Cover of Prevention of recurrence

Prevention of recurrence

Renal and ureteric stones: assessment and management

Intervention evidence review (K)

NICE Guideline, No. 118

Authors

.

London: National Institute for Health and Care Excellence (NICE); .
ISBN-13: 978-1-4731-3190-3
Copyright © NICE 2019.

1. Prevention of recurrence

1.1. Review question: What is the most clinically-effective and cost-effective non-surgical management for preventing the recurrence of future renal and ureteric stones?

1.2. Introduction

It is estimated that about one third of people affected by renal and ureteric stones will experience a recurrence at five years without treatment of the underlying cause. This rate of recurrence rises to 75% after 20 years with no treatment (reference Phillips, 2015 Cochrane review). As such, it is crucial to determine the most clinically and cost effective long-term management options for people who have, or who have had renal and ureteric stones.

Currently, there is variation in practice on the use of pharmacological management in the UK for the prevention of stone recurrence. Some patients are given general dietary advice while others are manged with medication to lower urinary calcium, increase urinary citrate levels, or alter urinary pH. Developing recommendations from evidence worldwide could help to inform clinical practice and future research studies in the UK.

1.3. PICO table

For full details see the review protocol in appendix A.

Table 1. PICO characteristics of review question.

Table 1

PICO characteristics of review question.

1.4. Clinical evidence

1.4.1. Included studies

Seventeen studies (19 papers) were included in the review;2, 7, 13, 16, 17, 25, 28, 45, 47, 66, 69, 70, 83, 84, 104, 106, 119, 125, 130 these are summarised in Table 2 below. Evidence from these studies is summarised in the clinical evidence summary below (Table 3).

One Cochrane review was identified however it was excluded as it included drugs that were not included in this review protocol.

As per the protocol, for strata where there was no RCT evidence for children, the search was widened to include cohort studies. Two cohort studies were identified for inclusion.83,104 Both of these compared potassium citrate to no intervention. 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 thiazides versus placebo in adults, there was heterogeneity between the studies when they were meta-analysed for the outcome of recurrence rate. Pre-specified subgroup analyses (see Appendix A:) were unable to be performed, so a random effects meta-analysis was applied to this outcome, 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.

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. Adults
Table 3. Clinical evidence profile: potassium citrate versus no intervention.

Table 3

Clinical evidence profile: potassium citrate versus no intervention.

Table 4. Clinical evidence profile: potassium citrate versus placebo.

Table 4

Clinical evidence profile: potassium citrate versus placebo.

Table 5. Clinical evidence profile: Magnesium supplement versus placebo.

Table 5

Clinical evidence profile: Magnesium supplement versus placebo.

Table 6. Clinical evidence profile: allopurinol versus placebo.

Table 6

Clinical evidence profile: allopurinol versus placebo.

Table 7. Clinical evidence profile: thiazides versus no intervention.

Table 7

Clinical evidence profile: thiazides versus no intervention.

Table 8. Clinical evidence profile: thiazides versus placebo.

Table 8

Clinical evidence profile: thiazides versus placebo.

Table 9. Clinical evidence profile: thiazides versus magnesium.

Table 9

Clinical evidence profile: thiazides versus magnesium.

Table 10. Clinical evidence profile: thiazides versus allopurinol.

Table 10

Clinical evidence profile: thiazides versus allopurinol.

Table 11. Clinical evidence profile: allopurinol + thiazides versus no intervention.

Table 11

Clinical evidence profile: allopurinol + thiazides versus no intervention.

Table 12. Clinical evidence profile: allopurinol + thiazides versus placebo.

Table 12

Clinical evidence profile: allopurinol + thiazides versus placebo.

Table 13. Clinical evidence profile: allopurinol + thiazides versus allopurinol.

Table 13

Clinical evidence profile: allopurinol + thiazides versus allopurinol.

Table 14. Clinical evidence profile: thiazides + allopurinol versus thiazides.

Table 14

Clinical evidence profile: thiazides + allopurinol versus thiazides.

Table 15. Clinical evidence profile: magnesium supplement (2460 mg) + thiazides versus thiazides.

Table 15

Clinical evidence profile: magnesium supplement (2460 mg) + thiazides versus thiazides.

Table 16. Clinical evidence profile: magnesium supplement (2460 mg) + thiazides versus no intervention.

Table 16

Clinical evidence profile: magnesium supplement (2460 mg) + thiazides versus no intervention.

1.4.5.2. Children
Table 17. Clinical evidence profile: potassium citrate versus no intervention (non-randomised studies).

Table 17

Clinical evidence profile: potassium citrate versus no intervention (non-randomised studies).

See appendix F for full GRADE tables.

1.5. Economic evidence

1.5.1. Included studies

No relevant health economic studies were identified.

