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Corresponding author: Michael S. Leib, DVM, MS, Diplomate ACVIM, Department of Small Animal Clinical Sciences, C.R. Roberts Professor Small Animal Medicine, Virginia-Maryland Regional College of Veterinary Medicine, Virginia Tech, Blacksburg, VA 24061; e-mail: firstname.lastname@example.org or email@example.com.
Background: The coadministration of prednisone and ultralow-dose aspirin has been recommended for the management of various diseases, but the safety of this combination in dogs has not been studied.
Hypotheses: The gastroduodenal lesions associated with prednisone and ultralow-dose aspirin administration will be similar to those caused by prednisone alone, but both treatments will result in more severe lesions than placebo.
Methods: Randomized, blinded, placebo-controlled study of 3 treatment groups for 27 days: placebo, prednisone, and prednisone and aspirin. Gastroduodenoscopy was performed before and on days 5, 14, and 27 of treatment and mucosal lesions scores were assigned. Mucosal lesion scores were compared by a Kruskal-Wallis test. Clinical signs were compared by the Friedman's chi-square test (significance at P < .05).
Results: There were no significant differences in the gastroduodenal lesion scores among groups, or within groups at any time during the study. Significantly more dog-days of diarrhea occurred in the prednisone and aspirin group during treatment, compared with baseline. No significant differences in clinical signs were found among any of the groups.
Conclusion: The concurrent use of prednisone and ultralow-dose aspirin did not increase the severity of gastroduodenal lesions compared with prednisone or placebo. Coadministration of prednisone and ultralow-dose aspirin increases the frequency of mild, self-limiting diarrhea in some dogs.
Several immunosuppressive drugs have been used for treatment of autoimmune and immune-mediated disorders. Treatment with immunosuppressive dosages of corticosteroids is the mainstay of treatment for many of these disorders, including immune-mediated hemolytic anemia (IMHA). In addition to the morbidity and mortality resulting from severe acute anemia, thromboembolic events also occur in 30–100% of these dogs.1–7 Thromboembolic sequelae contribute substantially to the morbidity and mortality of IMHA patients. Ultralow-dose aspirin has been recommended to decrease the frequency of thromboembolic events.7,8
Aspirin modulates thrombotic events by irreversibly acetylating platelet cyclooxygenase (COX) leading to decreased thromboxane A2 synthesis, thereby impairing platelet function in a dose-dependent manner.1,9 As a nonselective COX inhibitor, aspirin also causes gastrointestinal ulceration in dogs at dosages of 10–35 mg/kg q8–12h.10–15 Ultralow-dose aspirin, 0.5 mg/kg/d, may decrease platelet aggregation while minimizing detrimental effects of COX-1 suppression on gastrointestinal mucosal health.7,8,16,17 In 1 retrospective study evaluating prognostic factors, survival rates, and treatment protocols for 151 dogs with IMHA, dogs treated with ultralow-dose aspirin in conjuction with a variety of protocols were shown to have a survival advantage over those that did not receive ultralow-dose aspirin.7 Clinical evidence of adverse effects of ultralow-dose aspirin when administered in conjunction with immunosuppressive doses of glucocorticoids has not been recognized in dogs,7 but the use of ultralow-dose aspirin as antithrombotic therapy in IMHA patients is a relatively new therapeutic application.
When evaluating a treatment protocol involving concurrent use of prednisone and ultralow-dose aspirin in dogs with IMHA it is difficult to distinguish the effects of medications (prednisone and ultralow-dose aspirin) on gastroduodenal integrity from the effects of sequelae of IMHA (eg, disseminated intravascular coagulation or gastroduodenal ischemia secondary to hypoxia or thrombosis). By evaluating these differences in healthy dogs, the confounding effects IMHA and its sequelae may have on the gastroduodenal mucosa are eliminated. Gastroduodenal lesions (eg, hemorrhages, erosions, ulcers) may develop as a result of concurrent administration of prednisone and a nonselective nonsteroidal antiinflammatory drug (NSAID), but these lesions may go unnoticed if the dogs do not develop overt clinical signs of gastroduodenal hemorrhage.14,18 Our study's hypothesis is that there will be no statistically significant differences in the gastroduodenal mucosal scores between dogs treated with prednisone alone and those treated with prednisone and ultralow-dose aspirin, but both treatment groups will have higher gastroduodenal scores than dogs treated with placebo.
