Introduction
Nonsteroidal anti-inflammatory drugs are frequently prescribed for companion animals with cancer for their palliative and anticancer properties, with the nonselective COX inhibitor piroxicam the most widely studied NSAID in dogs with cancer.1–6 Nonsteroidal anti-inflammatory drugs are efficacious against cancer as a single agent in dogs and potentiate the activity of cytotoxic chemotherapeutics.1–9 For example, the combination of piroxicam and vinblastine results in an overall response rate (complete remission plus partial remission) of 58%, compared with 22% for vinblastine alone, in dogs with urothelial carcinoma.9 Results are similar for combinations of piroxicam and cisplatin, carboplatin, or mitoxantrone in dogs with urothelial carcinoma.2,4,8
Despite the importance of NSAIDs for cancer treatment, their use in dogs is limited primarily by their association with GI AEs. The anti-inflammatory activity of NSAIDs is mediated by inhibition of COX-2, but concurrent inhibition of COX-1 may lead to GI AEs. Cyclooxygenase-1 is responsible for the health of the GI tract by maintaining mucosal blood flow, mucus secretion, and fluid and bicarbonate secretion; mucus, fluid, and bicarbonate protect the GI mucosa from irritation and erosion secondary to exposure to gastric acid.10 Up to 30.8% of dogs with cancer receiving daily piroxicam experience GI AEs.6 Although most NSAID-associated GI AEs in dogs are mild, severe AEs such as GI ulceration and perforation can occur. The use of COX inhibitors is also associated with GI AEs in people. Up to 70% of people receiving NSAIDs long term report GI AEs, with up to 25% developing GI ulcers and up to 4% developing GI perforation.11–15 In 1 study,16 61% of healthy dogs developed GI mucosal lesions within 28 days from the start of NSAID treatment, with 38% of dogs developing > 25 hemorrhages or erosions or ≥ 1 invasive mucosal erosion.
A recent retrospective study17 that includes an investigation of the risk factors for GI AEs in dogs with cancer that were receiving piroxicam reveals concurrent administration of GI drugs (including H2RAs, PPIs, antidiarrheals, and antiemetics) as the only significant treatment-related risk factor for the development of GI AEs. Dogs receiving any of these medications have a 2.6-fold increased risk of GI AEs. The risk of developing clinically significant GI AEs does not differ between dogs that receive these drugs prior to initiating piroxicam administration and dogs that receive these drugs only concurrently with piroxicam.17 Long-term treatment with H2RAs and PPIs in dogs and people is associated with the development of diarrhea, pH-induced microbiome alterations, and rebound acid hypersecretion.18–24
At the PUVTH, dogs that are receiving NSAIDs prior to or after referral commonly also receive gastric acid suppressants, particularly the H2RA famoti-dine and the PPI omeprazole. The addition of gastric acid suppressants is often regarded as a benign treatment that is more likely to be beneficial rather than harmful, but the findings of the aforementioned retrospective study17 challenge this notion and therefore prompted the design of a prospective, randomized, placebo-controlled, double-blinded clinical trial to further investigate these findings. The objective of the study reported here was to assess the impact of prophylactic administration of H2RAs and PPIs on the incidence and severity of GI AEs in dogs with cancer treated with piroxicam. Prophylactic administration of H2RAs and PPIs in dogs with cancer treated with piroxicam was hypothesized to result in increased frequency and severity of GI AEs.
