Trial of Tadalafil, Tamsulosin and Combination for Access Sheath Deployment
| Status: | Enrolling by invitation |
|---|---|
| Conditions: | Nephrology, Nephrology |
| Therapuetic Areas: | Nephrology / Urology |
| Healthy: | No |
| Age Range: | 18 - 99 |
| Updated: | 8/25/2018 |
| Start Date: | June 7, 2017 |
| End Date: | June 1, 2019 |
Medication Facilitated Ureteral Access Sheath Deployment During Ureteroscopy and Endoscopic-Guided Percutaneous Nephrolithotomy: A Randomized Double-Blind Placebo Controlled Trial of Tadalafil, Tamsulosin and Combination
Extensive literature exists on the use of alpha-blocker medications for the removal of kidney
stones. Alpha blockers relax certain muscles and help small blood vessels remain open. They
work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the
walls of smaller arteries and veins, which causes the vessels to remain open and relaxed.
This improves blood flow and lowers blood pressure. There are studies that demonstrate
alpha-blockers decrease ureteral pressure and help the ureter "relax."
Recent studies have shown that phosphodiesterase inhibitors may also help with ureteral stone
passing. A phosphodiesterase inhibitor is a drug that blocks an enzyme that inhibits
relaxation of smooth muscle. This means that it can help smooth muscle, such as the muscle
that lines the ureter, to relax. While ureteral relaxation is helpful in the passage of
ureteral stones, our study seeks to use this finding by pretreating participants with an
older generation alpha blocker or a phosphodiesterase inhibitor prior to passage of a
ureteral access sheath in cases in which ureteroscopy is being used to approach a ureteral or
renal stone.
By relaxing the ureter, it is possible that a larger access sheath can be safely placed. This
may allow for facilitating passage of the ureteroscope and extraction of stone fragments
while precluding the development of potentially damaging intrarenal pressure from the flow of
irrigant. The ureteral access sheath also protects the ureter from damage during the
procedure. Placement of the largest access sheath possible is helpful in that larger stone
fragments can be retrieved, the flow of irrigant is improved, and the surgical field is kept
clear of blood or debris. To date, nobody has studied whether use of an uro-selective alpha
blocker, alone, or in combination with a 5 phosphodiesterase inhibitor will result in passage
of larger access sheaths.
In this study participants will be randomized into 1 of 4 categories: Flomax (alpha-blocker),
Cialis (5-phosphodiesterase inhibitor), a combination of the 2, or a placebo arm. In this
study the placebo, or no active drug, is the current standard of care and will serve as a
control from the other 3 groups.
stones. Alpha blockers relax certain muscles and help small blood vessels remain open. They
work by keeping the hormone norepinephrine (noradrenaline) from tightening the muscles in the
walls of smaller arteries and veins, which causes the vessels to remain open and relaxed.
This improves blood flow and lowers blood pressure. There are studies that demonstrate
alpha-blockers decrease ureteral pressure and help the ureter "relax."
Recent studies have shown that phosphodiesterase inhibitors may also help with ureteral stone
passing. A phosphodiesterase inhibitor is a drug that blocks an enzyme that inhibits
relaxation of smooth muscle. This means that it can help smooth muscle, such as the muscle
that lines the ureter, to relax. While ureteral relaxation is helpful in the passage of
ureteral stones, our study seeks to use this finding by pretreating participants with an
older generation alpha blocker or a phosphodiesterase inhibitor prior to passage of a
ureteral access sheath in cases in which ureteroscopy is being used to approach a ureteral or
renal stone.
By relaxing the ureter, it is possible that a larger access sheath can be safely placed. This
may allow for facilitating passage of the ureteroscope and extraction of stone fragments
while precluding the development of potentially damaging intrarenal pressure from the flow of
irrigant. The ureteral access sheath also protects the ureter from damage during the
procedure. Placement of the largest access sheath possible is helpful in that larger stone
fragments can be retrieved, the flow of irrigant is improved, and the surgical field is kept
clear of blood or debris. To date, nobody has studied whether use of an uro-selective alpha
blocker, alone, or in combination with a 5 phosphodiesterase inhibitor will result in passage
of larger access sheaths.
In this study participants will be randomized into 1 of 4 categories: Flomax (alpha-blocker),
Cialis (5-phosphodiesterase inhibitor), a combination of the 2, or a placebo arm. In this
study the placebo, or no active drug, is the current standard of care and will serve as a
control from the other 3 groups.
Technological improvements such as the miniaturization and development dual lumen
ureteroscopes have improved the urologists' ability to treat urolithiasis1. The quality of
flexible ureterorenoscopy is dependent on adequate visualization of the upper urinary tract.
Adequate irrigation and visualization are compromised by debris from stone fragmentation
and/or any bleeding during treatment. Fortunately, use of an ureteral access sheath (UAS)
increases irrigant flow and reduces intrarenal pressure 2.