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.

1.6. Unit costs

Illustrations of unit costs for the interventions identified in the clinical review are demonstrated below.

Table 18. UK costs of drugs.

Table 18

UK costs of drugs.

1.6.1. Economic considerations: trade-off between net clinical effects and costs

Some illustrative examples of cost offset calculations are demonstrated below.

Example 1:

These medications will most likely have to be taken for the lifetime of the patient, hence large costs can accrue.

There is therefore a trade-off with regards to;

  • potential intervention avoided from stones that do not recur (because of the treatment),
  • and whether that would outweigh the costs of the preventative treatment.

Say for someone aged 45, likely to live for another 40 years, then that is 40 years of the treatment. Depending on the cost of the treatment, this is likely to be roughly around the cost of 1 or 2 surgeries (if we say a conservative £100 per year multiplied by 40 years = £4,000). So the intervention would have to be effective enough for each individual to avoid possibly several stone recurrences.

Example 2:

If we have data on the recurrence of stones in terms of how long before another stone forms, or the average number of stones a person will have in their lifetime, and we knew how effective the interventions were, we could work out the trade-off. For example;

Sakhaee 2009102 states that the median time for a recurrence after the first event is approximately every 5 years. Over a 40 year period this would be 8 episodes. Robertson 2006100 states that the average stone patient will have between 3 or 4 episodes over their lifetime. Let’s take the midpoint of say 6 episodes over the lifetime of an average patient.

Let us also use a rate ratio of 0.7 (the average of all the studies that report rate ratios).

This means there would be 1.8 stone episodes avoided with pharmacological prevention of recurrence interventions. If these episodes would cost an average of £2,000 each to treat, and assuming that only 50% would require treatment, then that would be £1,800 of treatment costs avoided over the patient’s lifetime. To make the preventative treatments cost neutral, then over a 40 year period these interventions would have to cost less than £45 per year.

Example 3:

Let’s assume we can use the rates/probabilities from the review and put them all in the same timeframe of 1 year. Then we could compare effectiveness across the interventions.

We could also assume, that each year the probability of developing a stone would be the same, and that someone who develops a stone within a year is treated, and then they will go back into the pool of people who are at risk of developing a stone. So below is just a 1 year example assuming this would be the same repeatedly over time.

Table 19 below is using the outcomes that are reported as rates from the clinical review, and these have all been converted to 1 year probabilities using the following formula;

P = 1-EXP(-instantaneous rate*t)where P = probability, t = time
(Equation 1)

Rates may be more appropriate than probabilities because; a person can develop more than one stone over time, and also it is the stones that will be treated rather than the people, that will influence resource use (unless multiple stones in one individual can be treated at the same time).

Table 20 is using probabilities from the review (rather than rates) and these have all been converted to 12 month probabilities, using the following method;

A probability over time is converted to an instantaneous rate using the formula;

R = -[LN(1-P)]/twhere R = rate, P = probability, t = time
(Equation 2)

Then as above, an instantaneous rate can be used to convert to a 1 year probability.

Table 19. Illustrating if interventions are cost saving over a year using rates from clinical review.

Table 19

Illustrating if interventions are cost saving over a year using rates from clinical review.

Table 20. Illustrating if interventions are cost saving over a year using probabilities from clinical review.

Table 20

Illustrating if interventions are cost saving over a year using probabilities from clinical review.

1.6.2. Resource costs

The committee has made recommendations based on this review that potassium citrate, and thiazides, should be ‘considered’.

Unlike for stronger recommendations stating that interventions should be adopted, it is not possible to make a judgement about the potential resource impact to the NHS of recommendations regarding interventions that could be used, as uptake is too difficult to predict.

However, the committee noted that where this recommendation is implemented there is not expected to be a substantial impact on resources.

1.7. Evidence statements

1.7.1. Clinical evidence statements

1.7.1.1. Adults
Potassium citrate versus no intervention

One study compared potassium citrate with no intervention. This study reported recurrence as new stone formation in patients who were stone-free at baseline; the evidence suggested a clinically important benefit in favour of potassium citrate (n=56). The same study also reported recurrence as number of stone-free patients of those who were stone-free at baseline (n=34) and those who had residual stones at baseline (n=56); this evidence suggested a clinically important benefit in favour of potassium citrate. Further stone episode outcomes were reported for increased and unchanged stone size in patients with residual stones <5mm at baseline; this evidence suggested a clinically important benefit in favour of potassium citrate (n=34). The quality of the evidence was Moderate to Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Potassium citrate versus placebo