Materials and Methods
Animals
Owners of dogs that had a cytologic or histologic diagnosis of cancer were recruited for participation through the medical oncology service at the PUVTH in a prospective, randomized, placebo-controlled, double-blinded clinical trial comparing the incidence and severity of GI AEs in dogs with cancer treated with piroxicam alone or in combination with omeprazole or famotidine. From the previous study,17 most of the dogs that received piroxicam and had AEs were receiving gastric acid suppressants (42.9% receiving an H2RA alone, 22.4% receiving an H2RA plus other GI medications, 4.1% receiving a PPI plus other GI medications, and 2% receiving a PPI alone). On the basis of that data, the incidence of GI AEs was estimated to be 25% in dogs receiving piroxicam alone and 67% in dogs receiving the combination of piroxicam and a gastric acid suppressant. Sample size was calculated on the basis of having 3 treatment groups, power of 0.8, α of 0.05, and estimated incidence of GI AEs of 25% (piroxicam alone) versus 67% (piroxicam plus gastric acid suppressant). Given these parameters, a sample size of 72 dogs (24/group) was the recruitment target required to detect a significant difference among the groups. Dogs were eligible for inclusion if their owners had elected treatment with single agent piroxicam. Dogs were excluded if their owners reported that their dogs had chronic GI disease, NSAID-induced GI AEs, or current GI signs (eg, vomiting, diarrhea, anorexia, hematochezia, or melena); were currently being administered antiemetics, probiotics, or gastroprotectants, including H2RA, PPI, antacids, and sucralfate; or had serum biochemical evidence of kidney dysfunction (serum creatinine concentration > 1.5 mg/dL, with urine specific gravity < 1.030) or liver dysfunction (hypoalbuminemia, hyperbilirubinemia, hypocholesterolemia, and hypoglycemia). Dogs were required to have a 2-week washout period between study enrollment and radiation treatment and administration of cytotoxic chemotherapeutics, corticosteroids, and other NSAIDs. Dogs that were currently receiving a gastroprotectant were not eligible, even with a washout period. Dogs were randomized at enrollment with a simple random number generator.a Clinicians and owners were blinded to the randomization scheme.
Treatments
All dogs received 0.3 mg of piroxicamb/kg (0.14 mg/lb), PO, every 24 hours. The 3 treatments were 1 mg of famotidinec/kg (0.45 mg/lb), PO, every 12 hours, 1 mg of omeprazoled/kg, PO, every 12 hours, or placebo (lactosee), PO, every 12 hours. Drugs were compounded according to the PUVTH's standard compounding protocols under the supervision of registered PUVTH pharmacists and following all relevant Indiana and federal pharmacy laws and in compliance with the General Chapter <795> Nonsterile Compounding in the US Pharmacopeia. A standard size and number of capsules were prepared for each dose of famotidine, omeprazole, and placebo on the basis of each dog's body weight (Supplementary Appendix S1, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.259.4.385). Commercially available 20-mg omeprazole capsules and 40-mg famotidine tablets were used. Omeprazole capsules were emptied and weighed to distribute the appropriate dose into the appropriate number of capsules. Famotidine tablets were crushed and weighed to distribute the appropriate dose into the appropriate number of capsules. Lactose powder was packed into the appropriate number and size of capsules to match the number and size of each of the study drugs.
Data collection
Prior to enrollment, collected data were dog signalment and tumor type. Baseline CBC, serum biochemical analyses, and urinalysis were performed to confirm a dog's eligibility for the study. Dogs were assessed at 4-week intervals; assessments included serum bio-chemical analyses and determination of urine specific gravity on days 28, 56, and 84 plus CBC and complete urinalysis on day 84. Owners completed surveys at the time of the reevaluation appointment on days 28, 56, and 84; surveys included questions regarding appetite, eating habits, defecation habits, vomiting, and energy level over the previous 4 weeks (Supplementary Appendix S2, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.259.4.385). Owners were also encouraged to contact the PUVTH between reevaluation appointments if they noticed changes (possible AEs) in their dogs that could be attributable to NSAIDs (eg, diarrhea, vomiting, inappetence, me-lena, or hematochezia). Owners who reported any observed change and AEs were interviewed, and AEs were scored according to the Veterinary Comparative Oncology Group's Common Terminology Criteria for Adverse Events (version 1.1; Appendix; Supplementary Appendix S3, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.259.4.385).25 Dogs that experienced a grade 2 or higher AE were removed from the study and treated according to the preference of the attending clinician.
