A prospective randomized study of efficacy of 2 treatment protocols in preventing recurrence of clinical signs in 51 male cats with obstructive idiopathic cystitis

Abstract Background Urethral obstruction (UO) is a common complication of feline idiopathic cystitis (FIC). Robust treatment recommendations to prevent its recurrence are scarce. Objectives To evaluate meloxicam treatment for prevention of clinical recrudescence in male cats with obstructive FIC. Animals Fifty‐one client‐owned cats. Methods Prospective, randomized clinical trial. Every male cat with FIC‐associated UO was deemed eligible for the study and was recruited during hospitalization. After discharge, cats were treated with phenoxybenzamine and alprazolam for 2 weeks, with (24 cats) or without (27 cats) low‐dose meloxicam (0.025 mg/kg/day PO) and monitored for 6 months. Results Cumulative number (%) of cats with recurrent UO at 10 days, 1‐, 2‐, and 6‐months after discharge was 1 (2%), 2 (4%), 4 (8%), and 8 (16%), respectively. Overall, 12 (24%) cats experienced signs of recurrent FIC within 6 months, with (8 cats) or without (4 cats) concurrent UO. No difference in the cumulative incidence of UO within 6 months was detected with addition of meloxicam (odds ratio [95% confidence interval], 0.63 [0.13‐2.97]; P = .70). All cats were alive at 6 months. Conclusions and Clinical Importance No clinical benefit was detected with the addition of low‐dose meloxicam to phenoxybenzamine and alprazolam treatment for 2 weeks after discharge. Nevertheless, this study was underpowered to identify potential differences, and its findings must be corroborated in larger studies.

effective long-term management protocols.
Owing to the consequences of recurrence, and lack of evidencebased, effective treatment protocols, we aimed to evaluate the efficacy of a 2-week-long, low-dose oral meloxicam treatment in reducing recurrence of urethral obstruction (rUO) in male cats with obstructive FIC. Our primary hypothesis was that low-dose meloxicam treatment would decrease inflammation during 2 weeks of administration, when FIC was expected to persist, and consequently reduce long-term recurrence rates. A secondary objective was to investigate possible prognostic markers for recrudescence of clinical signs and the outcome.

| Cats and definitions
This study was conducted in a referral teaching hospital between the years 2016 and 2018 and was approved by the institutional ethics committee. Male cats with obstructive FIC were prospectively enrolled with their owner's consent. None of the cats had received any medication before admission. Additional inclusion criteria included resolution of azotemia and the ability to fully empty the UB before discharge. Obstructive FIC was diagnosed based on the presence of compatible history, clinical signs, and physical examination findings, including stranguria, hematuria, pollakiuria, periuria, and unsuccessful voiding attempts, in addition to a tense, painful UB, unamenable to manual voiding. 3 Upon enrollment to the study, abdominal sonography, urinalysis, and urine culture were performed in all cats, whereas survey radiographs and contrast retrograde urethrography were performed in only 20 of 51 cats (39%), due to owners' financial constraints. Nevertheless, all cats that had presented with a recurrent episode during the follow-up period of this study eventually underwent contrast retrograde urethrography. Data extracted from medical records for statistical analyses included the signalment, season, number of episodes of FIC-related signs, environment, type of diet before hospitalization and after discharge, clinical signs and duration thereof, vital signs upon admission, weight, duration and type of urinary catheter used during hospitalization and antibiotic treatment.

| Collection of samples and laboratory methods
Blood samples for serum chemistry (Cobas 6000; Roche, Mannheim, Germany; at 37 C) and CBC (Advia 2120c, Siemens, Erfurt, Germany) were collected in plain tubes with gel separators and potassium-EDTA tubes, respectively. In some cases, at the attending clinician's discretion, and depending on the owners' financial constraints, only serum creatinine and electrolytes, PCV, and total solids in plasma (measured by refractometry) were measured. Urine samples (5 mL) were collected by cystocentesis for routine urinalysis and urine culture before urinary catheterization and initiation of fluid therapy.

| Treatment and study design
All cats were initially stabilized, and the UO was relieved by catheterization. Medical decisions before relieving the obstruction (eg, type of fluid, administration of IV dextrose, insulin or bicarbonate to control hyperkalemia, medical stabilization before relieving the UO, and the choice of urinary catheter type) and the timing of urinary catheter removal (eg, after azotemia had resolved and urine color and turbidity had improved) were made at the attending clinicians' discretion.
Cats were then randomly assigned to treatment after discharge by drawing the treatment protocol from a sealed envelope to receive either of the following 2 protocols: (1)  (2) phenoxybenzamine and alprazolam alone (control group). In addition, owners were instructed to change the diet to a therapeutic urinary diet and to implement husbandry and environmental measures as previously described. 16 Cats were subsequently followed up for 6 months. Recurrence of FIC-related clinical signs and rUO were recorded at 10 days, 1-, 2-, and 6-months after discharge. analyses were used to assess the predictive performance of the heart rate (HR) at presentation for the presence of hyperkalemia. Log transformation of continuous variables was used to achieve normal distribution (as determined by the Shapiro-Wilk test and Q-Q plots), where appropriate. All tests were 2-tailed, and P < .05 was considered significant.