Material and Methods
Eighteen purpose-bred, mixed breed dogs (9 males, 9 females) with a mean age of 14 months (range, 12–24 months) and a mean body weight of 15.6 kg (range, 12.2–17.9 kg) were acclimated to research housing conditions for 2 weeks. The dogs were entered into the study based on normal physical examination, CBC, serum biochemical profile, and urinalysis. Ivermectina (200 μg/kg SC once) and fenbendazoleb (50 mg/kg PO q24h for 3 consecutive days, repeated in 2 weeks) were administered to all dogs during the acclimation period, except those with a herding phenotype, which received fenbendazole only.19 All dogs had a negative zinc sulfate fecal flotation before the first gastroduodenoscopy. This study was approved by the Institutional Animal Care and Use Committee of Virginia Polytechnic Institute and State University, and all animals were cared for in accordance with the principles outlined in the NIH Guide for Care and Use of Laboratory Animals.
The study was subdivided into 2 periods: Period 1 consisted of 10 days (day 10 through day 1) before the initiation of oral medications. Period 2 consisted of 27 days (days 1–27) during which all dogs received oral medications or placebos depending on their treatment groups. Dogs were observed every 8 hours during periods 1 and 2 by an observer who was blinded to the treatment groups and to the medications being administered. The number of bowel movements was recorded and the presence of melena, hematochezia, or mucus was noted. Feces were graded from 1 to 5 using a previously described scale,15 with scores <4 considered to be diarrheic. Vomiting episodes and the presence of hematemesis also were recorded. A dog-day of diarrhea or vomiting represented any day in which 1 or more episodes of diarrhea or vomiting was observed in a dog. Dogs were fed a commercial maintenance cereal-based dog foodc twice daily according to the manufacturer's recommendations. Each dog's appetite was scored from 1 to 3 each day. One was assigned when all food was consumed, 2 for decreased appetite, and 3 for anorexia.
Dogs were anesthetized for gastroduodenoscopy, lesion scoring, and photography, 7 days before drug administration, and 5, 14, and 27 days after initiation of drug administration. Atropine sulfate (0.05 mg/kg IM) and acepromazine (0.1 mg/kg IM) were used as premedications, an IV catheter was placed, and anesthesia was induced with thiopental (10–15 mg/kg IV to effect). After endotracheal intubation, general anesthesia was maintained with isoflurane in oxygen (100 mL/kg/min), and 0.9% NaCl solution was delivered at 10 mL/kg/h IV. Dogs were placed in left lateral recumbency and gastroduodenoscopy was performed in a manner that would not create iatrogenic lesions before endoscopic scoring.12,14,15,20
Upon entry into the stomach, the endoscope was advanced into the gastric body, and the gastric body was insufflated to distend rugal folds and allow lesion scoring of the gastric body. The gastric body was evaluated as the endoscope was advanced along the greater curvature to the level of the pyloric antrum. After the antrum and pylorus were visualized, the endoscope tip was partially retroflexed to further evaluate the angularis incisura and the lesser curvature. The endoscope then was fully retroflexed to assess the gastric cardia. The tip of the endoscope was straightened and advanced through the antrum and pyloric sphincter and into the proximal descending duodenum, which also was scored. The endoscope then was retracted into the body of the stomach where brush cytology samples were obtained to identify the presence or absence of spiral bacteria (on day 7 only).
During visual evaluation, each region of the stomach (gastric body, pyloric antrum, angularis incisura, and cardia) and the duodenum was photographed with a still video recorder,d and gastric lesions were scored at that time by an experienced observer who was blinded to the treatment groups (MSL). Scores were assigned from 1 to 11 for each region, based on a previously described scale (Table 1).12,14,15,20 Mucosal hemorrhages were small, reddened lesions with intact mucosa. An erosion was defined as a defect in the mucosal epithelium. An ulcer had a wide mucosal defect with depth in the center and raised margins. Each region was scored based on the most severe lesions present. Scores for all regions were summed, and a total score was given to each dog for each endoscopic examination.