Statistical analysis
Numerical data were assessed for normality with the Shapiro-Wilk test, and summary statistics were expressed as median and range. Nonparametric numerical data obtained from the 3 treatment groups were compared with the Kruskal-Wallis ANOVA by ranks. Proportion distributions between 2 or 3 treatment groups were compared with the Fisher exact test because > 50% of expected frequencies were < 5.
Results
Dogs were enrolled at the PUVTH from July 2018 through August 2019. The last follow-up examination was performed in October 2019. During the study enrollment period, 447 new dogs were evaluated, and 48 owners elected to treat their dogs with piroxicam alone. Thirty-nine dogs were enrolled in the study and randomized to a treatment group. The median age at presentation was 10.0 years (range, 3.1 to 14.5 years), and the median body weight was 19.9 kg (43.8 lb; range, 2.9 to 51.1 kg [6.4 to 112.4 lb]). Two dogs were sexually intact males, 23 were neutered males, and 14 were spayed females. Thirty-eight dogs had 1 tumor that was sampled, with tumors confirmed as urothelial carcinoma (n = 10), soft tissue sarcoma (7), melanoma (3), squamous cell carcinoma (3), pulmonary adenocarcinoma (2), anal sac adeno-carcinoma (2), hemangiosarcoma (2), acanthomatous ameloblastoma (2), heart base mass (2), GI stromal tumor (1), nasal transitional carcinoma (1), thyroid carcinoma (1), prostatic adenocarcinoma (1), and mammary carcinoma (1). One dog had 2 suspected primary tumors (a heart base mass and a pulmonary mass) but they were not sampled.
Because of the frequency of GI AEs observed in dogs of 2 of the treatment groups, recruitment was halted at 39 dogs and an interim data analysis was performed after all enrolled dogs had reached day 56. Given the clinical and statistical differences among the treatment groups identified on interim data analyses, the study was terminated and unblinded after the day 56 mark had been reached by all dogs. Of the 39 dogs, 13 had been randomized to each treatment group. Five dogs were excluded from the analysis. Three had died or were euthanized because of disease progression prior to follow-up examination with no reported GI signs (famotidine, n = 1; placebo, 2), 1 was immediately lost to follow-up after beginning the study (famotidine), and 1 was enrolled but did not start the study because the owner elected to pursue surgery instead (famotidine). After the above exclusions, the famotidine group had 10 dogs, the omeprazole group had 13 dogs, and the placebo group had 11 dogs for analysis (Supplementary Figure S1, available at: avmajournals.avma.org/doi/suppl/10.2460/javma.259.4.385). Differences among groups with respect to sex, age, or body weight were not significant (P ≥ 0.167; Table 1).
Comparison of characteristics of 34 dogs with various tumor types that received piroxicam (0.3 mg/kg [0.14 mg/lb], PO, q 24 h) plus famotidine (1 mg/kg [0.45 mg/lb], PO, q 12 h), omeprazole (1 mg/kg, PO, q 12 h), or placebo (lactose; PO, q 12 h) for 56 days and that were included in a prospective, randomized, placebo-controlled, double-blinded study to evaluate the incidence and severity of GI AEs among the 3 treatment groups. Age (P = 0.711), sex (P = 0.167), and body weight (P = 0.763) were not significantly different among treatment groups.
| Treatment (No. of dogs) | Median age (range [y]) | Sex (No.) | Mean body weight (range [kg])* | Tumor type (No.) |
|---|---|---|---|---|
| Famotidine (10) | 10.2 (3.1–12.1) | Spayed female (2) Neutered male (7) Sexually intact male (1) |
23.2 (6–40.5) | Melanoma (3) Urothelial carcinoma (2) Soft tissue sarcoma (2) Anal sac adenocarcinoma (1) Acanthomatous ameloblastoma (1) Pulmonary adenocarcinoma (1) |
| Omeprazole (13) | 10.6 (6.8–14.3) | Spayed female (5) Neutered male (8) |
15.1 (2.88–35.9) | Urothelial carcinoma (3) Soft tissue sarcoma (3) Squamous cell carcinoma (1) Hemangiosarcoma (1) Acanthomatous ameloblastoma (1) Mammary carcinoma (1) Anal sac adenocarcinoma (1) Nasal transitional carcinoma (1) > 1 tumor (1)† |
| Placebo (11) | 9.8 (4.5–13.1) | Spayed female (7) Neutered male (4) |
19.9 (6.8–5.1.1) | Urothelial carcinoma (4) Squamous cell carcinoma (2) Soft tissue sarcoma (2) GI stromal tumor (1) Thyroid carcinoma (1) Heart base mass (1) |
To convert kilogram to pound, multiply by 2.2.