Ureteral access sheath technology was significantly improved by a member of our investigative
team (RVC) thereby making it more widely acceptable3-5. The design changes allowed for easier
deployment of the access sheath and the newer design was made to be kink resistant. This
iteration of the device is easily deployed over a guidewire and has varying lengths such that
it can be passed to the level of the stone in each case. Today's ureteral access sheaths
range in size from 11-French to 16-French in diameter. The use of a ureteral access sheath
has been shown to decrease intraoperative time, provide higher stone free rates, incur less
cost due to shorter operating room times, and lead to fewer secondary procedures5,6. The
access sheath should also, in theory, lower the risk of urinary tract infection due to
decreased intrarenal pressure thereby resulting in less pyelovenous and less pyelolymphatic
backflow. Lastly, use of an access sheath minimizes damage to the fragile flexible
ureteroscope and thus increases their longevity while decreasing repair costs7.
Despite the above findings use of the UAS has not been universally embraced. A single study
by Traxer et al., showed the incidence of low grade ureteric injury using UAS was 46% and
that with serious injuries (i.e. urothelial tears) occurred in 13%8. However, a follow-up
study by the same group showed no evidence of delayed long-term ureteral stricture formation;
in fact, the patients who had a ureteral access sheath deployed there was a lower risk of
post-operative complications9. Further, other studies have shown that the rate of ureteral
stricture formation following use of a ureteral access sheath is 1.4% compared to a baseline
rate of 1-3% during routine ureteroscopy without an access sheath10. In the afore cited
study, the solitary occurrence of a post-ureteral access sheath ureteral stricture occurred
at the ureteropelvic junction in a patient who underwent four endoscopic procedures for
struvite stones; in all four surgeries, the access sheath was deployed at the level of iliac
vessels well below the site of the patient's stricture10. Of note, porcine models have shown
decrease ureteral blood flow following the acute deployment of a large access sheath, however
over time the flow normalized and in follow-up there was no increase in post procedural
ureteral stricture formation11.
Most urologists who place a ureteral access sheath do so without any pretreatment for
ureteral relaxation. At our institution, the investigators routinely use alpha blockers
(tamsulosin) as an adjunctive medical therapy to possibly relax the ureteral muscle; the
medication is begun one week prior to surgery as it takes five days for the medicine to reach
a steady state. It has been the investigator's experience that they are able to place larger
ureteral access sheaths (i.e. 14 and 16 French size) with this approach. Additionally,
examination of the ureter at the end of the procedure has shown minimal effect from placement
of the access sheath; to date, the study team has not had any patient return with a post
procedural ureteral stricture. Of note, it is the investigator's practice that if there is
any resistance to deployment of the ureteral access sheath, then a smaller sized sheath is
used; should the smaller sheath encounter resistance to its passage then a ureteral stent is
placed and the procedure is postponed for a week. Stent placement in a ureter facilitates
subsequent placement of an access sheath8,12.
An extensive literature exists on the role of alpha-blocker medications on the relaxation of
ureteral smooth muscle13. This is due to the numerous alpha-1 receptors along the ureter,
particularly in the distal ureter14,15. This knowledge originally led to the development of
medical expulsive therapy in the treatment of ureteral stones. Several meta-analyses have
shown that alpha blockers help passage of distal ureteral stones in the 5-10mm range, in less
time and with less pain. The most extensively studied medication in this regard has been
tamsulosin In addition to alpha blockade, recent in vitro studies have shown that
phosphodiesterase-5 (PDE-5) inhibitors such as a tadalafil, commonly known by its tradename
Cialis, also facilitate ureteral relaxation18-20. This has been substantiated by clinical
studies which showed that sildenafil compared to placebo improved stone passage by 27%21.
Further when tadalafil was added to tamsulosin the result was improved stone passage; the
combined medications were well tolerated22,23.
ureteroscopes have improved the urologists' ability to treat urolithiasis1. The quality of
flexible ureterorenoscopy is dependent on adequate visualization of the upper urinary tract.
Adequate irrigation and visualization are compromised by debris from stone fragmentation
and/or any bleeding during treatment. Fortunately, use of an ureteral access sheath (UAS)
increases irrigant flow and reduces intrarenal pressure 2.
Ureteral access sheath technology was significantly improved by a member of our investigative
team (RVC) thereby making it more widely acceptable3-5. The design changes allowed for easier
deployment of the access sheath and the newer design was made to be kink resistant. This
iteration of the device is easily deployed over a guidewire and has varying lengths such that
it can be passed to the level of the stone in each case. Today's ureteral access sheaths
range in size from 11-French to 16-French in diameter. The use of a ureteral access sheath
has been shown to decrease intraoperative time, provide higher stone free rates, incur less
cost due to shorter operating room times, and lead to fewer secondary procedures5,6. The
access sheath should also, in theory, lower the risk of urinary tract infection due to
decreased intrarenal pressure thereby resulting in less pyelovenous and less pyelolymphatic
backflow. Lastly, use of an access sheath minimizes damage to the fragile flexible
ureteroscope and thus increases their longevity while decreasing repair costs7.
