Medical expulsive therapy

National Guideline Centre (UK)

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Medical expulsive therapy

Renal and ureteric stones: assessment and management

Intervention evidence review (D)

NICE Guideline, No. 118

National Guideline Centre (UK).

London: National Institute for Health and Care Excellence (NICE); 2019 Jan.

ISBN-13: 978-1-4731-3190-3

1. Medical expulsive therapy

1.1. Review question: Is medical expulsive therapy clinically and cost-effective in managing people with ureteric stones?

1.2. Introduction

Most acute stone episodes are initially treated with a period of observation as spontaneous passage of a stone often occurs. The passage of the stone is influenced by the size and site of the stone, the smaller stones <5mm having the greatest chance of stone passage along with stones in the distal ureter as this site is closest to the bladder. The majority of stones are expelled in 4-6 weeks but during this period the patient will often experience deterioration in quality of life, as they have concerns about episodes of severe pain and admission to hospital as well as the economic implications of not being able to work. There would therefore be considerable benefit to patients and the health system if this potential time to stone passage in suitable patients could be reduced by medical expulsive therapy which is the medication used to enhance the passage of stones or stone fragments. A similar benefit to promoting stone passage may also be present if medical expulsive therapy is used following active stone treatment, SWL and ureteroscopy to remove residual fragments. It has been shown that both alpha blockers and calcium channel blockers may have a role in medical expulsive therapy though there are no clear guidelines on their use in initial conservative management or following definitive stone treatment.

1.3. PICO table

For full details see the review protocol in appendix A.

Table 1

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

A search was conducted for randomised trials comparing the effectiveness of alpha blockers or calcium channel blockers versus each other, placebo, no treatment or steroids alone or as an adjunctive therapy to surgery for people with ureteric stones. Seventy-one studies (72 papers) were included in the review;¹^, ³^, ⁵^–⁹^, ¹⁴^–¹⁷^, ²⁰^–²²^, ²⁴^, ²⁸^–³¹^, ⁴²^, ⁴³^, ⁴⁹^, ⁵⁷^, ⁵⁸^, ⁶⁰^, ⁶²^, ⁶³^, ⁶⁵^, ⁶⁸^–⁷⁰^, ⁷⁶^, ⁸⁶^, ⁹²^, ⁹³^, ⁹⁵^, ¹⁰³^, ¹¹⁴^, ¹¹⁶^, ¹²⁵^, ¹³⁰^, ¹³⁷^, ¹³⁸^, ¹⁴⁰^, ¹⁴³^, ¹⁴⁷^, ¹⁵⁰^, ¹⁵²^–¹⁵⁴^, ¹⁶⁵^, ¹⁷⁰^, ¹⁷¹^, ¹⁷⁴^, ¹⁷⁶^, ¹⁷⁹^, ¹⁸⁶^, ¹⁸⁷^, ¹⁹⁴^, ¹⁹⁶^, ¹⁹⁷^, ¹⁹⁹^, ²⁰⁶^, ²⁰⁸^, ²¹³^, ²¹⁵^, ²¹⁶^, ²¹⁸^, ²¹⁹^, ²²²^, ²²⁴ these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 7-23).

In adults with distal ureteric stones <10mm, 7 studies compared alpha blockers versus calcium channel blockers, 32 studies compared alpha blockers versus no treatment, 13 studies compared alpha blockers versus placebo, 3 studies compared calcium channel blockers versus no treatment and 1 study compared calcium channel blockers versus placebo.

In adults with mid ureteric stones <10mm, 1 study compared alpha blockers versus calcium channel blockers, 1 study compared alpha blockers versus no treatment and 2 studies compared alpha blockers versus placebo. No evidence was identified comparing calcium blockers versus no treatment or placebo for mid ureteric stones.

In adults with proximal ureteric stones <10mm, 1 study compared alpha blockers versus calcium channel blockers, 3 studies compared alpha blockers versus no treatment and 2 studies compared alpha blockers versus placebo. No evidence was identified comparing calcium blockers versus no treatment or placebo for proximal ureteric stones.

Three studies compared alpha blockers versus no treatment, and 2 studies compared alpha blockers versus placebo in children with distal ureteric stones <10mm. No evidence was identified comparing alpha blockers versus calcium channel blockers, calcium blockers versus no treatment or calcium channel blockers versus placebo in children. No evidence was identified for mid or proximal ureteric stones in children.

No evidence was identified for medical expulsive therapy alone (not as an adjunct to surgery) for ureteric stones >10mm in adults or children.

In adults with distal ureteric stones, 6 studies compared alpha blockers as adjunctive therapy to surgery versus surgery only for stones <10mm, 1 study compared alpha blockers as adjunctive therapy to surgery versus surgery only for stones 10-20mm and 1 study compared alpha blockers as adjunctive therapy to surgery versus placebo and surgery for stones <10mm. No evidence was identified comparing alpha blockers versus calcium channel blockers as adjunctive therapy to surgery, or calcium channel blockers as adjunctive therapy to surgery versus placebo or surgery only.

In adults with mid ureteric stones 10-20mm, 1 study compared alpha blockers as adjunctive therapy to surgery versus surgery only. No evidence was identified for alpha blockers versus calcium channel blockers as adjunctive therapy to surgery, alpha blockers versus placebo as an adjunctive therapy to surgery, or calcium channel blockers as adjunctive therapy to surgery versus placebo or surgery only. No evidence was identified for mid ureteric stones <10mm.

In adults with proximal ureteric stones, 6 studies compared alpha blockers as adjunctive therapy to surgery versus surgery only for stones <10mm, 4 studies compared alpha blockers as adjunctive therapy to surgery versus surgery only for stones 10-20mm, and 1 study compared alpha blockers as adjunctive therapy to surgery versus placebo and surgery for stones <10mm. No evidence was identified comparing alpha blockers versus calcium channel blockers as adjunctive therapy to surgery or calcium channel blockers as adjunctive therapy to surgery versus placebo or surgery only.

No evidence was identified for medical expulsive therapy as an adjunctive therapy to surgery for ureteric stones in children.

See also the study selection flow chart in appendix C, study evidence tables in appendix D, forest plots in appendix E and GRADE tables in appendix H.

1.4.2. Excluded studies

See the excluded studies list in appendix I.

1.4.3. Heterogeneity

For the comparison of alpha blockers versus Calcium channel blockers for distal ureteric stones <10mm in adults, there was substantial heterogeneity between the studies when they were meta-analysed for the outcome of stone passage. For the comparison of alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in adults, there was substantial heterogeneity between the studies when they were meta-analysed for the outcomes of time to stone passage, stone passage, pain intensity (number of pain episodes) and analgesic use (number of times and diclofenac dose). For the comparison alpha blockers versus placebo for distal ureteric stones <10mm in adults, there was substantial heterogeneity between the studies when they were meta-analysed for the outcomes of stone passage and analgesic use (number of people using analgesics and diclofenac dose). For the comparison alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in children, there was substantial heterogeneity between the studies when they were meta-analysed for the outcome of time to stone passage. For the comparison alpha blockers versus placebo for distal ureteric stones <10mm in children, there was substantial heterogeneity between the studies when they were meta-analysed for the outcome of time to stone passage and pain intensity (daily pain episodes). For the comparison alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for proximal ureteric stones <10mm in adults, there was substantial heterogeneity between the studies when they were meta-analysed for the outcomes pain intensity (VAS), time to stone passage and analgesic use (number of people using analgesia). Where pre-specified subgroup analyses (see Appendix A:) were either unable to be performed, or did not explain the heterogeneity, a random effects meta-analysis was applied to these outcomes, and the evidence was downgraded for inconsistency in GRADE.

1.4.4. Summary of clinical studies included in the evidence review

Table 2

Summary of studies included in the evidence review.

See appendix D for full evidence tables.

1.4.5. Quality assessment of clinical studies included in the evidence review

1.4.5.1. Distal ureteric stones, <10mm, adults

Table 3

Clinical evidence summary: Alpha blockers versus placebo for distal ureteric stones <10mm in adults.

Table 4

Clinical evidence summary: Alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in adults.

Table 5

Clinical evidence summary: Calcium channel blockers versus placebo for distal ureteric stones <10mm in adults.

Table 6

Clinical evidence summary: Calcium channel blockers versus no treatment (pain management only) for distal ureteric stones <10mm in adults.

Table 7

Clinical evidence summary: Alpha blockers versus Calcium channel blockers for distal ureteric stones <10mm in adults.

1.4.5.2. Mid ureteric stones <10mm in adults

Table 8

Clinical evidence summary: Alpha blockers versus placebo for mid ureteric stones <10mm in adults.

Table 9

Clinical evidence summary: Alpha blockers versus no treatment (pain management only) for mid ureteric stones <10mm in adults.

Table 10

Clinical evidence summary: Calcium channel blockers versus placebo for mid ureteric stones <10mm in adults.

Table 11

Clinical evidence summary: Alpha blockers versus Calcium channel blockers for mid ureteric stones <10mm in adults.

1.4.5.3. Proximal ureteric stones <10mm in adults

Table 12

Clinical evidence summary: Alpha blockers versus placebo for proximal ureteric stones <10mm in adults.

Table 13

Clinical evidence summary: Alpha blockers versus no treatment (pain management only) for proximal ureteric stones <10mm in adults.

Table 14

Clinical evidence summary: Calcium channel blockers versus placebo for proximal ureteric stones <10mm in adults.

Table 15

Clinical evidence summary: Alpha blockers versus Calcium channel blockers for proximal ureteric stones <10mm in adults.

1.4.5.4. Distal ureteric stones <10mm in children

Table 16

Clinical evidence summary: Alpha blockers versus placebo for distal ureteric stones <10mm in children.

Table 17

Clinical evidence summary: Alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in children.

1.4.5.5. Adjunctive therapy: distal ureteric stones <10mm in adults

Table 18

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for distal ureteric stones <10mm in adults.

Table 19

Clinical evidence summary: Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only for distal ureteric stones <10mm in adults.