One dog had a heart base mass and a pulmonary mass that were not sampled.
The most common GI AEs were vomiting (n = 12 dogs), diarrhea (10), anorexia (7), signs of colitis (4), signs of enteritis (2), signs of nausea (2), dysphagia (1), fecal incontinence (1), flatulence (1), and hematochezia (1). Several dogs had > 1 GI AE (Table 2). Of the 34 dogs, 23 (67.6%) had GI AEs by day 56, and 10 (29.4%) dogs had GI AEs that were graded as ≥ 2. The percentage of dogs in each group that had GI AEs by day 56 was significantly (P = 0.037) different. Compared with placebo (4/11 [36.4%; 95% CI, 10.9% to 69.2%]), more dogs in the omeprazole group (11/13 dogs [84.6%; 95% CI, 54.6% to 98.1%]; P = 0.032) and in the famotidine group (8/10 dogs [80%; 95% CI, 44.4% to 97.5%]; P = 0.081) had GI AEs by day 56. The percentages of dogs that had GI AEs that were graded as ≥ 2 were 9.1%, 20.0%, and 53.8% in the placebo, famotidine, and omeprazole groups, respectively. In addition to experiencing more GI AEs overall, significantly (P = 0.034) more dogs that received omeprazole, versus placebo, had AEs that were graded as ≥ 2. Differences in the percentages of dogs that had AEs of ≥ 2 were not significant (P > 0.197) between the famotidine and omeprazole groups and between the famotidine and placebo groups.
Heat map indicating the frequency and severity of GI AEs for the dogs of Table 1.
A shaded box indicates that a dog had a GI AE, with the shade indicating the severity of the GI AE on the basis of the Veterinary Comparative Oncology Group's Common Terminology Criteria for Adverse Events.25
White = no AE. Light gray = grade 1 AE. Medium gray = grade 2 AE. Black = grade 3 AE.
Several dogs at the time of enrollment (day 0) had increased serum liver enzyme activities without overt evidence of liver dysfunction (eg, hypoalbuminemia, hyperbilirubinemia, hypocholesterolemia, and hypoglycemia). For dogs in the famotidine group, 1 dog had increased ALT activity (72 U/L; reference interval, 3 to 69 U/L), 1 had increased ALP activity (549 U/L; reference interval, 20 to 157 U/L), and none had increased GGT activity. For dogs in the omeprazole group, 8 dogs had increased ALT activity (median, 92 U/L; range, 73 to 333 U/L), 6 had increased ALP activity (median, 359 U/L; range, 227 to 845 U/L), and 1 had increased GGT activity (18 U/L; reference interval, 5 to 16 U/L). For dogs in the placebo group, 6 dogs had increased ALT activity (median, 116 U/L; range, 76 to 232 U/L), 4 had increased ALP activity (median, 631.5 U/L; range, 169 to 907 U/L), and 1 had increased GGT activity (23 U/L).