Two studies compared potassium citrate with placebo. One study reported the outcome recurrence rate (stone formation per patient per year); this evidence suggested a clinically important benefit in favour of potassium citrate (n=38). One study reported outcomes for recurrence, defined as new stone formation and stone-free; this evidence suggested a clinically important benefit in favour of potassium citrate (1 study; n=38). Further stone episode and intervention outcomes included increased stone size and procedures to remove stones, for which the evidence suggested a clinically important benefit in favour of potassium citrate (1 study; n=38). One study reported the outcome minor adverse events (unspecified; causing withdrawal from study) and the evidence suggested a clinically important benefit in favour of placebo (n=38). One study reported outcomes for kidney function. This evidence suggested no clinical difference between potassium citrate and placebo (n=18). The quality of the evidence ranged from Moderate to Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Magnesium supplement versus placebo

One study compared magnesium supplementation with placebo. The evidence suggested a clinically important benefit in favour of magnesium in terms of recurrence, defined as calculi observed and recurrence rate (n=82). The quality of the evidence was Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Allopurinol versus placebo

Two studies compared allopurinol with placebo. One study reported the outcome recurrence rate as the rate of calculous events per patient per year, and the evidence suggested a clinically important benefit in favour of allopurinol (n=60). There was a suggested clinically important benefit of allopurinol when recurrence was defined as new stones (1 study; n= 60), and no clinical difference between the interventions when recurrence was not defined (1 study; n =52). In terms of stone episodes, defined as number of people with increased stone size, there was a suggested clinically important benefit in favour of allopurinol (1 study; n=60). The quality of the evidence ranged from Moderate to Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Thiazides versus no intervention

Four studies compared thiazides versus no intervention. One study reported the outcome recurrence rate as the number of stones per patient per year and this evidence suggested a clinically important benefit in favour of thiazides (n=175). There was a suggested clinically important benefit of thiazides in terms of recurrence when the outcome was defined across different time-points as the number of participants stone free (1 study; n=175), the number of participants without a new stone formation (1 study; n=41), the number of participants free from recurrence (1 study; n=41), and the number of hypercalciuric patients with recurrences (1 study; n=32). There was a clinically important benefit of no intervention in terms of recurrence defined as the number of normocalciuric patients with recurrence (1 study; n=41). In terms of adverse events, one study reported two minor adverse events, including study discontinuation due to clinical hypotension (dizziness and hypotension), and study discontinuation due to silent severe hypokalaemia; this evidence suggested no clinical difference between thiazides and no intervention in adults (1 study; n=50). Another study reported minor adverse events as treatment discontinued due to side effects including orthostatic reaction, dizziness, gastrointestinal symptoms, muscle cramp and erectile dysfunction; this evidence suggested a clinically important benefit in favour of no intervention when compared with thiazides (1 study; n=41). One study reported the outcome creatinine clearance, as a measure of kidney function; this evidence suggested no clinical difference between thiazides and no intervention (1 study; n=40). The quality of the evidence was Moderate to Very Low to. The main reasons for downgrading evidence included risk of bias and imprecision.

Thiazides versus placebo

Six studies compared thiazides with placebo. There was a clinically important benefit of thiazides in terms of recurrence rate (2 studies; n=135). There was no clinical difference between thiazides and placebo in terms of recurrence when the definition was not specified (1 study; n=50). When recurrence was defined as verified and probable stone or spontaneous passage of newly formed stone, there was a clinically important benefit of thiazides (3studies; n=169). One study reported stone interventions (SWL) and the evidence suggested a clinically important benefit of thiazides (n=100). One study reported stone episodes as residual fragments or growth; this evidence suggested a clinically important benefit in favour of thiazides (n=100). Three studies reported minor adverse events. The evidence suggested no clinical difference between thiazides and placebo for minor adverse events including an attack of gouty arthritis, impotence characterised as transient and mild, and hypopotassaemia (1 study; n=48); one study reported general discomfort, nausea, dyspepsia, fatigue and vertigo as a minor adverse event and this evidence suggested a clinical benefit in favour of placebo when compared with thiazides (n=48). One study reported weariness, nausea and symptoms of low blood pressure as a minor adverse event; this evidence suggested a clinically important benefit of placebo when compared with thiazides (n=48). One study reported intracellular acidosis and hypocitraturia induced by hypopotassemia secondary to administration of thiazides as a minor adverse event; this evidence suggested a clinically important benefit in favour of placebo when compared with thiazides (n=100). The quality of the evidence ranged from Moderate to Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Thiazide versus magnesium

One study compared thiazides with magnesium. There was a clinically important benefit in terms of recurrence rate, and in terms of recurrence defined as calculi observed (1 study; n=93). The quality of the evidence was Very Low. The main reason for downgrading the evidence was risk of bias.

Thiazides versus allopurinol

One study compared thiazides with allopurinol. This study reported the outcome recurrence (unspecified) and the evidence suggested no clinical difference between the interventions (n=46). The quality of the evidence was Low. The main reason for downgrading the evidence was risk of bias.