Table 20

Clinical evidence summary: Alpha blockers as adjunctive therapy to ureteroscopy versus placebo and ureteroscopy for distal ureteric stones <10mm in adults.

1.4.5.6. Adjunctive therapy: distal ureteric stones 10-20mm in adults

Table 21

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for distal ureteric stones 10-20mm in adults.

1.4.5.7. Adjunctive therapy: mid ureteric stones 10-20mm in adults

Table 22

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for mid ureteric stones 10-20mm in adults.

1.4.5.8. Adjunctive therapy: proximal ureteric stones <10mm in adults

Table 23

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for proximal ureteric stones <10mm in adults.

Table 24

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus placebo and shock wave lithotripsy for proximal ureteric stones <10mm in adults.

1.4.5.9. Adjunctive therapy: proximal ureteric stones 10-20mm in adults

Table 25

Clinical evidence summary: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for proximal ureteric stones 10-20mm in adults.

Table 26

Clinical evidence summary: Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only for proximal ureteric stones 10-20mm in adults.

See appendix F for full GRADE tables.

1.5. Economic evidence

1.5.1. Included studies

One health economic study was identified in adults with the relevant comparison and has been included in this review.¹⁵³ This is summarised in the health economic evidence profile below (Table 27) and the health economic evidence table in appendix H.

No relevant health economic studies were identified in children.

1.5.2. Excluded studies

No health economic studies that were relevant to this question were excluded due to assessment of limited applicability or methodological limitations.

See also the health economic study selection flow chart in appendix G.

1.5.3. Summary of studies included in the economic evidence review

Table 27

Health economic evidence profile: MET (tamsulosin or nifedipine) versus placebo and tamsulosin versus nifedipine.

1.5.4. Unit costs

Where several studies evaluated the same intervention in different doses we used the highest dose reported. Calculation for tablets and capsules for tamsulosin and nifedipine were made as capsules formulation of these drugs was identified in the cost utility analysis¹⁵³

Table 28

UK costs of alpha blockers and calcium channel blockers.

1.6. Resource costs

The recommendations made in this review are likely to have a substantial impact on resources.

Additional savings are likely to be made for the following reasons: MET are very inexpensive drugs, the cost of providing these would be outweighed by the savings from downstream resource use avoided because of the effectiveness of MET at helping stones to pass. Further work is being carried out to quantify the potential resource impact in this area.

1.7. Evidence statements

1.7.1. Clinical evidence statements

Distal ureteric stones

Thirteen studies compared alpha blockers to placebo in adults with distal ureteric stones <10mm. For the outcomes of stone passage and time to stone passage, the evidence suggested a clinically important benefit in favour of alpha blockers (6-13 studies; n=3788-5154). For the outcomes of hospitalisation, use of healthcare services (emergency department, doctor, nurse or outpatient visits) and quality of life, the evidence suggested no clinical difference (1-3 studies; n=210-580). The evidence suggested a clinically important benefit in favour of placebo in terms of unspecified adverse events, and no clinical difference for all other adverse event outcomes (2-7 studies; n=198-3728). For the outcome of pain intensity, measured by the visual analogue scale and EQ-5D, the evidence suggested no clinically important difference between interventions (1 study; n=219-279). For reducing the number of people experiencing pain episodes, the evidence suggested a clinically important benefit in favour of alpha blockers (1 study; n=150). In terms of the average number of pain episodes and pain intensity measured by verbal numeric pain scale, the evidence suggested no clinical difference (1-2 studies; n=219-367). The evidence suggested a clinically important benefit in favour of alpha blockers for reducing the number of people using analgesics and analgesic dose (Ketorolac and Diclofenac), but no clinical difference in the average number of episodes of analgesic use, days of analgesic use or Buprenorphine dose (3 studies; n=153-3693). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. In addition, four outcomes for stone passage and analgesic use (number of people using analgesics and Diclofenac dose) were downgraded for inconsistency.

Thirty-two studies compared alpha blockers to no treatment in adults with distal ureteric stones <10mm. For the outcomes of stone passage and time to stone passage, the evidence suggested a clinically important benefit in favour of alpha blockers (18-31 studies; n=1642-2530). For the outcome of adverse events (dizziness, headache, hypotension, retrograde ejaculation, and unspecified), the evidence suggested no clinical difference (2-9 studies; n=163-716). The evidence suggested a clinically important benefit in favour of alpha blockers for reducing hospitalisations, but no clinical difference between interventions in terms of reducing use of healthcare services (return to emergency department/primary care visit) (2-8-studies; n=77-587). Eleven studies reported reduction in the number of pain episodes and the evidence suggested a clinically important benefit in favour of alpha blockers (11 studies; n=1077). Three studies reported the number of people experiencing pain and this evidence also suggested a clinically important benefit in favour of alpha blockers (3 studies; n=240). In terms of colicky pain episodes, the evidence from one study suggested no clinical difference between interventions (1study; n=72). One study reported pain intensity measured by visual analogue scale and the evidence suggested a clinically important benefit in favour of no treatment (pain management only) (1 study; n=103). For reducing the number of people using analgesics, the average number of days of analgesic use, and the dose of analgesics (Diclofenac, Ketorolac and Pethidine), the evidence suggested a clinically important benefit in favour of alpha blockers (1-4 studies; n=64-301) but no clinical difference for average number of times analgesics were used or Buprenorphine dose (1-4 studies; 65-421). The quality of the evidence was Low to Very Low. The main reasons for downgrading the evidence were risk of bias, imprecision and inconsistency. One outcome for adverse events (headache) was downgraded for indirectness.

One study compared calcium channel blockers to placebo in adults with distal ureteric stones <10mm. This evidence suggested no clinical difference between interventions in terms of stone passage, time to stone passage, use of healthcare services (doctor, nurse or outpatient visits), hospitalisation and quality of life (1 study; n=113-535). For the outcome of adverse events, the evidence suggested a clinical benefit in favour of placebo (1 study; n=315) For the outcomes of analgesic use and pain intensity, measured on the visual analogue scale and EQ-5D, the evidence suggested no clinically important difference between interventions (1 study; n=157-314). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Three studies compared calcium channel blockers versus no treatment in adults with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of calcium channel blockers for stone passage but no clinical difference for time to stone passage (1-3 studies; n=70-179). For reducing hospitalisations, the evidence suggested a clinically important benefit of calcium channel blockers (2 studies; n=129), but no clinical difference in the average number of pain episodes (1 study; n=70). For the outcome of adverse events, the evidence suggested no clinical difference in hypotension or dizziness (1 study; n=50-59). The evidence suggested a clinical benefit in favour of calcium channel blockers for reducing the dose of analgesic (Diclofenac) (1 study; n=50). The quality of the evidence was Moderate to Very Low. The main reason for downgrading the quality of the evidence was risk of bias. In addition, two outcomes for adverse events (hypotension) and pain intensity (pain episodes) were downgraded for imprecision.

Seven studies compared alpha blockers to calcium channel blockers in adults with distal ureteric stones <10mm and the evidence suggested a clinically important benefit in favour of alpha blockers for the outcome stone passage (7 studies; 4189). Two studies reported the outcome time to stone passage and this evidence suggested no clinical difference between alpha blockers and calcium channel blockers (2 studies; n=182). Reduction in the number of hospitalisations was reported by two studies and suggested a clinically important benefit in favour of alpha blockers (2 studies; n=133). For the outcome of hospitalisation in terms of excess admission days, there was no clinically important difference between alpha blockers and calcium channel blockers (1 study; n=493). For the outcomes of quality of life and use of healthcare services (doctor, nurse or outpatient visits) there was no clinically important difference between interventions (1 study; n=216-441). For the outcome of adverse events, the evidence suggested a clinically important benefit in favour of calcium channel blockers for dizziness and headache, and a clinically important benefit in favour of alpha blockers for adverse events leading to discontinuation, but no clinical difference for hypotension, flushing or unspecified adverse events (1-2 studies; n=63-3189). The evidence suggested a clinically important benefit in favour of alpha blockers for reducing the number of people using analgesia and the number of analgesic injections used, but no clinical difference in terms of days of analgesic use, analgesic dosage or the number of people using analgesia (1-2 studies; n=50-3497). One study reported reduction in the number of pain episodes and this evidence suggested a clinically important benefit of alpha blockers (1 study; n=70). The quality of the evidence was High to Very Low. The main reasons for downgrading the evidence were risk of bias and imprecision. In addition, two adverse event outcomes were downgraded for indirectness and two outcomes for stone passage and analgesic use were downgraded for inconsistency.

Mid ureteric stones

Two studies compared alpha blockers to placebo in adults with mid ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of placebo for stone passage and time to stone passage (1-2 studies; n=21-126). The evidence suggested clinically important benefit of placebo for use of healthcare services in terms of nurse visits and hospitalisation (1 study; n=74-81). For the outcomes of doctor and outpatient visits, the evidence suggested no clinically important difference between interventions (1 study; n=74-85). For the outcome of quality of life, the evidence suggested a clinically important benefit of placebo in terms of the SF36 mental component summary but no clinical difference for the SF36 physical component summary or EQ-5D (1 study; n=50-56). For the outcomes of adverse events, the evidence suggested no clinically important difference between interventions (1 study; n=63). For the outcomes of pain intensity (EQ-5D no pain/discomfort and extreme pain/discomfort) and analgesic use, the evidence suggested a clinically important benefit in favour of placebo (1 study; n=41-63), but no clinically important difference for pain intensity as measured on the visual analogue scale or EQ-5D moderate pain/discomfort (1 study; n=56-59). The quality of the evidence was Moderate to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Two studies compared alpha blockers to no treatment (pain management only) in adults with mid ureteric stones <10mm. For the outcome of stone passage, the evidence showed a benefit of alpha blockers (2 studies; n=27). In terms of reducing the time to stone passage, the evidence also suggested a clinically important benefit in favour of alpha blockers (1 study; n=16). For reducing the average number of episodes of analgesic use, the evidence suggested a clinically important benefit in favour of alpha blocker (1 study; n=16). The quality of the evidence was Low to Very Low. The main reason for downgrading the quality of the evidence was risk of bias. In addition, the outcomes for stone passage and analgesic use were downgraded for imprecision.