Despite the above findings use of the UAS has not been universally embraced. A single study
by Traxer et al., showed the incidence of low grade ureteric injury using UAS was 46% and
that with serious injuries (i.e. urothelial tears) occurred in 13%8. However, a follow-up
study by the same group showed no evidence of delayed long-term ureteral stricture formation;
in fact, the patients who had a ureteral access sheath deployed there was a lower risk of
post-operative complications9. Further, other studies have shown that the rate of ureteral
stricture formation following use of a ureteral access sheath is 1.4% compared to a baseline
rate of 1-3% during routine ureteroscopy without an access sheath10. In the afore cited
study, the solitary occurrence of a post-ureteral access sheath ureteral stricture occurred
at the ureteropelvic junction in a patient who underwent four endoscopic procedures for
struvite stones; in all four surgeries, the access sheath was deployed at the level of iliac
vessels well below the site of the patient's stricture10. Of note, porcine models have shown
decrease ureteral blood flow following the acute deployment of a large access sheath, however
over time the flow normalized and in follow-up there was no increase in post procedural
ureteral stricture formation11.
Most urologists who place a ureteral access sheath do so without any pretreatment for
ureteral relaxation. At our institution, the investigators routinely use alpha blockers
(tamsulosin) as an adjunctive medical therapy to possibly relax the ureteral muscle; the
medication is begun one week prior to surgery as it takes five days for the medicine to reach
a steady state. It has been the investigator's experience that they are able to place larger
ureteral access sheaths (i.e. 14 and 16 French size) with this approach. Additionally,
examination of the ureter at the end of the procedure has shown minimal effect from placement
of the access sheath; to date, the study team has not had any patient return with a post
procedural ureteral stricture. Of note, it is the investigator's practice that if there is
any resistance to deployment of the ureteral access sheath, then a smaller sized sheath is
used; should the smaller sheath encounter resistance to its passage then a ureteral stent is
placed and the procedure is postponed for a week. Stent placement in a ureter facilitates
subsequent placement of an access sheath8,12.
An extensive literature exists on the role of alpha-blocker medications on the relaxation of
ureteral smooth muscle13. This is due to the numerous alpha-1 receptors along the ureter,
particularly in the distal ureter14,15. This knowledge originally led to the development of
medical expulsive therapy in the treatment of ureteral stones. Several meta-analyses have
shown that alpha blockers help passage of distal ureteral stones in the 5-10mm range, in less
time and with less pain. The most extensively studied medication in this regard has been
tamsulosin In addition to alpha blockade, recent in vitro studies have shown that
phosphodiesterase-5 (PDE-5) inhibitors such as a tadalafil, commonly known by its tradename
Cialis, also facilitate ureteral relaxation18-20. This has been substantiated by clinical
studies which showed that sildenafil compared to placebo improved stone passage by 27%21.
Further when tadalafil was added to tamsulosin the result was improved stone passage; the
combined medications were well tolerated22,23.
Inclusion Criteria:
- Patients undergoing percutaneous nephrolithotomy (PCNL) or ureteroscopy (URS) for
renal or proximal ureteral urolithiasis
- A documented sterile urine culture within 1-2 weeks of the procedure
- ≥ 18 years old
- Ability to understand and the willingness to sign a written informed consent
Exclusion Criteria:
- Patients < 18-years-old
- Presence of ureteral stent or nephrostomy tube prior to scheduled procedure
- Patients requiring open, endoscopic, or laparoscopic procedure in the same setting as
the intended URS or PCNL
- Planned concurrent bilateral endoscopic ureteral procedures
- Patients currently taking alpha-blockers within 14 days of surgery
- Patients taking PDE-5 inhibitors within 14 days of surgery
- Pregnant women
- Active urinary tract infection (UTI) or uncontrolled HIV
- Uncorrected coagulopathy
- Patients who cannot stop their blood thinners, and/or non-steroidal anti-inflammatory
medications 5-7 days prior to the procedure
- Patients allergic to tamsulosin or tadalafil
- Patients with upcoming cataract surgery due to risk of floppy iris syndrome
- Patients with history of priapism
- Patients with hereditary retinitis pigmentosa
- Patients concurrently using nitrates for myocardial infarction (MI) or angina
- Patients with high risk cardiovascular disease: left ventricular outflow obstruction,
MI in last 90 days, unstable angina, stroke in last 6 months, uncontrolled arrhythmias
- Patients with renal impairment (CrCl < 30 mL/min) or severe hepatic impairment
(Child-Pugh score ≥ 10)
- Patients using CYP3A4 inhibitors such as clarithromycin, ritonavir, ketoconazole, or
Iitraconazole
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