Allopurinol plus thiazides versus no intervention

One study compared allopurinol plus thiazides with no intervention. The study reported the outcome recurrence as the number of stone-free patients; this evidence suggested a clinically important benefit in favour of allopurinol plus thiazides when compared with no intervention (1 study; n=45). This study also reported the outcome creatinine clearance, as a measure of kidney function; the evidence suggested no clinical difference between allopurinol plus thiazides and no intervention (1 study; n=45). The quality of the evidence was Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Allopurinol plus thiazides versus placebo

One study compared allopurinol plus thiazides with placebo. This study reported the outcome recurrence (unspecified), and the evidence suggested no clinical difference between allopurinol plus thiazides and placebo (1 study; n=50). The quality of the evidence was Low. The main reason for downgrading evidence was risk of bias.

Allopurinol plus thiazides versus allopurinol

Two studies compared allopurinol plus thiazides with allopurinol. The evidence suggested no clinical difference between allopurinol plus thiazides and allopurinol in terms of recurrence rate (1 study; n=87). In terms of recurrence, there was a suggested clinically important benefit of allopurinol alone when compared with allopurinol plus thiazides when recurrence was defined as the number of people with new stones (1 study; n=87), and no clinical difference when recurrence was not defined (1 study; n=46). The quality of the evidence was Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Thiazides plus allopurinol versus thiazides

Two studies compared thiazides plus allopurinol with thiazides. The evidence suggested no clinical difference between the interventions in terms of recurrence (unspecified) (1 study; n=44) or recurrence when defined as the number of stone-free patients (1 study; n=43). One study reported two minor adverse events, including study discontinuation due to clinical hypotension, and study discontinuation due to silent severe hypokalaemia; this evidence suggested no clinical difference between thiazides plus allopurinol and thiazides (1 study; n=50). One study reported creatinine clearance, as a measure of kidney function; this evidence suggested no clinical difference between thiazides plus allopurinol and thiazides (1 study; n=43). The quality of the evidence was Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Magnesium supplement + thiazides versus thiazides

One study compared magnesium supplement plus thiazide with thiazide alone. This study reported the outcome recurrence, defined as the number of people free from recurrence. The evidence suggested a clinically important benefit in favour of combined magnesium and thiazide. The same study also reported minor adverse events as treatment discontinued due to side effects including orthostatic reaction, dizziness, gastrointestinal symptoms, muscle cramp and erectile dysfunction; this evidence suggested a clinically important benefit in favour of thiazide alone (n=33). The quality of the evidence was Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

Magnesium supplement + thiazides versus no intervention

One study compared magnesium supplement plus thiazide with no intervention. This study reported the outcome recurrence, defined as the number of people free from recurrence. The evidence suggested a clinically important benefit in favour of combined magnesium and thiazide. The same study also reported minor adverse events as treatment discontinued due to side effects including orthostatic reaction, dizziness, gastrointestinal symptoms, muscle cramp and erectile dysfunction; this evidence suggested a clinically important benefit in favour of no intervention (n=40). The quality of the evidence was Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

1.7.1.2. Children
Potassium citrate versus no intervention

Two non-randomised studies in children compared potassium citrate with no intervention. One of the studies reported the outcome recurrence rate (stone formation rate in children after PNL, per patient per year); this evidence suggested a clinically important benefit in favour of potassium citrate (n=42). One study reported recurrence as the new detection of a stone or spontaneous passage of a non-pre-existing stone in patients following PNL; this evidence suggested a clinically important benefit in favour of potassium citrate (n=42). One study reported recurrence as new stone formation in patients stone-free following SWL; this evidence suggested a clinically important benefit in favour of potassium citrate (n=52). One study reported stone recurrence or regrowth, and stone stability in children with residual fragments following SWL; this evidence suggested a clinically important benefit in favour of potassium citrate (n=44). The quality of the evidence was Very Low. The main reasons for downgrading evidence included risk of bias and imprecision.

1.7.2. Health economic evidence statements

  • No relevant economic evaluations were identified.

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 recurrence rate, stone episodes/stone interventions, use of healthcare services, quality of life, major adverse events (if admission to hospital) and minor adverse events (no admission to hospital) were the outcomes critical for decision making. Kidney function and pain intensity (visual analogue scale) were also considered as important outcomes.

Evidence was reported for recurrence rate, stone episodes, stone interventions and minor adverse events. There was no evidence for the quality of life, use of healthcare services, major adverse events or pain intensity. For the purposes of this review, stone episodes and stone interventions were considered as two separate outcomes, and ‘recurrence’ was considered as a further outcome of critical importance.