One study compared calcium channel blockers to placebo in adults with mid ureteric stones <10mm. This evidence suggested a clinically important benefit of placebo for time to stone passage but no clinical difference between interventions for stone passage (n=24-84). For the outcomes of hospitalisation and use of healthcare services (doctor or nurse visits), the evidence suggested no clinically important difference between interventions (n=77-81), but for the outcome of use of healthcare services in terms of outpatient visits, the evidence suggested a clinically important benefit of calcium channel blockers (n=81). For adverse events and quality of life (SF36 mental component summary, and EQ-5D), the evidence suggested no clinical difference, but for the SF36 physical component summary of quality of life, the evidence suggested a clinically important benefit of placebo. For the outcome of pain intensity in terms of EQ-5D no pain/discomfort or extreme pain/discomfort, the evidence suggested a clinically important benefit of placebo (n=53). For the outcomes of adverse events, analgesic use and pain intensity in terms of EQ-5D moderate pain/discomfort, or as measured on the visual analogue scale, the evidence suggested no clinically important difference between interventions (n=36-59). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

One study compared alpha blockers to calcium channel blockers in adults with mid ureteric stones <10mm. This evidence suggested a clinically important benefit of calcium channel blockers for stone passage but no clinical difference for time to stone passage (n=19-81). The evidence suggested a clinically important benefit of calcium channel blockers for use of healthcare services in terms of nurse and outpatient visits, but no clinical difference in terms of hospitalisation, doctor visits and quality of life (EQ-5D and the SF36 mental component summary of quality of life) (n=50-81). For the outcome of quality of life in terms of the SF36 physical component summary, the evidence suggested a clinically important benefit of alpha blockers (n=50). For the outcomes of adverse events, pain intensity and analgesic use, the evidence suggested no clinical difference between alpha blockers and calcium channel blockers (n=39-60). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Proximal ureteric stones

Two studies compared alpha blockers to placebo in adults with proximal ureteric stones <10mm. This evidence suggested no clinical difference between interventions for the outcomes of stone passage and time to stone passage (1-2 studies; n=23-257). For use of healthcare services in terms of outpatient visits, the evidence suggested a clinically important benefit of placebo, but in terms of hospitalisation, doctor and nurse visits, the evidence suggested no clinical difference between interventions (1 study; n=141-176). For the outcomes of quality of life (SF36 mental component summary and EQ-5D), the evidence suggested no clinical difference, but in terms of the SF36 physical component summary, the evidence suggested a clinically important benefit of alpha blockers (1 study; n=84). For the outcomes of pain intensity in terms of EQ-5D no pain/discomfort, extreme pain/discomfort and analgesic use (pain medication use), the evidence suggested a clinically important benefit of alpha blockers (1 study; n=85). For the outcomes of adverse events and pain intensity in terms of EQ-5D moderate pain/discomfort, the evidence suggested a clinically important benefit of placebo (1 study; n=85-113). The evidence suggested no clinically important difference between interventions when analgesic use was measured by the number of days of pain medication use, and when pain intensity was measured on the visual analogue scale (1 study; n=74-111). The quality of the evidence was High to Very Low. The reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Four studies compared alpha blockers to no treatment in adults with proximal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage (4 studies; n=213). For reducing time to stone passage, the evidence also suggested a clinically important benefit in favour of alpha blockers (2 studies; n=133). The evidence suggested no clinical difference for outcomes of quality of life and analgesic use (1-2 studies; n=79-133). The quality of the evidence was Low to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

One study compared calcium channel blockers placebo in adults with proximal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of placebo for stone passage and adverse events, but no clinically important difference for time to stone passage (n=21-181). The evidence suggested a clinically important benefit of placebo for use of healthcare services in terms of outpatient visits, but for the outcomes of hospitalisation, doctor and nurse visits, and quality of life, the evidence suggested no clinically important difference between interventions (n=70-179). When analgesic use was measured as pain medication use, the evidence suggested a clinically important benefit of calcium channel blockers (n=97). For the outcomes of analgesic use (number of days of pain medication use) and pain intensity (as measured on the visual analogue scale and EQ-5D), the evidence suggested no clinical difference between interventions (n=74-97). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

One study compared alpha blockers to calcium channel blockers in adults with proximal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage but no clinically important difference for time to stone passage or adverse events (n=22-180). For the outcomes of quality of life, hospitalisation and use of healthcare services in terms of doctor, nurse and outpatient visits, the evidence suggested no clinically important difference between interventions (n=88-179). The evidence suggested a clinically important benefit of alpha blockers for pain intensity as measured on the visual analogue scale and EQ-5D no pain/discomfort, but a clinically important benefit of calcium channel blockers for moderate pain/discomfort (n=91-114). For the outcomes of analgesic use and pain intensity in terms of EQ-5D extreme pain/discomfort, the evidence suggested no clinically important difference between interventions (n=75-116). The quality of the evidence was High to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Children

Two studies compared alpha blockers to placebo in children with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage, time to stone passage and the number of pain episodes (2 studies; n=98). The evidence suggested a clinically important benefit in favour of placebo for headaches/dizziness, but no clinical difference between the interventions for headaches or hypotension (1 study; 1=37-61). The quality of the evidence was Low to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. In addition, outcomes for time to stone passage and pain intensity were downgraded for inconsistency.

Three studies compared alpha blockers to no treatment in children with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage, time to stone passage and analgesic use (average number of episodes of analgesic use) (1-3 studies; n=63-147). The evidence suggested no clinical difference between interventions in terms of unspecified adverse events (2 studies; n=102). The evidence also suggested no clinical difference in average number of daily pain episodes (1 study; n=63). The quality of the evidence was Low to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. In addition, the outcome for time to stone passage was downgraded for inconsistency.

MET as an adjunctive therapy to surgery

Distal ureteric stones

Five studies compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only in adults with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage, but no clinical difference in time to stone passage (2-5 studies; n=207-383). For the outcome of adverse events, the evidence suggested a clinically important benefit of SWL only for dizziness, abnormal ejaculation and headache, but no clinical difference for hypotension (1-2 studies; n=67-206). For reducing hospitalisations, the evidence suggested a clinically important benefit in favour of alpha blockers (1 study; n=88). The evidence suggested a clinically important benefit in favour of alpha blockers for reducing analgesic use (average number of episodes of analgesic use and dose of Diclofenac) (1 study; n=88-119). The quality of the evidence was Low to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. In addition, the outcomes for stone passage and analgesic use (dose of Diclofenac) were downgraded for indirectness.

One study compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only in adults with distal ureteric stones 10-12mm. This evidence suggested no clinical difference between interventions in terms of the time to stone passage or pain intensity measured by visual analogue scale(n=38). The quality of the evidence was Very Low. The main reasons for downgrading the quality of the evidence were risk of bias, indirectness and imprecision.

One study compared alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only in adults with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage (n=98). The evidence also showed a benefit of alpha blockers for reducing length of hospital stay (n=98). The quality of the evidence was Moderate to Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

One study compared alpha blockers as adjunctive therapy to ureteroscopy versus placebo and ureteroscopy in adults with distal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage and reducing the number of people using analgesics (n=102). The evidence also suggested a clinically important benefit in favour of alpha blockers for reducing the average number of pain episodes (n=102). The quality of the evidence was Low to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

Mid ureteric stones

One study compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only in adults with mid ureteric stones 10-20mm. This evidence suggested no clinical difference between interventions in terms of the time to stone passage or pain intensity measured by visual analogue scale (n=28). The quality of the evidence was Very Low. The main reasons for downgrading the quality of the evidence were risk of bias, indirectness and imprecision.

Proximal ureteric stones

Six studies compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only in adults with proximal ureteric stones <10mm. This evidence a clinically important benefit in favour of alpha blockers for stone passage (6 studies; n=405). The evidence also suggested a clinically important benefit in favour of alpha blockers in terms of outcomes for quality of life, emergency department visits, pain intensity (visual analogue scale and average number of pain episodes) and analgesic dose (Diclofenac) (1-6 studies; n=54-405), but no clinical difference in terms of the time to stone passage, hospitalisation or the number of people using analgesia (1-4 studies; n=54-320). For the outcome of adverse events, the evidence suggested no clinically important difference between interventions in terms of retrograde ejaculation or dizziness (1-2 studies; n=84-172). The quality of the evidence was Moderate to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. In addition, outcomes for time to stone passage and pain intensity were downgraded for inconsistency, and analgesic use (in terms of the number of people using analgesia) was downgraded for inconsistency and indirectness.

Two studies compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only in adults with proximal ureteric stones 10-20mm. This evidence suggested a clinically important benefit in favour of alpha blockers for time to stone passage and stone passage, but no clinical difference in pain intensity (visual analogue scale) (1-2 studies; n=57). The quality of the evidence was Very Low. The main reasons for downgrading the quality of the evidence were risk of bias, indirectness and imprecision.

One study compared alpha blockers as adjunctive therapy to shock wave lithotripsy versus placebo and shock wave lithotripsy in adults with proximal ureteric stones <10mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage and time to stone passage (n=49). The quality of the evidence was Low. The main reasons for downgrading the quality of the evidence were risk of bias, indirectness and imprecision.

Two studies compared alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only in adults with proximal ureteric stones 10-20mm. This evidence suggested a clinically important benefit in favour of alpha blockers for stone passage (2 studies; n=254). For the outcomes of time to stone passage and hospitalisation, the evidence suggested no clinical difference between interventions (1-2 studies; n=89-165). The evidence suggested no clinical difference between interventions for dizziness, but a clinically important benefit in favour of alpha blockers for reducing the number of people experiencing pain episodes (1 study; n=89). The quality of the evidence was Moderate to Very Low. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision.

