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Are glucocorticoids or NSAIDs effective in idiopathic feline urinary tract disease signs than no treatment or placebo?
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PICO question
In cats with idiopathic feline urinary tract disease (FLUTD), are glucocorticoid or non-steroidal anti-inflammatory drugs more effective than placebo or no treatment in reducing clinical signs attributable to cystitis?
Clinical bottom line
Category of research question
Treatment
The number and type of study designs reviewed
Three randomised controlled trials have examined the efficacy of prednisolone or non-steroidal anti-inflammatory drugs (NSAIDs) in reducing the clinical signs of feline lower urinary tract disease compared to a placebo whilst one retrospective cohort study compared the reoccurrence of FLUTD in cats treated with meloxicam and without meloxicam
Strength of evidence
Weak
Outcomes reported
One small controlled trial compared prednisolone to a placebo and found no clinical differences in dysuria, microscopic haematuria, and occult blood for cats diagnosed with idiopathic non-obstructive feline lower urinary tract disease (FLUTD) hospitalised for 10 days. The study however had a very small sample size. Furthermore, the external validity of the study to similar patients discharged to their home environment is unclear.
The second small controlled trial compared meloxicam to a placebo in cats diagnosed with obstructive FLUTD. Statistical analysis was applied to determine if there were significant differences in voiding behaviour, general demeanour, haematuria, food intake and abdominal pain as assessed by the veterinarians in charge during hospitalisation and owners at discharge. No statistically significant differences (P>0.05) were calculated between the two treatment groups based on the owner questionnaire and veterinarian assessment but small samples in each treatment probably limited statistical power.
The third small controlled trial compared the reoccurrence of feline idiopathic cystitis (FIC), related clinical signs and recurrent urinary obstruction in cats at 10 days, 1, 2 and 6 months after discharge when treated with phenoxybenzamine and alprazolam, with or without the addition of meloxicam. No statistically significant differences were found in the reoccurrence of obstructed or non-obstructed FIC for cats treated with either meloxicam or no meloxicam. However, full details of each intervention group were not sufficient to assess for balance of prognostic factors, subjective scoring of clinical signs was not detailed, and the study was underpowered for the actual obstruction rates reported.
The fourth paper was a retrospective cohort study that examined the association of different treatment factors with 30 days reobstruction. The study found no significant association between the use of meloxicam and the rate of reobstruction but a number of confounders were present
Conclusion
Three small randomised controlled trials and a single retrospective cohort study failed to find a significant association between the use of glucocorticoids or NSAIDs with severity of FLUTD clinical signs or risk of reobstruction. Clinical outcome measures were heterogeneous and studies were significantly underpowered and/or at risk for bias and/or confounding. There is insufficient evidence to recommend the use of either drug category in decreasing time to resolution or severity of clinical signs in cases of idiopathic FLUTD or FIC
How to apply this evidence in practice
The application of evidence into practice should take into account multiple factors, not limited to: individual clinical expertise, patient’s circumstances and owners’ values, country, location or clinic where you work, the individual case in front of you, the availability of therapies and resources.
Knowledge Summaries are a resource to help reinforce or inform decision making. They do not override the responsibility or judgement of the practitioner to do what is best for the animal in their care.
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Appraisal, application and reflection
Three studies examined whether clinical signs of FLUTD can be improved with glucocorticoids or NSAIDs whilst one study examined if the use of meloxicam significantly reduced the reoccurrence of FLUTD. None found a statistically significant difference of either drug class in reducing the clinical signs of idiopathic FLUTD/FIC. All had significant limitations in terms of statistical power and/or external validity and/or risk of bias.
External validity is defined as to whether casual relationships may be generalised and applicable to different measures5. Internal validity in contrast represents whether the variables operated adequately represent the theories and hypothesis proposed5. Whilst it is useful to know if there is a difference between glucocorticoid or NSAIDs versus no treatment at all for controlling the signs of FLUTD, the treatment options tested should be validated and applicable to the general FLUTD population. Clinical signs of feline cystitis may be elicited or exacerbated by stressful circumstances, which may include hospitalisation and/or diet change6,7 thus the conditions for patients in the Osborne et al. (1996) paper may not be applicable to cats discharged from hospital to their home environment. There was no mention of whether there was a sudden food change for the hospitalised patients. Steckler & McLeroy (2008) emphasise the importance of knowing that a program is likely to be effective in other settings and populations. Through this, the results of not only Osborne et al. (1996) but also the others should be interpreted with caution as it is unclear how the risk of reoccurrence and the lack of resolution reported in any hospital setting may relate to the risk of reoccurrence and persistence in a home population.