1.8.1.2. The quality of the evidence

In adults, the quality of the evidence in this review ranged from a GRADE rating of very low to moderate. In children, the quality of the evidence was very low, based on two non-randomised studies. The main reasons for downgrading the quality of the evidence were risk of bias and imprecision. The presence of selection bias in terms of a lack of adequate randomisation and allocation concealment commonly resulted in a high or very high risk of bias rating.

No evidence was found for the following comparisons listed in the protocol: sodium citrate; oral bicarbonate; chelating agents: D-penicillamine, Tiopronin (or Thiola or mercaptopropionylglycine) (for cystinuria); captopril (for cystinuria); Ca supplements, pyridoxine; methionine; prophylactic antibiotics.

1.8.1.3. Benefits and harms

Evidence for people with both symptomatic and asymptomatic stones was searched for; however no evidence was identified for the asymptomatic population. The committee therefore agreed that the recommendations should only apply to those with symptomatic stones.

Potassium citrate in adults

The committee considered the evidence for potassium citrate in adults compared to no intervention or placebo and noted there was very low to moderate quality evidence in favour of potassium citrate for outcomes related to stone recurrence, stone episodes and stone intervention. These outcomes were measured at 12 and 36 months. The committee considered that 12 months is a short follow up period, and may not be a sufficient length of time to measure stone recurrences. However, the committee noted that the results at 36 months were consistent with the 12 month evidence. It was noted that there was no clinically important difference between the interventions in terms of kidney function. The committee discussed that these outcomes were measured at 3 months, which may not be a sufficient length of time to capture meaningful changes in these outcomes. There were more adverse events leading to study discontinuation in the potassium citrate group, however no reasons were given for these events, therefore it was not possible to fully consider the trade-off between benefits and harms of intervention. The committee considered that there may be concerns associated with potassium citrate in some populations, as increased potassium in patients with impaired renal function can cause hyperkalaemia which is associated with adverse events. Overall, they concluded that there was not enough evidence to make a conclusion regarding safety.

The evidence was discussed with reference to the available information on study participants’ stone composition and biochemical abnormalities. The committee noted that all the evidence was based on people with calcium oxalate or calcium oxalate and calcium phosphate stones, however included a mixture of urine metabolic abnormalities. All of the evidence came from a population of recurrent stone formers.

The committee highlighted that potassium citrate is currently used in UK clinical practice off-licence for calcium oxalate stones, although practice can vary, and that there may be issues with availability and long term prescription. From clinical experience, the committee also noted that the taste of potassium citrate might be a negative factor for treatment adherence.

Overall, the committee agreed that both the evidence and clinical experience supported the use of potassium citrate based on stone composition and irrespective of urine biochemical abnormalities. However, there were concerns regarding the size of the studies and the amount of evidence, as well as concerns relating to safety and the adverse events evidence; therefore a consider recommendation was made.

Potassium citrate in children

The committee considered the evidence for potassium citrate in children compared with no intervention and noted this was of very low quality, from non-randomised studies. They also noted that both studies were based on a population who had undergone previous treatment with either PCNL or SWL. The evidence favoured potassium citrate for the prevention of recurrence when compared with no intervention. There was no evidence for major or minor adverse events; therefore the committee were not able to consider potential harms. However it was noted that as with the adult population, potassium citrate is not very palatable and therefore there are sometimes problems with adherence to treatment.

The committee also discussed the evidence with reference to the available information on study participants’ stone composition and urine biochemical abnormalities. Although the evidence did not relate to specific urine biochemical abnormalities, the committee agreed these would be tested as part of standard UK clinical practice in the paediatric population, typically at a specialist centre. The committee also noted that if hypercalciuria and/or hypocitraturia are identified in the urine during metabolic testing, potassium citrate is likely to be used in the paediatric population. The committee considered that the evidence suggested that potassium citrate is beneficial regardless of urine metabolic abnormality, however agreed that the evidence was not sufficiently convincing to change current practice and the expert opinion of the committee by recommending its use for all children with a calcium oxalate stone regardless of urine metabolic abnormality. Therefore, the committee recommended that potassium citrate should only be considered in children with a specific stone composition and urine biochemical abnormality. They also agreed that although the evidence was based on those who had had previous treatment with SWL or PCNL, based on consensus and clinical experience, the recommendations should apply to this population irrespective of previous treatment, as child stone formers are much more likely to have a metabolic abnormality and are therefore a high risk group.

Thiazides in adults

When compared to no intervention, there was a benefit of thiazides in terms of all outcomes relating to recurrence, when the population was people with hypercalciuria. One study included a subgroup of people with normocalciuria, and for this population there was a benefit of no intervention in terms of recurrence, suggesting that thiazides are only beneficial for those with hypercalciuria.