Because of the aforementioned results, the frequency and severity of GI AEs categorized by whether serum ALT, ALP, or GGT activities were increased were determined. Fifteen of 34 dogs (44.1%) had increased ALT activity on day 0, and 19 (55.9%) did not. Of the 15 dogs with increased ALT activity, 10 had GI AEs by day 56, whereas 13 of the 19 dogs with ALT activity within the reference interval had GI AEs by day 56. Eleven of 34 dogs (32.4%) had increased ALP activity on day 0, and 23 (67.6%) did not. Of the 11 dogs with increased ALP activity, 8 dogs had GI AEs by day 56, whereas 15 of 23 with ALP activity within the reference interval had GI AEs by day 56. Two of 33 (6.1%) dogs had increased GGT activity on day 0, and 31 (93.9%) did not; GGT activity was not available for 1 dog because results provided by the primary care veterinarian did not include a result for GGT activity. One of the 2 dogs with increased GGT activity had GI AEs by day 56, whereas 22 (71%) with GGT activity within the reference interval had GI AEs by day 56. Differences in the numbers of dogs that had GI AEs on the basis of whether serum ALT, ALP, and GGT activities were increased were not signifi-cant (P > 0.521).
Discussion
Consistent with the hypothesis, dogs that received piroxicam and omeprazole had significantly more and severer GI AEs than those that received piroxicam and placebo. Similarly, dogs that received piroxicam and famotidine also had more and severer GI AEs compared with those that received piroxicam and placebo, but the differences were not significant, possibly because the study was stopped early. In the present study, dogs that received piroxicam and placebo had a similar frequency of GI AEs (36.4%), compared with the frequency that is reported6 for treatment with piroxicam alone (up to 30.8%), and those AEs were generally mild. The findings of the present study were also consistent with those of a retrospective study17 in which concurrent administration of gastroprotectants with piroxicam to dogs with cancer is associated with a 2.6-fold increased risk of GI AEs. The previous study17 also indicates age as a significant risk factor for the development of GI AEs, whereas the present study did not indicate this association. Neither study identified body weight as a significant risk factor in the development of GI AEs.
The mechanism of how piroxicam plus famoti-dine or omeprazole caused GI AEs in the dogs of the present study is unknown. Previous research26–30 of dogs that are administered omeprazole and famoti-dine identifies AEs, including pH-induced changes in the GI microbiota, hypergastrinemia, vomiting, and diarrhea. Similar effects are documented in people.19–21,23 In the present study, GI AEs occurred more frequently (67.6% of dogs) than was expected on the basis of previous research29,31 on famotidine and omeprazole alone (frequency, 8.7% to 38% of dogs). One possible explanation for the increased frequency of GI AEs in the present study was that the use of H2RAs or PPIs may have resulted in changes in the GI microbiome, thus favoring bacterial populations that may have then caused these dogs that were receiving piroxicam to be more prone to GI AEs. Alternatively, coadministration of piroxicam and famotidine or omeprazole may have altered piroxicam pharmacokinetics, resulting in prolonged or possibly higher serum or tissue piroxicam concentrations and therefore more GI AEs. Endoscopic evaluation of GI lesions is noted in a previous report31 to determine the clinical importance of reported GI AEs. However, the present study solely relied on owners' reports of GI AEs, and because of the study design, owners were biased to identify even low-level GI AEs. Furthermore, the previous report31 involves shorter courses (mean, 4 to 5 days) of gastric acid suppressant administration, whereas the present study included up to 56 days of administration; therefore, the results of those studies may not indicate the effects of long-term gastric acid suppressant administration. A study that reveals the impact of coadministration of H2RAs or PPIs on piroxicam pharmacokinetics in dogs was not available at the time of the present study; however, a study32 in people reveals that coadministration of piroxicam and omeprazole or famotidine results in no changes to piroxicam pharmacokinetics.
One limitation of the present study included the small sample size, which may have contributed to type II error for the famotidine group. Yet, given the trend toward significantly more dogs treated with famotidine and piroxicam having GI AEs (vs placebo) and the significant difference observed in the frequency of GI AEs in dogs treated with omeprazole and piroxicam (vs placebo), continuing the study was considered unethical and study enrollment stopped. Another limitation was that liver function was not directly assessed. Famotidine and omeprazole are metabolized by the liver; thus, liver dysfunction may result in prolonged or possibly higher serum or tissue concentrations of these drugs.21,22 Because liver function was not directly assessed, whether liver dysfunction may have influenced the study results could not be determined. Despite randomization, more dogs with increased serum ALT, ALP, and GGT activities on day 0 had been enrolled in the omeprazole and placebo groups, versus in the famotidine group. However, no associations between increased liver enzyme activities on day 0 and the frequency or severity of GI AEs were observed.
