostatic hyperplasia impact index is 32 perceptible to patients? J Urol 1995; 154: 1770–4

3 National Institute for Health and Clinical Excellence. The management of lower urinary tract symptoms in men. (Clinical Guideline 97.) 2010. https://guidance.nice.org.uk/CG97

4 Nickel JC, Brock GB, Herschorn S, Dickson R, Henneges C, Viktrup L. Proportion of tadalaﬁl-treated patients with clinically meaningful improvement in lower 1 urinary tract symptoms associated with benign prostatic hyperplasia – integrated data 2 from 1499 study participants. BJU Int 2015; 115: 815–21

5 McGlothin A, Lewis R. Minimal clinically important difference: deﬁning what really matters to patients. JAMA 2014; 312: 1342–3

Video: Patients not p-values

May 27, 2015/by admin Z.9

Proportion of tadalafil-treated patients with clinically meaningful improvement in lower urinary tract symptoms associated with benign prostatic hyperplasia – integrated data from 1499 study participants

John Curtis Nickel, Gerald B. Brock*, Sender Herschorn†, Ruth Dickson‡, Carsten Henneges§ and Lars Viktrup¶

Department of Urology, Queen’s University, Kingston, *University of Western Ontario, London, †Division of Urology, University of Toronto, ‡Eli Lilly Canada Inc., Toronto, ON, Canada, §Lilly Deutschland GmbH, Bad Homburg, Germany, and ¶Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN, USA

Read the full article