When compared to placebo, there was no difference between interventions in terms of recurrence rate, based on a population with no well-defined metabolic cause of renal stone formation. This also suggests that thiazides may only be beneficial for people with a specific urine metabolic abnormality. There was no clinical difference between groups in terms of recurrence when the definition of recurrence was not specified and measured at 2 months. However the committee agreed that this was not a sufficient length of time to see a recurrence of stones, therefore no conclusions could be drawn from this outcome. When recurrence was measured at between 1 and 3 years, there was a benefit of thiazides over no intervention. This evidence was based on a population of people with mixed or unspecified urine metabolic abnormalities. In terms of stone interventions and stone episodes, one study showed a benefit of thiazides in terms of reducing the need for SWL and in terms of changes in stone size. The committee noted that the population included a mix of urine metabolic abnormalities, but the majority of participants had hypercalciuria. They also discussed that this study used thiazides as an adjunct to SWL, and suggested that using thiazides in this way reduces the need for repeat procedures. They considered that this is not usual practice, and agreed that further research to replicate these findings may be of benefit to inform future practice.

When compared to allopurinol, there was no clinical difference between interventions in terms of recurrence, however this outcome was measured at 2 months and therefore the committee again agreed that they could not draw conclusions from this evidence.

When compared to magnesium, there was a benefit of thiazides in terms of recurrence and recurrence rate, however the committee did note that this was based on a single study.

Across all comparisons there was no clinical difference or a harm of thiazides in terms of adverse events; however the committee noted that these events were generally not serious. From clinical experience they noted that thiazides tend to be well tolerated. The committee noted that thiazides are currently used in UK clinical practice for adults with recurrent calcium oxalate stones and hypercalciuria, but as an off-licence treatment.

All of the evidence was based on a population with either calcium oxalate stones, a mixture of calcium oxalate and calcium phosphate stones, or calcium stones with no further detail. The majority of calcium stones have a composition of predominantly calcium oxalate. The committee noted that pure calcium oxalate stones are rare, and therefore most stones labelled calcium or calcium oxalate will usually be a mixture of calcium oxalate and calcium phosphate. They noted that stones containing over 50% calcium phosphate are also a small group compared to calcium oxalate stones, and would generally not be treated with thiazides as calcium phosphate stones are associated with rare distal tubulopathies and certain infections. They agreed that the recommendation should apply to those with predominantly calcium oxalate stones.

Overall, the committee noted that there seems to be some benefit of thiazides, and that the majority of the evidence favouring thiazides was based on a population of purely or majority hypercalciuria. They noted that evidence from normocalciurics showed no benefit of thiazides, and there was conflicting evidence when the population had a mix of urine metabolic abnormalities. Therefore, they agreed thiazides should be considered for those with hypercalciuria. They discussed that thiazides work by inducing a natriuresis, and that if more sodium is ingested this will cancel out the effect of the thiazide. Therefore, they agreed that sodium intake should be restricted as a prerequisite to treatment with thiazides.

Magnesium supplementation in adults

The committee highlighted that magnesium supplementation has limited use within current UK clinical practice. They indicated that magnesium levels would typically be measured in cases of hypocalcemia, and that this is a small and targeted population. Very low quality evidence favoured magnesium supplementation for the prevention of recurrence in adults when compared with placebo.

The committee discussed that over half of participants had no urine biochemical abnormality, yet there was a potential benefit in terms of recurrence, suggesting that magnesium may be beneficial regardless of urine biochemical abnormality. However, the committee was aware from clinical expertise and experience that magnesium may lead to adverse events relating to the bowels, and as there was no evidence for adverse events to inform this, did not feel that it could be recommended. Further, the evidence showing a potential benefit of magnesium was of very low quality and based on a single study. The committee agreed that recommending magnesium was not justified on the basis of the evidence, and on the consensus of the committee.

Allopurinol in adults

The committee discussed that allopurinol is not commonly used in UK clinical practice but agreed that evidence for this treatment should be considered. They noted that very low to low quality evidence in a population of predominantly calcium oxalate stones favoured allopurinol for outcomes related to the prevention of recurrence when compared with placebo, and moderate quality evidence showed no clinical difference. The committee discussed how this evidence did not seem to make clinical sense, as allopurinol is used to alter uric acid and may in some way modulate calcium, but the mechanism of effect on calcium stones was unclear to the committee. The committee considered this evidence and the absence of any replicated evidence since this was published over 30 years ago. There was no evidence for the major or minor adverse events outcomes, but the committee highlighted potentially serious side effects with using allopurinol, such as acute kidney injury and problems with the blood cell count.