Adequate sample size is essential in avoiding type II error (failure to detect a statistically significant effect when one exists)8. Osborne et al. (1996), Dorsch et al. (2016), and Hetrick & Davidow, (2013) did not provide details of sample size calculation nor did they present a power analysis but we can infer that statistical power was likely low. Nivy et al. (2019) and colleagues performed a sample size calculation assuming a population with a much higher risk for FIC recurrence actually occurred in their trial, thus high risk for type II error was also present.
Randomisation and blinding are key features of most controlled trials to balance groups for important prognostic variables and to minimise biased outcome ascertainment (e.g. randomisation to avoid selection bias and blinding to avoid information bias). In the paper by Dorsch et al. (2016) the study was unblinded midway, leading to risk of ascertainment bias. In the paper by Nivy et al. (2019) it is unclear whether group balance for prognostic variables was achieved.
Although cohort studies are often at higher risk for selection bias, this is less likely to be true of the study by Hetrick & Davidow (2013) since hospital protocol, rather than clinician choice, appeared to determine treatments for obstructed FLUTD. However, because three interventions in the hospital protocol were altered over the same time period and no adjusted analysis was reported for the effects of analgesic agent, results are at high risk for unmeasured confounding.
Finally, the heterogeneous outcomes reported limit evidence synthesis: each publication differed in methods of assessment of FIC. For Nivy et al. (2014) and Hetrick & Davidow (2013), recurrence of obstruction was a primary and intuitively valid objective outcome. However, method of subjective scoring of non-obstructive cystitis signs was not transparent in two publications (Osborne et al., 1996; and Nivy et al., 2019); in the third publication (Dorsch et al., 2016), subjective scoring method was transparent but lacked detail on inter-rater reliability and validation; moreover, it is unclear how the raters were blinded.
Further study is needed to delineate what role, if any, glucocorticoids or NSAIDs have in the treatment of FLUTD/FIC. Adequately powered randomised controlled trials and/or meta-analysis are required; standardised and validated outcomes to assess bladder pain/dysuria are required.
In conclusion, there are no studies which appear to provide evidence for the use of steroidal or NSAIDs in decreasing symptoms or duration of clinical signs associated with FLUTD.
Glucocorticoids are not considered analgesics and there is insufficient evidence to suggest they provide a profound benefit in human interstitial cystitis. Glucocorticoids may elevate risk for diabetes mellitus in certain cats and carry some risk for secondary bacterial infection thus also cannot currently be recommended for FIC10.
Although NSAIDs are considered a mainstay for management of chronic pain, they are not considered a first line treatment for the use in feline urinary cystitis-related cases11. The leading risk and adverse effects of NSAIDs includes nephrotoxicity, gastric ulcers, gastric perforations, and anorexia in cats11. Given the risk of adverse gastro-intestinal and renal side effects of NSAIDs in cats, the current evidence does not propose that the use of NSAIDs shortens the clinical signs of FIC and it is critical that veterinarians report and notify the risk factors if they choose to use NSAIDs as an adjunctive treatment to owners, colleagues and future proposing studies alike.
Opioids have been considered effective first-line analgesia for pain in cats11 but currently in regards to the use of glucocorticoids and NSAIDs, pending higher quality studies with greater statistical power is required as there is no high-quality evidence for the use of glucocorticoid or NSAIDs in the treatment of FIC.
The plethora of emerging and numerous research on the aetiology of FIC has focused on multi-factorial factors including but not limited to behaviour, housing, environmental, dietary, litter type, cohabitation of with other cats or pets in the household, enrichment availability, anatomical formation, age, obesity, neuter states and even neurohormonal pathways12,13,14. The most effective treatment outcomes should be focusing on these factors as the foremost and then the use of pharmacological drugs as an additional secondary action if required.
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