1.7.2. Health economic evidence statements

Interventions studied only in separate pairwise analyses:
- One cost-utility analysis found that placebo was not cost effective compared to MET in people with symptomatic ureteric stones of ≤ 10 mm (ICER: £42,000 per QALY gained).
- One cost-utility analysis found that Nifedipine was not cost effective compared to Tamsulosin in people with symptomatic ureteric stones of ≤ 10 mm (ICER: £43,500 per QALY gained)

1.8. The committee’s discussion of the evidence

1.8.1. Interpreting the evidence

1.8.1.1. The outcomes that matter most

The committee agreed that time to stone passage, stone passage, use of healthcare services/hospitalisation, quality of life, and adverse events (hypotension, dizzy spells, falls, floppy iris, retrograde ejaculation, headaches, flushing) were the outcomes that were critical for decision-making. Pain intensity and analgesic use were also considered as an important outcome.

Evidence was reported for all of the critical and important outcomes.

1.8.1.2. The quality of the evidence

For the majority of evidence included in this review, the quality ranged from a GRADE rating of high to very low. This was due to lack of blinding, presence of selection bias, missing data and drop out, and risk of measurement bias, resulting in a high or very high risk of bias rating. Additionally, the imprecise nature of the results extracted and analysed in this review, and the presence of heterogeneity for some outcomes, further downgraded the quality of the evidence. It was also difficult to classify several studies according to the strata specified in the protocols, because the results were not stratified by stone size; for this reason, some of the evidence was downgraded for indirectness.

1.8.1.3. Benefits and harms

Evidence for people with both symptomatic and asymptomatic stones was searched for, however only 1 study included a population of people with asymptomatic stones, and this evidence suggested that there was no difference in the outcomes between people with symptomatic or asymptomatic stones. As there was no other evidence for people with asymptomatic stones, the committee were not confident that those with asymptomatic stones can be treated the same as those with symptomatic stones. They concluded that the recommendations should only apply to those with symptomatic stones.

It is important to note that the population that MET would be appropriate for would generally be people who were symptomatic but whose pain is not ongoing after treatment with analgesia.

Medication versus each other/placebo/no treatment

Distal ureteric stones <10mm

Alpha blockers

When alpha blockers were compared to placebo, the committee noted that there was a benefit of alpha blockers in terms of stone passage, time to stone passage, pain when measured as the number of people experiencing pain episodes, and analgesic use when measured as the number of people using analgesics during follow-up and average ketorolac or diclofenac dose. There was no difference between the groups in terms of all other pain and analgesic use outcomes, quality of life, use of healthcare services or hospitalisation. In terms of adverse events, there was a benefit of placebo in terms of unspecified adverse events, but no difference between interventions for all other outcomes. This suggests that alpha blockers are not associated with an increased risk of experiencing adverse effects.

When compared to no treatment (pain relief only), there was a benefit of alpha blockers in terms of stone passage and time to stone passage based on two meta-analyses of 32 and 18 studies respectively. There was also a benefit of alpha blockers in terms of hospitalisation, and analgesic use (number of people using analgesics and average dose of analgesia). The committee noted that evidence from one study demonstrated a potential benefit of no treatment (pain relief only) in terms of pain intensity when measured on a visual analogue scale, but that this conflicted with other meta-analyses demonstrating a benefit of alpha blockers in terms of the number of pain episodes and the number of people experiencing pain. The committee considered that overall, there was some evidence that alpha blockers may have an analgesic effect as well as improving stone passage, which may have implications for the patient as well as from a resource use perspective, as it may reduce the amount of analgesia required. There was no difference between the interventions in terms of adverse events, which again demonstrated that alpha blockers are not associated with an increased risk of adverse effects. The committee agreed that this evidence suggests that there is a benefit of treating people with distal ureteric stones <10mm with alpha blockers compared to no treatment.

Calcium channel blockers

When compared to placebo, there was no difference between interventions in terms of stone passage or time to stone passage. There was no difference between the intervention in terms of quality of life, hospitalisation, use of healthcare services or any pain and analgesic use outcomes, but more people discontinued from the study due to adverse events in the calcium channel blocker group compared to placebo. The committee noted that this evidence was from a single study; however they did consider that this study is from the UK and has been influential in terms of shaping current practice.

When calcium channel blockers were compared to no treatment, there was a benefit of calcium channel blockers for stone passage, hospitalisation, and analgesic use (Diclofenac dose). There was no clinical difference between interventions in terms of time to stone passage or adverse events. The committee considered that compared to no treatment, there did seem to be a benefit of calcium channel blockers. When compared to placebo, the evidence was less convincing, but they committee noted that the evidence was from a single study.

Alpha blockers versus calcium channel blockers

The committee noted that there were more stones passed, fewer patients requiring hospitalisation, fewer people discontinuing due to adverse events, fewer diclofenac injections and fewer people using analgesia for those receiving alpha blockers, compared to calcium channel blockers. The committee noted that the group receiving calcium channel blockers experienced fewer episodes of dizziness and headaches, but there was no difference between the interventions in terms of other reported outcomes, such as time to stone passage, all other adverse events, quality of life, hospitalisation, use of healthcare services, and analgesic use in terms of length of use and dose. The committee considered that the only outcomes demonstrating a clinical benefit of calcium channel blockers over alpha blockers were dizziness and headaches, and agreed that these were not very serious adverse events. The committee discussed that the benefits of alpha blockers in terms of increased stone passage, less hospitalisation and less pain, outweighed the experience of dizziness and headache. The committee considered that these benefits would reduce requirements for pain medication and may reduce the need for surgical intervention.

The committee noted that current practice is partly based on the findings of the SUSPEND trial, a large UK study which showed no benefit of alpha blocker or calcium channel blockers when compared to placebo. They considered that this is the only UK study included in the review, and so may best represent UK practice and the UK population. However, they also noted that including this study in the analysis still led to an overall benefit of alpha blockers. Therefore they agreed that this single study does not outweigh the body of evidence suggesting that alpha blockers and calcium channel blockers may be beneficial, especially considering that there are no significant harms associated with either drug. The committee also considered that the strategy of the present review, as set out in the protocol, was to stratify the population into three groups; less than 10mm, 10-20mm and more than 20mm. However, some evidence in this area has used smaller size subgroups, of less than 5mm and 5-10mm, and the evidence suggests that there may be differences between these smaller sub groups that this review was unable to assess. This means that there is uncertainty in terms of the population of stones that may derive benefit of alpha blockers which meant that the committee were not confident enough in the evidence to make a strong recommendation. Therefore they agreed that alpha blockers should be considered for people with small distal ureteric stones. The committee considered the evidence for calcium channel blockers and noted that although there did seem to be evidence of a benefit when compared to no treatment, there was no benefit when compared to placebo. They also considered that in the head-to-head comparison with alpha blockers, alpha blockers were favoured. As placebo-controlled evidence is commonly considered the gold standard in pharmacological studies, the committee agreed that more weight should be placed on this evidence, compared to the no treatment comparison. Based on this, the committee agreed not to recommend calcium channel blockers.

Mid ureteric stones <10mm

Alpha blockers

When compared to placebo, there was a harm of alpha blockers for stone passage, time to stone passage, some quality of life measures, hospitalisation and analgesic use. There was no difference between the intervention and placebo for use of healthcare services in terms of doctor and outpatient visits, but more nurse visits in those taking alpha blockers. There were also more people with extreme pain or discomfort, and less people with no pain or discomfort in those taking alpha blockers. However the committee noted concerns regarding the quality and limited evidence with only two studies with 126 participants found for this comparator.

Compared to no treatment (pain relief only), there was a benefit of alpha blockers for all of the reported outcomes, including stone passage, time to stone passage, and analgesic use. The committee noted that the evidence came from a very small single study of just 16 people, and was low and very low quality, and agreed that based on this, they did not have confidence in extrapolating this data to clinical practice.

Calcium channel blockers

When compared to placebo, there was no difference between interventions for stone passage or time to stone passage. There were less outpatient visits in those taking calcium channel blockers, but no difference in terms of hospitalisation, doctor or nurse visits. Those taking calcium channel blockers also had poorer quality of life scores, and more people had extreme pain or discomfort than the placebo group. The committee noted that this evidence came from a single study.

Alpha blockers versus calcium channel blockers

There was a benefit of calcium channel blockers for stone passage, nurse and outpatient visits, and a benefit of alpha blockers for the quality of life physical component score. There was no difference between interventions for use of healthcare services in terms of doctor visits. The committee discussed that this evidence was from a single study of 81 participants and some of the evidence was of low quality, and therefore they agreed that they did not have confidence in the findings.

The committee noted that much of the evidence for the mid ureteric stones population was of low or very low quality, and that all of the evidence came from a very small number of studies with very small participant numbers. The committee therefore agreed that there was a lack of sufficient convincing evidence to make a recommendation. The committee also discussed that this population would be a small number of cases in clinical practice, and that there is no consensus on how these stones should be treated. Based on this, the committee decided not to make a recommendation.

Proximal ureteric stones <10mm

Alpha blockers

When compared to placebo, there was no clinical difference between the two groups in terms stone passage or time to stone passage. In the alpha blockers group there were better quality of life scores on the physical component subscale, and less people reporting pain or discomfort, but there were more outpatient visits and discontinuations due to adverse events. There was no difference between the intervention and placebo for use of healthcare services in terms of doctor and nurse visits.

When compared to no treatment, there was a benefit of alpha blockers for stone passage and time to stone passage. There was no clinical difference for quality of life (EuroQoL) and analgesic use (mean number of times analgesics were used). The committee noted that the evidence involved a small number of participants.

Calcium channel blockers

When compared to placebo, there was a benefit of placebo for stone passage, fewer outpatient visits and discontinuation due to adverse events. Those taking calcium channel blockers reported less analgesia use, and there were no differences between the interventions for all other outcomes. The committee noted that the evidence came from a single study.