Combined therapy (allopurinol/magnesium and thiazides) in adults

Low quality evidence favoured combined therapy for the prevention of recurrence when compared with no intervention, while very low quality evidence favoured allopurinol alone when compared with combined allopurinol and thiazide therapy. Also, very low to low quality evidence showed no clinical difference for other recurrence outcomes when combined allopurinol and thiazide therapy was compared with allopurinol alone, thiazides alone and placebo. There was also a benefit of combined magnesium and thiazide therapy in terms of recurrence compared to thiazide alone. The committee noted that evidence of harms in terms of minor adverse events was of low quality and showed no clinical difference between combined therapy (allopurinol and thiazides) when compared with thiazides alone, but there was a benefit of thiazide alone and no intervention when compared to combined thiazide and magnesium. There were no major adverse events reported.

The committee noted that combined therapy, consisting of allopurinol and thiazides, is not routinely used in UK clinical practice. They noted that this combination may be used if urine metabolic laboratory tests have been done. The results of each test are then treated for, individually. However, they noted that thiazides are usually used to treat calcium stones, whereas allopurinol is usually used to treat uric acid stones, therefore this combination may not make clinical sense. Overall, the committee considered the evidence and agreed that there seemed to be no additional benefit of combined therapy over either intervention alone, in overall biochemically unselected patients.

1.8.2. Cost effectiveness and resource use

No economic evidence was identified for this question.

Unit costs were presented to the committee to illustrate the variation in costs of the interventions in the clinical review. These ranged from below £20 per year for Allopurinol for example, to over £100 per year for the more supplement based interventions.

These interventions are likely to have to be taken for the patient’s lifetime. There is therefore a cost trade-off with regards to the cost of the interventions over the patient’s lifetime, versus the costs saved from stone events avoided if the treatment is successful.

Some cost-offset examples were presented to the committee to aid their consideration of cost effectiveness in the absence of evidence;

If the average age of onset of stones is 45, and the individual is likely to live for another 40 years, then an estimate of the number of recurrences a patient might have over their remaining lifetime is 6 episodes (see section 1.6.1 for more detail on assumptions). If we apply the average rate ratio from all the interventions that reported rates in the clinical review (for adults) (0.7) this means there would be 1.8 stone episodes avoided with prevention of recurrence interventions. If these episodes would cost an average of £2,000 each to treat, and assuming that only 50% would require treatment, then that would be £1,800 of treatment costs avoided over the patient’s lifetime. To make the preventative treatments cost neutral, over a 40 year period these interventions would have to cost less than £45 per year. It may be however that the number of recurrences is overestimated as some people may never develop another stone, and some are more likely to keep developing stones because of an underlying abnormality. Therefore, the cost of a preventative intervention would have to be even lower to offset fewer events avoided.

The clinical data for individual interventions (for adults) was also used to estimate some cost offsets. Using a cohort of 1000 people, and the same assumptions that intervention to remove a stone would cost £2,000 but only 50% of stones would need intervention, applying the costs of the interventions based on the unit costs presented; showed that interventions likely to be offset are potassium citrate, allopurinol, allopurinol plus thiazides, and thiazides. These informal calculations are highly dependent on the clinical data and the assumptions made and should be interpreted with caution.

The clinical data was sometimes difficult to interpret because some studies had populations that were in people with specific urine abnormalities (e.g. hypocitraturia), and some were in populations with mixed urine abnormalities (although still within predominantly one type of stone composition e.g. calcium oxalate stones). The committee opinion was that this showed there to be a benefit of prescribing to a mixed group of people who have had renal stones and not necessarily just those with certain urine metabolic abnormalities.

The potassium citrate data for adults showed a benefit to giving the intervention regardless of the presence of specific abnormalities. However an adverse event that might be a concern would be hyperkalemia. It was acknowledged that it would be a change in practice to recommend potassium citrate to all individuals who have ever had calcium stones, regardless of whether they had a metabolic abnormality.

It is also important to note that in order to identify the type of stone a stone analysis would be necessary, and there is a large variation in practice with regards to whether stone analysis takes place. Although, It is only possible to do a stone analysis if the stone is available for testing which would be in about 50% of patients – therefore this reduces the population eligible for stone analysis. It is important to consider the cost effectiveness of the pathway as a whole, because tests can be expensive and would only be cost effective if there is adequate benefit from the treatment that would be given to those identified from the test.

For example; potassium citrate could be given to those with a predominantly calcium oxalate stone, as that is what the evidence suggests (so based on stone composition regardless of urine metabolic abnormality presence). It costs around £25 to undertake a stone analysis, if 1000 people with renal stones had their stone analysed, then that would cost around £25,000. If the prevalence of a calcium oxalate stone was around 70%, then 700 people could benefit from potassium citrate. Giving potassium citrate for 1 year to 700 people would cost around £64,000, which leads to total costs of testing and treatment of around £89,000. To offset this cost, around 44 stones that would need treatment in those 700 people would need to be prevented (if treatment cost £2,000), to offset the cost of identifying those people who could benefit from the potassium citrate. This means avoiding around 6% of stones in a year in those people being treated. The effectiveness difference between the intervention and control arm for potassium citrate versus placebo or no treatment was higher than this 6%. As mentioned earlier these are informal calculations and need to be viewed with caution.