Gastric mucosal brushing samples obtained at baseline (on day 7) were applied to glass slides, stained with Dip Quick stain,e and viewed under 100 × objective for presence of spiral bacteria consistent with Helicobacter spp.21 Because spiral bacteria were observed in all 18 dogs, stratification of groups based on Helicobacter spp. status was not deemed necessary.
On day 0, 18 dogs were randomly divided into 3 groups of 6. Each dog in the placebo group (Group NN) was administered 2 placebo capsules (containing sucrose powder) and a placebo solution (0.05 mL/kg PO q24h of an almond oil and sucrose powder mixture, identical in appearance to the aspirin-containing solution administered to the prednisone and ultralow-dose aspirin group [Group PA]). The prednisone group (Group PN) was administered an immunosuppressive dosage, mean 2.3 mg/kg (range, 2.0–2.4) of prednisone (two 17.5 mg compounded capsules PO q24h) and 0.05 mL/kg of the same placebo solution as used for Group NN. Group PA was administered prednisone (two 17.5 mg compounded capsules, mean 2.3 mg/kg [range, 2.2–2.5] PO q24h) and aspirin (0.5 mg/kg [0.05 mL/kg] of aspirin in the form of an almond oil-based aspirin solution [10 mg/mL] PO q24h). Medications were given for 27 days. Dogs were weighed weekly and the aspirin dosage was adjusted as needed.
Both mucosal lesion scores and clinical signs were summarized by medians and range. For each combination of the clinical sign (eg, vomiting, diarrhea, inappetence) and periods, median scores were compared among the 3 treatment groups by the Kruskal-Wallis test. Furthermore, for each combination of clinical sign and treatment group, median scores were compared between period 1 and period 2 by the Friedman's chi-square test while controlling for dog as a blocking factor. Because the length of period 1 was 10 days, and the length of period 2 was 27 days, all scores in period 1 were multiplied by 2.7 before making this comparison.
For each combination of region or total mucosal lesion score and day of endoscopy (−7, 5, 14, or 27), median scores were compared among the 3 treatment groups by the Kruskal-Wallis test. Furthermore, for each combination of region and treatment, median scores were compared among days of endoscopy by the Friedman's chi-square test while controlling for dog as a blocking factor. Statistical significance was P < .05. All analyses were performed by SAS version 9.1.3.f
There were no significant differences in regional or total mucosal lesion scores among groups at any time (Fig 1). Additionally, no significant changes in regional or total mucosal lesion scores were seen over time within any of the groups (Fig 1). Median total mucosal lesion scores on day −7 were 5 for all 3 treatment groups (P= 1.0000). Median total mucosal lesion scores on day 5 were 5, 6, and 5 for groups NN, PN, and PA, respectively (P= .1629). Median total mucosal lesion scores on day 14 were 5, 5.5, and 5 for groups NN, PN, and PA, respectively (P= .8857). On day 27, median total mucosal lesion scores were 5 for all groups (P= .3007).
The median score for each region in each treatment group at each time point was 1. Median regional scores did not differ among groups at any time point, nor were there any significant changes in median regional scores within any of the groups over time.
Foreign material was identified in 2 dogs during endoscopic evaluations: fragments of plastic bedding in 1 dog on days 7 and 5 (this material was not removed on day 7 but was later extracted with endoscopic forceps on day 5) and the spring from a ballpoint pen in the other dog on day 27. Mucosal lesions found in association with the presence of foreign material included multiple hemorrhages and erosions in 1 dog (these lesions were not present on day 7 but had formed by day 5) and a single linear erosion in the other dog. The lesions did not produce any adverse clinical signs and had no effect on median group scores (regional or total).
There were no differences among any of the groups regarding the number of dog-days of vomiting throughout the study period (P= .3679), and all vomiting events were self-limiting. Additionally, there were no differences between the number of dog-days of vomiting within each group when comparing period 1 and period 2 (group NN, P= .3173; group PN, P= .1573; group PA, P= 1.000).