Alpha blockers versus calcium channel blockers

The committee noted that alpha blockers appeared to be more clinically effective than calcium channel blockers in terms of stone passage and some pain outcomes. However, there were more people with only moderate pain or discomfort in the calcium channel blockers group. There were no differences for all other outcomes. The committee considered that this evidence came from a single study and included some low quality evidence; therefore, the committee agreed that the evidence was not strong enough to draw conclusions from.

The committee noted that the majority of comparisons for this population were based on evidence from small studies or single studies. They discussed that the evidence for alpha blockers versus calcium channel blockers suggested a benefit of alpha blockers, and that there was a lot of uncertainty surrounding the outcomes due to low quality evidence and small participant numbers. They agreed that overall, there was a lack of convincing evidence, and so no recommendation could be made for this group.

Children and young people, distal ureteric stones <10mm

Alpha blockers

The committee considered the evidence for children, and noted that all of the evidence was for distal ureteric stones <10mm. When alpha blockers (tamsulosin and doxazosin) were compared to no treatment (pain management only), the evidence suggested a benefit of alpha blockers in terms of stone passage, time to stone passage and analgesic use but no difference between the groups in terms of the number of pain episodes and unspecified adverse events. The committee noted from clinical experience that children may spontaneously pass stones more easily than adults.

When compared to placebo, there was a benefit of alpha blockers in terms of stone passage, time to stone passage and the number of pain episodes. There was a benefit of placebo in terms of headaches/dizziness, but no difference between interventions for all other adverse events.

The committee also considered that current practice for alpha blockers is varied, but that they are considered much safer for children than calcium channel blockers. Overall, the committee considered that this evidence suggests that conservative management is more likely to succeed with the use of alpha blockers, which may make the need for surgery less likely. The committee agreed that given the benefits of alpha blockers in terms of increasing stone passage and reducing the time to stone passage, as well as the potential analgesic effects and implications in terms of reducing the need for further intervention and no evidence of increased risk of harms, alpha blockers should be offered to children and young people with distal ureteric stones <10 mm.

MET as an adjunctive therapy to surgery

The committee considered the evidence for MET as an adjunctive therapy to surgery. It was noted that for all comparisons, the MET was alpha blockers, and there was no evidence for calcium channel blockers or other MET drugs. It was also noted that all of the evidence for MET as adjunctive was in an adult population, and there was no evidence for the paediatric population.

Distal ureteric stones <10mm

Alpha blockers as adjunctive to SWL versus SWL

When MET was adjunctive to SWL in people with stones less than 10mm, the committee noted that there was a benefit of alpha blockers as adjunctive to SWL for outcomes relating to stone passage, hospitalisation and pain, but a benefit of SWL alone for most adverse events outcomes. The committee considered that because the adverse events were not serious, the benefit of adjuvant alpha blockers in terms of stone passage outweighed the experience of such adverse events.

The committee agreed to make a recommendation to consider alpha blockers as adjuvant therapy when people are having SWL. This was because the added potential benefit of MET was potentially significant, and there was a lack of serious associated harms. Current practice for people with these stones is SWL without the use of MET, and therefore use of MET would be a change in practice.

Alpha blockers as adjunctive to URS versus URS

The committee also considered the evidence for alpha blockers as adjunctive to URS. The evidence demonstrated a benefit of alpha blockers as adjuvant to URS for stone passage and length of stay, compared to URS alone. The committee discussed that the evidence for stone passage was unusual, as it was agreed that when performing a URS most UK surgeons would either fragment the stones to fragments <2-3mm, which would be expected to pass, or remove all the fragments during the procedure. Therefore the committee agreed that the use of adjuvant alpha blockers is likely to add very little benefit to UK practice. They also considered that the evidence came from a single study of 98 people.

Alpha blockers as adjunctive to URS versus placebo + URS

Evidence also demonstrated a benefit of alpha blockers as adjuvant to URS when compared to placebo as adjuvant to URS, in terms of stone passage and pain related outcomes. The committee were concerned that the evidence was based on a single study and was low and very low quality. It was further noted that the study used a ballistic method during URS, rather than laser, which does not reflect UK practice and may make stone fragments more difficult to pass, therefore potentially overestimate the effect of alpha blockers.

Overall, the committee agreed that evidence for alpha blockers as adjunctive to URS (with or without placebo) was not convincing and not sufficient on which to base a recommendation. They considered that a research recommendation investigating the use of alpha blockers as adjunctive to URS may be beneficial in terms of providing high quality evidence to help address this gap in the evidence and inform future practice.

Distal ureteric stones 10-20mm

Alpha blockers as adjunctive to SWL versus SWL

The committee noted that evidence from a single study of 38 participants demonstrated no difference between the interventions. Further, this evidence was very low quality. Therefore the committee agreed that there was not convincing evidence of a benefit of adjuvant MET for people with 10-20mm stones, and decided not make a recommendation.

Mid ureteric stones 10-20mm

Alpha blockers as adjunctive to SWL versus SWL

There was evidence from one study in a population of mid ureteric stones. This study demonstrated no clinical difference between alpha blockers as adjunctive therapy to SWL and SWL only. The committee considered that this evidence came from a single study of 28 people, and was very low quality. The committee also considered that this was a small patient group and are not normally treated with SWL in UK clinical practice. They agreed that there was insufficient evidence to make a recommendation for this population.

Proximal ureteric stones <10mm

Alpha blockers as adjunctive to SWL versus SWL

When MET as adjunctive to SWL was compared to SWL alone in people with <10mm proximal ureteral stones, the committee noted a clinical benefit for alpha blockers for stone passage outcomes, quality of life outcomes, most pain outcomes, and use of healthcare services in terms of the number of ED visits at follow up. There was no clinical difference between interventions in terms retrograde ejaculation, dizziness, analgesic use and hospitalisation. The committee considered that the two adverse events are not serious and would not outweigh the benefits of increased stone passage and improved pain and quality of life.

Overall, the committee considered that the evidence for stone passage came from a number of studies and was of moderate quality; this was a key outcome of success and would lead to reduced downstream resource use. The benefits of the treatment were also thought to far outweigh any minor risks, therefore the committee made a consider recommendation for ureteric stones <10mm.

Alpha blockers as adjunctive to SWL versus placebo + SWL

When alpha blockers adjuvant to SWL was compared to placebo + SWL, the evidence demonstrated a clinical benefit for alpha blockers in terms of stone passage and time to stone passage. Although the evidence came from a single study, the committee noted that this supported the evidence for the comparison of alpha blockers adjuvant to SWL versus SWL alone.

Proximal ureteric stones 10-20mm

Alpha blockers as adjunctive to SWL versus SWL

Alpha blockers as adjuvant to SWL were also compared to SWL alone in people with 10-20mm stones. For this comparison the committee noted that the evidence was not conclusive. Although there was a clinical benefit of alpha blockers in terms of time to stone passage and stone passage, there was no difference between interventions in terms of pain. The committee noted that this was based on single studies and very low quality evidence. They agreed not to make a recommendation for alpha blockers as adjunctive to SWL for this stone size.

Alpha blockers as adjunctive to URS versus URS

When alpha blockers as adjuvant to URS were compared to URS alone in people with stones between 10-20mm, the committee noted that there was conflicting evidence. There was a suggested benefit of alpha blockers for stone passage and colic episodes, but no difference in terms of time to stone passage and outcomes relating to hospitalisation. The committee considered the evidence and discussed that usually during URS, the surgeon either removes all residual stones, or breaks them down to <2-3mm fragments to pass spontaneously. Therefore alpha blockers may increase the passage rate of residual stones when the latter method is used. The committee considered that although alpha blockers may be beneficial in terms in reducing the need for pain relief and increasing passage of residual stones, most of the evidence was from single studies, which limited the degree of confidence the committee could place in the results.

The committee agreed that as with the <10mm group, the evidence for MET as an adjunct to URS was not considered sufficient to make recommendations, and is not commonly used in current practice, so a research recommendation would be beneficial to inform future practice. They agreed that the research recommendation should include all stones less than 20 mm, and include any location within the ureter.

1.8.2. Cost effectiveness and resource use

One cost utility analysis (Pickard 2015) was identified from the literature and presented to the committee. This was a within trial, cost utility analysis based on SUSPEND, an RCT conducted in the UK, that compared two medical expulsive therapies (tamsulosin or nifedipine) to each other and then combined the groups to compare medical expulsive therapy, in general, to placebo. There was no economic evidence identified for the use of medical expulsive therapy as adjunctive to surgery.

The study was assessed as directly applicable, as it was a UK cost utility analysis taking the NHS perspective. The study also reported values of health effects expressed in terms of QALYs and used EQ-5D data collected directly from patients. The study was rated as having potentially serious limitations because the time horizon was only the 12 week period of the RCT and no extrapolation of study results took place beyond that period; so effects and costs from any stones that might have needed treatment after this period wouldn’t be captured by the analysis. Also, the estimates of relative treatment effects and resource use were not derived from a systematic literature review but from the study effectiveness data and records.

The study found that the use of medical expulsive therapy was associated with cost savings but also less QALYs (only slightly, so a negligible difference in QALYs). The cost savings are because the resource use involved in the MET group was overall lower (e.g. admission days, interventions undertaken), and is consistent with what we would think about the intervention, because if more people are passing their stone with MET, then there is less downstream resource use being consumed, such as time in hospital or other interventions.

We can change round the comparators for ease of interpretation of the ICER, so the more expensive and effective alternative (placebo – with its slightly higher QALYs) is compared to the less effective alternative (MET). This shows that the use of placebo compared to medical expulsive therapy was not cost effective (ICER of £42,000), therefore the alternative of medical expulsive therapy is a cost effective option because we are only comparing two alternatives, so if placebo is not cost effective according to the NICE threshold then that means the comparator is the cost effective choice. In effect, the placebo strategy involved more resource use overall (making it more costly), and there was a negligible difference in quality of life between the two strategies. When comparing tamsulosin to nifedipine, the study also found that tamsulosin was associated with cost savings but also less QALYs (again a negligible difference in QALYs). Tamsulosin was a cost effective option compared to nifedipine. The study results were sensitive to any changes in QoL values.