| Statistical analysis
Analyses were done using a statistical software package (SPSS 25.0, IBM, Chicago, Illinois).
Sample size was calculated using an additional statistical software (Gpower 3.0.10). The main outcome of the study for sample size calculation was the effect of treatment. Assuming recurrence rate of 50% in the control group and a risk ratio of 0.2, 19 cats in each group are required to demonstrate a difference with 95% statistical confidence and a power of 80%.

| RESULTS
The study included 51 male cats (intact, 7 cats; neutered, 44 cats), with overall median (interquartile range, IQR) age and body weight of Selected laboratory results at presentation to the hospital are presented in Table 1  No difference in recurrence was detected when cats were fed a prescription, kibble-based diet, compared to cats that were fed nonprescription, kibble-based diet. Similarly, no difference in recurrence rate was observed between cats that were fed a prescription kibble diet, with or without the addition of non-prescription canned food, to cats that were fed non-prescription diet (P > .3).
All cats survived to discharge and were alive at 6 months after discharge.

| DISCUSSION
In the present randomized, prospective clinical trial, cumulative rUO rates over a 6-month follow-up period were low and no differences in recurrence rates at multiple time points were detected with the addition of low-dose meloxicam. However, the study was underpowered to detect small differences.

Recurrence of clinical signs and UO is common in FIC, might result in
life-threatening complications, and occasionally might lead to euthanasia due to owners' consternation and financial constraints. 3 existing recommendations are often unsubstantiated. 3 Both treatment protocols used in this study included alprazolam and phenoxybenzamine.
The former was administered to reduce FIC-induced increased urethral pressure, 14 in addition to its anxiolytic effect, given the association between FIC and stress, 1,9 whereas the latter was chosen to reduce proximal urethral pressure. 14,19 The use of α-1 adrenergic antagonists to reduce proximal urethral pressure is widespread in FIC, due to the findings from urodynamic studies in cats. 17,18,[32][33][34][35] Because increased urethral pressure and anxiety are known causes and consequences of FIC, 1,3,9,14 all cats herein were administered a benzodiazepine and an α-1 adrenergic antagonist, whereas meloxicam treatment was randomly assigned only to the study group.
A plethora of evidence supports the inflammatory nature of FIC.
Mucosal edema, erythema, ulceration, and prominent blood vessels are noted macroscopically and microscopically, 1,3,36 whereas histological findings support the notion of chronic inflammation, with increased number of mucosal leukocytes and degranulated mast cells, concomitant increased suburethral proliferation, neovascularization, and elastin content. 37 17,20,26 Similarly, in the present study, a Dearth of information and inconsistent reports also concern dietary recommendations for preventing rUO. In 1, nonrandomized controlled study of a singular diet, a canned formulation proved superior to a dry one in reducing the incidence of rUO, 50 whereas other retrospective studies failed to demonstrate significant protective effects of diets, canned or dry. 32,51 The only grade I evidence 52 treatment recommendation for cats with FIC concerns the consumption of a commercial prescription, cystitis preventive diet, compared to control food, where the former, irrespective of its formulation, reduced the incidence of recurrent signs of FIC. 15 Although no differences in recurrence rates were detected between the 2 treatment groups, the present study was not designed, and was likely underpowered, to investigate the efficacy of preventive therapeutic diets.
In contrast with previous reports, neither the duration of urinary catheterization 32 nor the type of urinary catheter 17 was associated with rUO in our study. Furthermore, both hospitalization-and 6-month case fatality rates were nil, while previously reported case fatality rates of FIC ranged from 5.8% to 8.9%, 6,31,53,54 and none of our cats was euthanized, notwithstanding a similar recurrence rate to previous studies. 3,6,17,20,[30][31][32] Recurrence is purportedly a leading cause of euthanasia in FIC, leading to euthanasia of 21% of cats in 1 study. 31 The discrepancy between the present study and previous ones likely reflects differing attitudes among clinicians, owners, and institutions (eg, reluctance to euthanize and financial aid funds) and, possibly, improved critical case management.
In addition to the above-outlined limitations regarding cohort size, meloxicam dosing, and duration of treatment, this study had several additional limitations, which undermined standardization between the 2 treatment groups. Firstly, although all cat owners had been instructed to feed