There were no significant differences in dog-days of diarrhea among any of the groups at any point during the treatment period (period 2), P= .1917. There was a significant increase in the number of dog-days of diarrhea in the prednisone and aspirin group between period 1 (median, 0; range, 0–5) and period 2 (median, 2.5; range 0–18; P= .0253). There was a 1 week delay during period 2 before the increase in dog-days of diarrhea occurred in the prednisone and aspirin group, with only 1 dog-day of diarrhea during the 1st week of period 2, 13 dog-days during the 2nd week, 12 dog-days during the 3rd, and 13 dog-days during the 4th week. During period 1, 1 dog from group PA accounted for 5 of the 6 dog-days of diarrhea. A 2nd zinc sulfate flotation, a fecal direct saline smear, and Clostridium perfringens fecal enterotoxin assay22 were performed, but an etiology was not identified. This same dog had 15 of the 39 days of diarrhea observed in group PA during the treatment period, and a 2nd dog accounted for 18 of 39 days of diarrhea for this group. Both dogs had normal gastroduodenal mucosal scores during each endoscopic evaluation. Both dogs had a median grade of 3 for the days with diarrhea and tenesmus, mucus, hematochezia, or melena were not noted. The remaining 6 dog-days of diarrhea for group PA during period 2 were divided among 3 of the remaining 4 dogs (3 dog-days for 1st, 2 days for the 2nd, and 1 day for the 3rd dog). At no point during the study period did any dog show signs of dehydration, lethargy, or inappetence.
Body weight fluctuations were minimal throughout the study, leading to relatively minor adjustments in aspirin dosage.
Neither gastroduodenal lesion scores nor clinical signs differed significantly among the prednisone and aspirin group, the prednisone group, and the placebo group at any time during the study. Based on these results, prednisone at a dosage of 2.2 mg/kg/d with or without ultralow-dose aspirin (0.5 mg/kg/d) may be safely used for at least 27 days in healthy adult dogs. Despite these findings, individual dogs from each group did develop gastric or duodenal mucosal lesions or both of varying severity. No predilection site for lesions was detected, which is consistent with previous reports of NSAID- and corticosteroid-induced gastrointestinal injury,10,12,20,23,24 but conflicts with the findings of others in which the pyloric antrum was most affected.18,25–28 Some dogs in both the prednisone and prednisone and aspirin groups developed more severe gastroduodenal lesions than any dog in the placebo group. Some dogs may have subclinical gastrointestinal mucosal defects that predisposed them to gastrointestinal lesions while receiving treatment. Alternately, variations in pharmacokinetics (including drug absorption, metabolism, or tissue distribution) may exist among individual dogs, influencing the gastrointestinal effects of these medications. Also, the lesions seen may have no clinical relevance in healthy dogs but could have clinical relevance in sick, geriatric, or debilitated dogs.12,14,20
The combined or individual effects of prednisone and ultralow-dose aspirin on mucosal healing may explain the findings in the dog that had plastic bedding in his stomach on day 7 and had no mucosal lesions at that time but developed lesions by day 5. The foreign material was not removed at the time of identification (day 7) due to the authors' belief that the material would pass independently, and these lesions may have developed due to chronic injury over time as the material persisted, particularly if normal mucosal healing became compromised by prednisone and aspirin administration.29,30 The lesions simply may have developed as a result of the aspirin and prednisone therapy, or they may have resolved as a result of gastric adaptation31 by day 14 regardless of whether or not the foreign material had been extracted.31 Statistical evaluation of mucosal lesion scores was performed with these scores included, and the lesions caused by this foreign material had no significant impact on the median group scores (neither total nor regional).
There were no difference in the incidence of vomiting, diarrhea, or inappetence among treatment groups at any time during the study, but there were significantly more dog-days of diarrhea in the prednisone and aspirin group during period 2 when compared with period 1. The diarrhea was small bowel in origin and was mild, had a median fecal grade of 3, and diarrheal events were infrequent. Most of the diarrhea days were the result of 2 dogs. The diarrhea resolved in all dogs within 5 days of discontinuing aspirin therapy and decreasing the prednisone dose. This rapid response supports a causal role of the prednisone and aspirin combination in the pathogenesis of the diarrhea noted in this group. This study suggests that although diarrhea may develop in dogs receiving this combination of medications, the diarrhea is likely to be mild, infrequent, associated with limited morbidity, and should resolve rapidly when therapy is discontinued. However, caution should be exercised when applying these findings to older ill dogs, because gastrointestinal complications could be exacerbated by age or concurrent illness.