The Pickard study was included in the clinical review, and provided a conservative estimate of medical expulsive therapy’s effectiveness when compared to the other studies pooled in the review for the stone passage of alpha blockers versus placebo. The point estimate was very close to the no difference line, while the pooled estimate was further on the left, favouring alpha blockers. Higher effectiveness of alpha blockers could impact cost effectiveness of medical expulsive therapy compared to placebo, making the choice of alpha blockers (MET) even more cost effective than what the Pickard study estimated. The committee agreed that the magnitude of cost effectiveness of medical expulsive therapy compared to placebo is likely to be higher than the Pickard study demonstrated if the effectiveness of alpha blockers is in fact higher.

Unit costs of the interventions identified from the clinical review divided into alpha blockers and calcium blockers were presented using BNF prices and doses from clinical review data. Costs were presented monthly because from the trials people tended to take MET for around 4 weeks (although the committee noted that 2 weeks is also used in practice). The drug formulation was that of modified release tablets or capsules with alpha blockers represented by more drug options and calcium channel blockers represented only by nifedipine. There were differences between drug prices between the two categories and an attempt to identify the most and least expensive drug from the unit costs data was made; doxazosin (alpha blocker) was found to be the cheapest option and alfuzosin (alpha blocker) the most expensive one among alpha blockers. The GC members highlighted that the most commonly prescribed alpha blocker, tamsulosin was shown to be less expensive than nifedipine in the capsules formulation, but more expensive as a tablet.

Resource impact data were also presented, using an average monthly cost of medical expulsive therapy of £10.65 (similar to the tamsulosin tablet monthly cost), and the population with ureteric stones from HES hospital admitted activity 2015-16 data (calculus of ureter finished consultant episodes; 24,589). Even at the extreme scenario of medical expulsive therapy that would be recommended for use for all the people diagnosed with ureteric stones at hospitals, the resource impact wasn’t expected to meet the NICE threshold of ‘significant’, as the results showed that the annual NHS spending would be around £262,000. The data from HES may well underestimate the population with ureteric stones because there may be people coping with their stone who haven’t been admitted to hospital, but on the other hand the HES data is probably a mix of stone sizes whereas the recommendations are mainly for smaller stone size groups.

Passing the stone earlier will also have a QoL improvement, as an individual does not have a stone anymore (e.g. if pass a stone at 2 weeks instead of 4 weeks then that is an extra 2 weeks where the individual has returned to their normal QoL level). The time to stone passage for alpha blockers versus placebo was also shown to be clinically significant. The issue around short term pain and any associated improvement in quality of life from passing a stone earlier (or conversely the loss in quality of life from having a stone for a few more days if they didn’t have MET to pass the stone earlier) was discussed. An ICER example was provided using data from the clinical review showing MET (alpha blockers specifically) would help you pass your stone on average 4 days quicker (given 4 weeks of treatment costing around £10); using quality of life data derived from the Health Survey for England 2014 as the utility level for those who don’t have a stone (0.874), and the utility of patients with stones was from baseline data in the Pickard study (0.684 −(EQ-5D)). This showed that helping you pass your stone 4 days earlier would have an ICER of around £5,000. This is cost effective taking into account only a few days of pain avoided, and this is because the drug is so cheap. It was highlighted that avoiding pain of short duration wasn’t expected to contribute a significant improvement in the quality of life for people achieving stone passage, therefore the committee agreed with the incremental QALY estimates presented that were very small. Discussion indicated that in practice the cheapest drug is likely to be given, which is Tamsulosin in a capsule form, and is much cheaper than the tablet form (£4 a month versus £10 a month respectively), therefore the estimates used above are likely to be overestimates.

The above example has only taken into account the people who would pass their stone quicker with the drug, but not the large proportion of people who would pass their stone if they used MET (compared to if they didn’t), and what downstream treatment they could therefore avoid. The committee recognised that the use of MET could contribute in avoiding further downstream costs, such as surgery, from more people that passed their stone using MET.

More specifically; using as a reference point the clinical review data for the stone passage achieved with alpha blockers compared to no treatment for distal ureteric stones <10mm in adults (Table 4 in the evidence report);

327 more patients per 1000 that used alpha blockers passed their stones compared to the no treatment group.
It was assumed otherwise these 327 patients would undergo a lithotripsy (a conservative estimate, as some of the patients would undergo URS that is more costly, but some patients given more time may just pass the stone and not need treatment).
Therefore the cost from the interventions avoided considering a unit cost of £452 for an SWL session, were estimated to be £452 × 327 = £147,084. This is a conservative estimate considering only the cost of the intervention, without any retreatment or ancillary procedure cost needed for an unsuccessful first lithotripsy.
The cost of providing alpha blockers for 1 month for 1000 people, to avoid the 327 lithotripsies, would be around £10,000 (a conservative estimate assuming a cost of the drug of £10 a month, but this could be less as mentioned in the previous paragraph).
This makes an overall incremental saving from those additional people passing their stone with MET equal to £147,084 – £10,000 = £137,084 for every 1,000 people that medical expulsive therapy is provided for.

This saving would actually allow MET to be provided to over 13,000 people. The committee were confident that this recommendation has potential to be a cost saving recommendation because of the costs offset. Not everyone in the under 10mm stone size group would go on to need an intervention to clear their stone as some may pass spontaneously with more time. The Pickard study reported that for the placebo arm the proportion requiring no further intervention at 4 weeks was 86% in the <=5mm group and 61% in the >5mm group. Breaking this down even further by size was not possible but committee opinion was that stones of between 4-7mm are the ones where clinicians would be uncertain if they would pass, and <4mm would be given more time to pass and >7mm would usually require intervention. If treating 1000 people with MET costs £10,000, then this only has to avoid 22 sessions of SWL (which would be for 2.5% of the 1000 people (assuming one session per person)) or around 5 URS’s to make the intervention cost neutral. This is likely to be achievable given the low numbers, and so even if only a proportion of people go on to avoid treatment it is still likely that MET is cost saving.

The above is an illustrative calculation which is rather simplistic. As well as the interventions unit costs, the cost of other resources should be considered; such as appointments with staff including GPs and consultants, for review of medication therapy and any monitoring of adverse events. Additionally, the clinical review showed that MET was associated with fewer hospitalisations when compared to no treatment. MET had more adverse events, but mainly dizziness and headache, which the committee considered to be minor adverse events.

Used as an adjunct to surgery, alpha blockers were also shown to be effective at improving stone passage, which means further treatments could be avoided.

The committee agreed that MET is likely to be a cost effective if not cost saving treatment. However, the committee discussed that although for pragmatism the guideline clinical review broke down the stone subgroups into 10mm, new evidence in the field has sub grouped by smaller gradations (<5mm, and 5-10mm). Given the uncertainty around the effectiveness of MET in these smaller subgroups, the committee were not confident enough in the evidence to make a strong recommendation, and thus recommended that alpha blockers be considered for adults and children with distal ureteric stones less than 10mm. a consider recommendation was also made for alpha blockers as an adjunct to SWL.

A recommendation on nifedipine for adults was also discussed, but the committee felt that only the no treatment comparison showed effect, and not the placebo controlled trials. Although no treatment would be the real life comparison, and placebo is acknowledged to have an effect, the criteria that is commonly followed with pharmacological treatments is for placebo controlled trials to be the gold standard of proving efficacy. And as that isn’t the case for calcium channel blockers, the committee felt that the intervention didn’t meet the criteria of being effective that has been applied to alpha blockers for example.

1.8.3. Other factors the committee took into account

The committee noted that both alpha blockers and calcium channel blockers are not licensed specifically for renal stones, but they are licensed for other conditions. Alpha blockers are mainly used for men with symptomatic lower urinary tract symptoms and the management of acute retention of urine, with some also indicated for hypertension. Calcium channel blocker nifedipine is primarily licensed for Raynaud’s syndrome. Alpha blockers and calcium channel blockers are not licensed for children.

The committee noted that the evidence included studies that used Silodosin, and that this is not available in the UK.