Nonsteroidal anti-inflammatory drugs are frequently and effectively used in the treatment of cancer and many other conditions in dogs, but well-known AEs may accompany their use. The US FDA recently released recommendations on the information that veterinarians should provide their clients with pets that are prescribed NSAIDs, underscoring the frequency with which NSAIDs are used in pets.33 Many well-intentioned veterinarians prescribe prophylactic H2RAs and PPIs in the hope of minimizing the risk of GI AEs, including GI ulcers, as a result of NSAID administration, but this practice is not evidence based.22 The results of this prospective, randomized, placebo-controlled, double-blinded clinical study indicated that omeprazole and famotidine may increase the likelihood of dogs to have GI AEs when coadministered with piroxicam. On the basis of the results of the present (evidence-based) study, veterinarians should not prescribe H2RAs or PPIs in an attempt to minimize the risk of GI AEs for dogs that are being administered piroxicam. However, use of gastric acid suppressants in addition to piroxicam could be considered in dogs that have cancer with known risk factors for GI bleeding or have confirmed GI ulcerations and erosions.22 Yet, because of the risk of GI AEs, including GI ulcerations and erosions, in dogs receiving piroxicam, alternative treatments should likely be considered if risk factors for GI bleeding are present or GI ulcerations and erosions have been confirmed.
Follow-up studies are needed to investigate whether the findings of the present study are applicable to dogs receiving NSAIDs other than piroxicam or NSAIDs for indications other than cancer. Further study is also indicated to elucidate the underlying mechanism of action for the development of GI AEs in dogs that receive piroxicam and omeprazole or famotidine and to determine whether the development of GI AEs is restricted to nonselective COX inhibitors like piroxicam or whether the development of GI AEs is also possible when H2RAs or PPIs are coadministered with COX-1–sparing NSAIDs. Further study may also include direct visualization of the GI mucosa in dogs receiving these combinations of drugs to determine their gross impact (mucosal lesions) or their correlation with reported GI AEs.
Acknowledgments
Funded by the Veterinary Cancer Society's Resident Research Award. The funding source did not have any involvement in the study design, data analysis and interpretation, and writing of the manuscript.
The authors declare that there were no conflicts of interest.
Footnotes
Microsoft Corp, Redmond, Wash.
PCCA, Houston, Tex.
Teva, Parsippany, NJ.
Sandoz Inc, Princeton, NJ.
Fagron Inc, Saint Paul, Minn.
Abbreviations
| AE | Adverse event |
| ALP | Alkaline phosphatase |
| ALT | Alanine aminotransferase |
| COX | Cyclooxygenase |
| GGT | γ-Glutamyl transferase |
| GI | Gastrointestinal H2RA H2-receptor antagonist |
| PPI | Proton-pump inhibitor |
| PUVTH | Purdue University Veterinary Teaching Hospital |
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Appendix
General grading scheme for chemotherapeutic-associated AEs adapted from the Veterinary Comparative Oncology Group's Common Terminology Criteria for Adverse Events (version 1.1)25 for use in the present study that included an assessment of the impact of the prophylactic administration of omeprazole and famotidine on the incidence and severity of GI AEs in dogs with cancer treated with single agent piroxicam.
| Grade | Severity | Treatment |
|---|---|---|
| 1 | Asymptomatic or mild symptoms | Intervention not indicated |
| 2 | Moderate symptoms | Outpatient or noninvasive (eg, oral) interventions indicated |
| 3 | Severe or medically significant but not immediately life-threatening | Parenteral treatment and hospitalization often indicated |
| 4 | Life-threatening | Immediate hospitalization and urgent intervention required |
| 5 | Death because of AE | NA |
Increasing grade indicates increasingly severe AE.
NA = Not applicable.