Other interventions also considered to be effective from the clinical review were thiazides. These are low cost interventions, but would require some monitoring if prescribed. Thiazides are used for hypertension, therefore some patients would already be prescribed thiazides, given the high prevalence of hypertension.

Given concerns around; the quality of the evidence, that evidence for most outcomes came from single studies, concerns around adverse events that were not captured in the clinical review, uncertainty around cost effectiveness, and acknowledgment that any strong recommendations would be a change in current practice – the committee decided to make consider recommendations for the interventions they felt were clinically effective from the clinical review. The populations the interventions were recommended in were limited to recurrent stone formers, and limited further by stone compositions or metabolic abnormalities the committee felt the clinical evidence was demonstrated in. The use of potassium citrate and thiazides for renal stones is already current practice in some areas, resource impact is therefore likely to be small.

In children, only non-randomised evidence was identified comparing potassium citrate to no intervention. Children are a much smaller population, and it is standard practice to undertake screening for metabolic abnormalities in children, as they tend to be seen in specialist centres. The committee felt the evidence demonstrated effectiveness in children with mixed urine metabolic abnormalities. The recommendation might result in a change in practice as currently potassium citrate would be given in children with calcium in their urine or dependent on stone composition. However as a consider recommendation was made, the impact on practice is dependent on uptake, and children are a small population.

As mentioned above when discussing stone analysis, there is an implied pre-requisite that in order to treat by a specific stone composition or abnormality, then tests have taken place to identify these factors. No evidence was identified on the cost effectiveness of metabolic tests, and also as mentioned; the cost effectiveness of a test is dependent on the downstream factors such as prevalence of conditions identified from the tests and effectiveness of subsequent management. Clinical questions often assess individual parts of a pathway, but these need to be taken together when assessing cost effectiveness because individual parts of a pathway have an impact on the rest of the pathway. It has been shown that prevention of recurrence can be effective, and these costs may be offset by stones avoided, but the cost effectiveness of the whole testing pathway has not been formally proven. Therefore the recommendations from this review are ‘consider’ recommendations, from the perspective that; should composition or metabolic abnormality information be available for a patient, then a clinician might want to consider the treatments recommended in this review.

1.8.3. Other factors the committee took into account

The committee agreed that all pharmacological management approaches should be considered alongside dietary advice.

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Appendices

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 23. 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 24. Database date parameters and filters used

Medline (Ovid) search terms

Embase (Ovid) search terms

NHS EED and HTA (CRD) search terms

Appendix D. Clinical evidence tables

Download PDF (679K)

Appendix E. Forest plots

E.7. Thiazide versus magnesium in adults

Figure 42. Recurrence rate (36 months)

Figure 43. Recurrence

E.8. Thiazides versus allopurinol in adults

Figure 44. Recurrence (unspecified) (2 months)

E.10. Allopurinol + thiazides versus placebo in adults

Figure 47. Recurrence (unspecified) (2 months)

Appendix G. Health economic evidence selection

Figure 65. Flow chart of economic study selection for the guideline

Appendix H. Health economic evidence tables

None

Appendix I. Excluded studies

I.2. Excluded health economic studies

None

Appendix J. Research recommendations

J.1. Preventive treatments for patients with small residual kidney stone fragments following shockwave lithotripsy

Research question: What is the clinical and cost-effectiveness of empirical potassium citrate or bendroflumethiazide as preventative therapies for patients with small residual fragments following shockwave lithotripsy to renal and ureteric stones.

Why this is important:

Renal and ureteric stones affect a large proportion of the population at some time in their life and can be associated with extremely severe pain and significant morbidity. The incidence of kidney stones is increasing significantly as they are linked to poor diet, obesity, diabetes and hypertension. About half of stone formers will develop a further stone in the future. The most commonly used treatment for renal and ureteric stones is shockwave lithotripsy. This is a clinically effective and cost-effective treatment for the more common smaller stones. Sometimes following lithotripsy treatment, small fragments don’t washout completely and these patients are at an increased risk of future stone related problems such as pain, infections, or the need for further interventions. Previous studies have given some evidence that inexpensive empirical preventative treatments might help avoid such problems but the evidence quality is low, some of the evidence is contradictory and such preventative treatments have not been widely adopted in this scenario. A study to compare the clinical effectiveness and cost effectiveness of these approaches is required.

Table 40. Criteria for selecting high-priority research recommendations