References

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213.: Wang ZQ, Yuan L, Zhang XL, Dong XH, Yang BZ, Gao ZW. Effect of tamsulosin in medical expulsive therapy for proximal ureteral calculi after ureteroscopic holmium laser lithotripsy. Chinese Medical Sciences Journal. 2014; 29(2):128–30 [PubMed: 24998239]
214.: Yang D, Wu J, Yuan H, Cui Y. The efficacy and safety of silodosin for the treatment of ureteral stones: a systematic review and meta-analysis. BMC Urology. 2016; 16:23 [PMC free article: PMC4882785] [PubMed: 27233621]
215.: Ye Z, Yang H, Li H, Zhang X, Deng Y, Zeng G et al. A multicentre, prospective, randomized trial: comparative efficacy of tamsulosin and nifedipine in medical expulsive therapy for distal ureteric stones with renal colic. BJU International. 2011; 108(2):276–9 [PubMed: 21083640]
216.: Ye Z, Zeng G, Yang H, Tang K, Zhang X, Li H et al. Efficacy and safety of tamsulosin in medical expulsive therapy for distal ureteral stones with renal colic: a multicenter, randomized, double-blind, placebo-controlled trial European Urology. 2018; 73(3):385–91 [PubMed: 29137830]
217.: Yencilek F, Erturhan S, Canguven O, Koyuncu H, Erol B, Sarica K. Does tamsulosin change the management of proximally located ureteral stones? Urological Research. 2010; 38(3):195–9 [PubMed: 20182703]
218.: Yilmaz E, Batislam E, Basar MM, Tuglu D, Ferhat M, Basar H. The comparison and efficacy of 3 different alpha1-adrenergic blockers for distal ureteral stones. Journal of Urology. 2005; 173(6):2010–2 [PubMed: 15879806]
219.: Yuksel M, Yilmaz S, Tokgoz H, Yalcinkaya S, Bas S, Ipekci T et al. Efficacy of silodosin in the treatment of distal ureteral stones 4 to 10 mm in diameter. International Journal of Clinical and Experimental Medicine. 2015; 8(10):19086–92 [PMC free article: PMC4694437] [PubMed: 26770537]
220.: Zaytoun OM, Yakoubi R, Zahran AR, Fouda K, Marzouk E, Gaafar S et al. Tamsulosin and doxazosin as adjunctive therapy following shock-wave lithotripsy of renal calculi: randomized controlled trial. Urological Research. 2012; 40(4):327–32 [PubMed: 21837534]
221.: Zehri AA, Ather MH, Abbas F, Biyabani SR. Preliminary study of efficacy of doxazosin as a medical expulsive therapy of distal ureteric stones in a randomized clinical trial. Urology. 2010; 75(6):1285–8 [PubMed: 20189226]
222.: Zhang MY, Ding ST, Lü JJ, Lue YH, Zhang H, Xia QH. Comparison of tamsulosin with extracorporeal shock wave lithotripsy in treating distal ureteral stones. Chinese Medical Journal. 2009; 122(7):798–801 [PubMed: 19493392]
223.: Zheng S, Liu LR, Yuan HC, Wei Q. Tamsulosin as adjunctive treatment after shockwave lithotripsy in patients with upper urinary tract stones: a systematic review and meta-analysis. Scandinavian Journal of Urology and Nephrology. 2010; 44(6):425–32 [PubMed: 21080841]
224.: Zhou SG, Lu JL, Hui JH. Comparing efficacy of alpha1D-receptor antagonist naftopidil and alpha1A/D-receptor antagonist tamsulosin in management of distal ureteral stones. World Journal of Urology. 2011; 29(6):767–71 [PubMed: 21845472]
225.: Zhu Y, Duijvesz D, Rovers MM, Lock TM. Alpha-blockers to assist stone clearance after extracorporeal shock wave lithotripsy: a meta-analysis. BJU International. 2010; 106(2):256–61 [PubMed: 19889063]

Appendices

Appendix A. Review protocols

Table 29. Review protocol: Medical expulsive therapy

Table 30. Health economic review protocol

Appendix B. Literature search strategies

The literature searches for this review are detailed below and complied with the methodology outlined in Developing NICE guidelines: the manual 2014, updated 2017 https://www.nice.org.uk/guidance/pmg20/resources/developing-nice-guidelines-the-manual-pdf-72286708700869

For more detailed information, please see the Methodology Review. [Add cross reference]

B.1. Clinical search literature search strategy

Searches were constructed using a PICO framework where population (P) terms were combined with Intervention (I) and in some cases Comparison (C) terms. Outcomes (O) are rarely used in search strategies for interventions as these concepts may not be well described in title, abstract or indexes and therefore difficult to retrieve. Search filters were applied to the search where appropriate.

Table 31. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

Cochrane Library (Wiley) search terms

B.2. Health Economics literature search strategy

Health economic evidence was identified by conducting a broad search relating to renal and ureteric stones population in NHS Economic Evaluation Database (NHS EED – this ceased to be updated after March 2015) and the Health Technology Assessment database (HTA) with no date restrictions. NHS EED and HTA databases are hosted by the Centre for Research and Dissemination (CRD). Additional searches were run on Medline and Embase for health economics studies.

Table 32. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix C. Clinical evidence selection

Figure 1. Flow chart of clinical study selection for the review of medical expulsive therapy

Appendix D. Clinical evidence tables

Download PDF (2.5M)

Appendix E. Forest plots

E.1. Distal ureteric stones <10mm in adults

E.2. Mid ureteric stones <10mm in adults

E.2.1. Alpha blockers versus placebo

Figure 94. Time to stone passage (days)

Figure 95. Stone passage

Figure 96. Hospitalisation (excess admission days)

Figure 97. Use of healthcare services (visits)

Figure 98. Quality of life (SF36)

Figure 99. Quality of life (EQ5D)

Figure 100. Adverse events (discontinuation due to adverse events)

Figure 101. Pain intensity (VAS)

Figure 102. Pain intensity (EQ5D no pain/discomfort)

Figure 103. Pain intensity (EQ5D moderate pain/discomfort)

Figure 104. Pain intensity (EQ5D extreme pain/discomfort)

Figure 105. Analgesic use (pain medication use)

Figure 106. Analgesic use (number of days of pain medication use)

E.2.2. Alpha blockers versus no treatment (pain management only)

Figure 107. Time to stone passage

Figure 108. Stone passage

Figure 109. Analgesic use (number of times)

E.2.3. Calcium channel blockers versus placebo

Figure 110. Time to stone passage (days)

Figure 111. Stone passage

Figure 112. Hospitalisation (excess admission days)

Figure 113. Use of healthcare services (visits)

Figure 114. Quality of life (SF36)

Figure 115. Quality of life (EQ5D)

Figure 116. Adverse events (discontinuation due to adverse events)

Figure 117. Pain intensity (VAS)

Figure 118. Pain intensity (EQ5D no pain/discomfort)

Figure 119. Pain intensity (EQ5D moderate pain/discomfort)

Figure 120. Pain intensity (EQ5D extreme pain/discomfort)

Figure 121. Analgesic use (pain medication use)

Figure 122. Analgesic use (days of pain medication use)

E.2.4. Alpha blockers versus Calcium channel blockers

Figure 123. Time to stone passage (days)

Figure 124. Stone passage

Figure 125. Hospitalisation (excess admission days)

Figure 126. Use of healthcare services (visits)

Figure 127. Quality of life (SF36)

Figure 128. Quality of life (EQ5D)

Figure 129. Adverse events (discontinuation due to adverse events)

Figure 130. Pain intensity (VAS)

Figure 131. Pain intensity (EQ5D no pain/discomfort)

Figure 132. Pain intensity (EQ5D moderate pain/discomfort)

Figure 133. Pain intensity (EQ5D extreme pain/discomfort)

Figure 134. Analgesic use (pain medication use)

Figure 135. Analgesic use (number of days of pain medication use)

E.3. Proximal ureteric stones <10mm in adults

E.3.1. Alpha blockers versus placebo

Figure 136. Time to stone passage (days)

Figure 137. Stone passage

Figure 138. Hospitalisation (excess admission days)

Figure 139. Use of healthcare services (visits)

Figure 140. Quality of life (SF36)

Figure 141. Quality of life (EQ5D)

Figure 142. Adverse events (discontinuation due to adverse events)

Figure 143. Pain intensity (VAS)

Figure 144. Pain intensity (EQD no pain/discomfort)

Figure 145. Pain intensity (EQD moderate pain/discomfort)

Figure 146. Pain intensity (EQD extreme pain/discomfort)

Figure 147. Analgesic use (pain medication use)

Figure 148. Analgesic use (number of days of pain medication use)

E.3.2. Alpha blockers versus no treatment (pain management only)

Figure 149. Time to stone passage (days)

Figure 150. Stone passage

Figure 151. Quality of life (EuroQoL)

Figure 152. Analgesic use (number of times)

E.3.3. Calcium channel blockers versus placebo

Figure 153. Time to stone passage (days)

Figure 154. Stone passage

Figure 155. Hospitalisation (excess admission days)

Figure 156. Use of healthcare services (visits)

Figure 157. Quality of life (SF36)

Figure 158. Quality of life (EQ5D)

Figure 159. Adverse events (discontinuation due to adverse events)

Figure 160. Pain intensity (VAS)

Figure 161. Pain intensity (EQ5D no pain/discomfort)

Figure 162. Pain intensity (EQ5D moderate pain/discomfort)

Figure 163. Pain intensity (EQ5D extreme pain/discomfort)

Figure 164. Analgesic use (pain medication use)

Figure 165. Analgesic use (number of days of pain medication use)

E.3.4. Alpha blockers versus Calcium channel blockers

Figure 166. Time to stone passage (days)

Figure 167. Stone passage

Figure 168. Hospitalisation (excess admission days)

Figure 169. Use of healthcare services (visits)

Figure 170. Quality of life (SF36)

Figure 171. Quality of life (EQ5D)

Figure 172. Adverse events (discontinuation due to adverse events)

Figure 173. Pain intensity (VAS)

Figure 174. Pain intensity (EQ5D no pain/discomfort)

Figure 175. Pain intensity (EQ5D moderate pain/discomfort)

Figure 176. Pain intensity (EQ5D extreme pain/discomfort)

Figure 177. Analgesic use (pain medication use)

Figure 178. Analgesic use (number of days with pain medication use)

E.4. Distal ureteric stones <10mm in children

E.4.1. Alpha blockers versus placebo

Figure 179. Time to stone passage (days)

Figure 180. Stone passage (4 weeks)

Figure 181. Adverse events (headaches/dizziness)

Figure 182. Adverse events (headache)

Figure 183. Adverse events (hypotension)

Figure 184. Pain intensity (pain episodes)

E.4.2. Alpha blockers versus no treatment (pain management only)

Figure 185. Time to stone passage (days)

Figure 186. Stone passage

Figure 187. Adverse events (unspecified)

Figure 188. Pain intensity (daily pain episodes)

Figure 189. Analgesic use (ketorolac injections)

E.5. Adjunctive therapy: distal ureteric stones <10mm in adults

E.5.1. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only

Figure 190. Time to stone passage

Figure 191. Stone passage

Figure 192. Hospitalisation

Figure 193. Adverse events (abnormal ejaculation)

Figure 194. Adverse events (dizziness)

Figure 195. Adverse events (headache)

Figure 196. Adverse events (hypotension)

Figure 197. Analgesic use (number of analgesics)

Figure 198. Analgesic use (dosage)

E.5.2. Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only

Figure 199. Stone passage

Figure 200. Use of healthcare services (length of hospital stay)

E.5.3. Alpha blockers as adjunctive therapy to ureteroscopy versus placebo and ureteroscopy

Figure 201. Stone passage

Figure 202. Pain intensity (colic episodes)

Figure 203. Analgesic use (number of people using analgesia)

E.6. Adjunctive therapy: distal ureteric stones 10-20mm in adults

E.6.1. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only

Figure 204. Time to stone passage (days)

Figure 205. Pain intensity (VAS)

E.7. Adjunctive therapy: mid ureteric stones 10-20mm in adults

E.7.1. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only

Figure 206. Time to stone passage (days)

Figure 207. Pain intensity (VAS)

E.8. Adjunctive therapy: proximal ureteric stones <10mm in adults

E.8.1. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only

Figure 208. Time to stone passage (days)

Figure 209. Stone passage

Figure 210. Hospitalisation

Figure 211. Use of healthcare services (ED visits)

Figure 212. Quality of life (EQ5D)

Figure 213. Quality of life (EQ5D VAS)

Figure 214. Adverse events (dizziness)

Figure 215. Adverse events (retrograde ejaculation)

Figure 216. Pain intensity (VAS)

Figure 217. Pain intensity (colic episodes)

Figure 218. Analgesic use (dosage)

Figure 219. Analgesic use (number of people using analgesia)

E.8.2. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus placebo and shock wave lithotripsy

Figure 220. Time to stone passage (days)

Figure 221. Stone passage

E.9. Adjunctive therapy: proximal ureteric stones 10-20mm in adults

E.9.1. Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only

Figure 222. Time to stone passage (days)

Figure 223. Stone passage

Figure 224. Pain intensity (VAS, 0-10)

E.9.2. Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only

Figure 225. Time to stone passage (days)

Figure 226. Stone passage

Figure 227. Use of healthcare services (Hospitalisation time)

Figure 228. Hospitalisation (readmission)

Figure 229. Adverse events (dizziness)

Figure 230. Pain intensity (colic episodes)

Appendix F. GRADE tables

Table 33. Clinical evidence profile: Alpha blockers versus placebo for distal ureteric stones <10mm in adults

Table 34. Clinical evidence profile: Alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in adults

Table 35. Clinical evidence profile: Calcium channel blockers versus placebo for distal ureteric stones <10mm in adults

Table 36. Clinical evidence profile: Calcium channel blockers versus no treatment (pain management only) for distal ureteric stones <10mm in adults

Table 37. Clinical evidence profile: Alpha blockers versus Calcium channel blockers for distal ureteric stones <10mm in adults

Table 38. Clinical evidence profile: Alpha blockers versus placebo for mid ureteric stones <10mm in adults

Table 39. Clinical evidence profile: Alpha blockers versus no treatment (pain management only) for mid ureteric stones <10mm in adults

Table 40. Clinical evidence profile: Calcium channel blockers versus placebo for mid ureteric stones <10mm in adults

Table 41. Clinical evidence profile: Alpha blockers versus Calcium channel blockers for mid ureteric stones <10mm in adults

Table 42. Clinical evidence profile: Alpha blockers versus placebo for proximal ureteric stones <10mm in adults

Table 43. Clinical evidence profile: Alpha blockers versus no treatment (pain management only) for proximal ureteric stones <10mm in adults

Table 44. Clinical evidence profile: Calcium channel blockers versus placebo for proximal ureteric stones <10mm in adults

Table 45. Clinical evidence profile: Alpha blockers versus Calcium channel blockers for proximal ureteric stones <10mm in adults

Table 46. Clinical evidence profile: Alpha blockers versus placebo for distal ureteric stones <10mm in children

Table 47. Clinical evidence profile: Alpha blockers versus no treatment (pain management only) for distal ureteric stones <10mm in children

Table 48. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for distal ureteric stones <10mm in adults

Table 49. Clinical evidence profile: Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only for distal ureteric stones <10mm in adults

Table 50. Clinical evidence profile: Alpha blockers as adjunctive therapy to ureteroscopy versus placebo and ureteroscopy for distal ureteric stones <10mm in adults

Table 51. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for distal ureteric stones 10-20mm in adults

Table 52. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for mid ureteric stones 10-20mm in adults

Table 53. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for proximal ureteric stones <10mm in adults

Table 54. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus placebo and shock wave lithotripsy for proximal ureteric stones <10mm in adults

Table 55. Clinical evidence profile: Alpha blockers as adjunctive therapy to shock wave lithotripsy versus shock wave lithotripsy only for proximal ureteric stones 10-20mm in adults

Table 56. Clinical evidence profile: Alpha blockers as adjunctive therapy to ureteroscopy versus ureteroscopy only for proximal ureteric stones 10-20mm in adults

Appendix G. Health economic evidence selection

Figure 231. Flow chart of economic study selection for the guideline

Appendix H. Health economic evidence tables

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Appendix I. Excluded studies

I.1. Excluded clinical studies

Table 57. Studies excluded from the clinical review

I.2. Excluded health economic studies

None

Appendix J. Research recommendations

J.1. Alpha blockers and ureteroscopy

Research Question: What is the clinical and cost effectiveness of tamsulosin as an adjunct to ureteroscopy?

Why this is important:

Kidney and ureteric stones affect about 15% of the male population and 5% of the female population at some point in their lives. The incidence of kidney stones has been increasing because of their link to poor diet, obesity and diabetes. Kidney and ureteric stones can cause severe pain and morbidity. Ureteroscopy is a commonly used method of treating stones in the kidney or ureter, whereby a narrow telescope is advanced up the ureter and laser energy is applied to the stone through a small fibre. Fragments may be left to wash out or removed with a basket.

The ureteric is intrinsically narrow but its wall contains muscle which is known to relax when the patient is given a medication called tamsulosin, which is in common use for prostatic problems. Tamsulosin has been shown to improve the spontaneous passage rate of small ureteric stones and also fragment-clearance following shockwave lithotripsy and NICE guidelines have recommended alpha blockers such as tamsulosin are considered for such purposes.

The success of ureteroscopic stone clearance can be inhibited by the ureter being excessively tight. This might prevent the insertion of the ureteroscope into the ureter (failed access) or reduce the effectiveness of laser fragmentation or the spontaneous clearance of fragments. Ureteric stents are often used as a post-treatment safety measure if the ureter is felt to be tight or swollen up during a procedure. Ureteric stents are known to cause significant irritation symptoms due to mechanical rubbing in the urinary tract. There is also some evidence that these symptoms might be reduced by tamsulosin. Nevertheless, the studies that these finding are based on are small and the evidence quality is low so tamsulosin is not in widespread routine use for these purposes. A definitive RCT is required to determine if such a recommendation would be appropriate.

PICO question	Population: Adults with ureteric or renal stones up to 20mm in size undergoing ureteroscopic treatment and no stent Intervention(s): Tamsulosin 400mcg od for 1 week prior to ureteroscopy and for 4 weeks after Comparison: Double-blind placebo controlled Outcomes: Primary outcome: Stone free rate as assessed by CT KUB at 4 weeks Secondary outcomes: failed access rate, operation time, stenting rate, needs for repeat ureteroscopy or adjunctive procedures, hospitalisation/ED attendance?, pain scores, quality of life (EQ-5D-3L), stent symptoms, side effects, failed insertion of access sheath, cost per QALY.
Importance to patients or the population	Kidney stones are extremely common and cause significant morbidity. Ureteroscopy is a commonly used and effective method of treating kidney stones. The success of stone clearance can be inhibited by the tightness of the ureter. Simple measures to relax the ureter peri-operatively might improve the success of the procedure, reduce the need for secondary procedures and improve the procedure related morbidity and quality of life.
Relevance to NICE guidance	The NICE guidelines panel felt that the current evidence was of too low quality to make a current recommendation on the use of tamsulosin for this purpose.
Relevance to the NHS	Tamsulosin is inexpensive and widely used by urologists. Ureteroscopic stone treatments are very common and improvements in its success rate will reduce the need for expensive secondary procedures and may reduce the cost of treatment related morbidity
National priorities	There is a strong link between diabetes, obesity and kidney stones and limiting the impact of these conditions is one of the top research priorities of the NHS. It is also a priority to test interventions and maximize effectiveness and cost-effectiveness.
Current evidence base	The current evidence is restricted to one or two studies with small numbers of participants for most outcome measures.
Equality	The recommendation is unlikely to impact on equality issues.
Study design	Double-blind placebo controlled RCT with health economic analysis
Feasibility	The trial is feasible and should be straightforward to carry out. There are a large number of such patients and a UK kidney stone trial network has already been established. The SUSPEND and TISU trials demonstrate this.
Other comments	The length of pre-treatment tamsulosin might be reviewed.
Importance	Medium: the research is relevant to the recommendations in the guideline, but the research recommendations are not key to future updates.

Final

Intervention evidence review (D)

This evidence review was developed by the National Guideline Centre

Disclaimer: The recommendations in this guideline represent the view of NICE, arrived at after careful consideration of the evidence available. When exercising their judgement, professionals are expected to take this guideline fully into account, alongside the individual needs, preferences and values of their patients or service users. The recommendations in this guideline are not mandatory and the guideline does not override the responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or their carer or guardian.

Local commissioners and/or providers have a responsibility to enable the guideline to be applied when individual health professionals and their patients or service users wish to use it. They should do so in the context of local and national priorities for funding and developing services, and in light of their duties to have due regard to the need to eliminate unlawful discrimination, to advance equality of opportunity and to reduce health inequalities. Nothing in this guideline should be interpreted in a way that would be inconsistent with compliance with those duties.

NICE guidelines cover health and care in England. Decisions on how they apply in other UK countries are made by ministers in the Welsh Government, Scottish Government, and Northern Ireland Executive. All NICE guidance is subject to regular review and may be updated or withdrawn.

Bookshelf ID: NBK577650PMID: 35133754

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National Guideline Centre (UK). Medical expulsive therapy: Renal and ureteric stones: assessment and management: Intervention evidence review (D). London: National Institute for Health and Care Excellence (NICE); 2019 Jan. (NICE Guideline, No. 118.)
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