There have been no published studies evaluating the effects of chronic administration of immunosuppressive dosages of prednisone on canine gastroduodenal mucosa, but several studies have demonstrated adverse gastrointestinal sequelae after short term administration of high doses of methylprednisolone and dexamethasone alone or in combination with NSAIDs.9,24,25,27,32–34 Corticosteroids are believed to cause gastrointestinal ulceration by inhibition of prostaglandin synthesis by phospholipase A blockade.35–37 Corticosteroids also have been shown to inhibit healing of existing ulcers by altering the composition of gastric mucus, decreasing the rate of mucosal cell turnover, inhibiting capillary and fibroblast proliferation, and enhancing collagen breakdown in the late stages of inflammation.29,30,35,36,38,39 Aspirin has adverse effects on the gastric mucosa by a combination of direct cytotoxicity and COX-1 inhibition, resulting in decreased prostaglandin synthesis, compromising the mucosal barrier and leading to ulceration and delayed mucosal healing.10–15,20,40 There are no published studies evaluating the gastroduodenal effects of ultralow-dose aspirin in dogs, and it is unclear whether or not these effects also occur at a dosage of 0.5 mg/kg/d. Based on the results of this study, it seems unlikely that ultralow-dose aspirin would have any adverse gastrointestinal effects independently. However, it is well-established that humans receiving low-dose aspirin (75–81 mg/d) are at increased risk of gastrointestinal ulceration, particularly when there is concurrent use of corticosteroids or NSAIDs in addition to aspirin or in the presence of comorbid conditions.41,42 The same risk may be present in dogs treated with long term ultralow-dose aspirin.
Although there were no detectable differences in gastroduodenal mucosal lesions among study groups, mucosal damage involving regions of the gastrointestinal tract distal to the proximal duodenum may have occurred. Such an occurrence could explain the significant increase in dog-days of diarrhea noted in group PA during period 2 in the absence of abnormal gastroduodenal mucosa. Lesions have been identified in the large and small intestines of both dogs and humans treated with NSAIDs or corticosteroids.40,43–46 Although gross endoscopic appearance has been well correlated with the presence of histologic disease in dogs and cats with clinical gastrointestinal disease,47 histologic changes associated with aspirin-induced gastrointestinal disease in dogs have not correlated to gross mucosal appearance.31 The possibility exists that treatment groups may have developed significantly different histologic changes that were not detected grossly. Furthermore, dogs in this study may have acquired increased mucosal permeability or decreased mucosal absorptive capacity in the absence of grossly evident mucosal lesions. Noninvasive evaluation of gastrointestinal permeability and mucosal absorptive capacity employing the oral administration of sugar probes was not performed in this study.48–52 Finally, dogs in the present study may have had gastrointestinal hemorrhage that was not evident upon gross inspection of feces, because 100–200 mL of blood is required to produce gross evidence of melena.53 Although, fecal occult blood testing is a more sensitive method for detecting gastrointestinal hemorrhage, requiring 20–50 times less blood than what is necessary to produce melena, the standard guaiac fecal occult blood test yields an excessive number of false positives as a result of dietary protein intake.53,54 Fecal occult blood testing was not performed in this study.
A treatment protocol utilizing ultralow-dose aspirin with immunosuppressive dosages of prednisone currently is being recommended in the management of IMHA,7,8 and concurrent use of these drugs also may be indicated in less common disease processes, such as systemic lupus erythematosus and certain protein-losing nephropathies (eg membranous glomerulonephritis, minimal change disease).16,55–57 In these disorders, an immunosuppressive dosage of corticosteroids is necessary for treatment of the underlying condition, and ultralow-dose aspirin may be used to reduce the risk of thromboembolic events. Clinical studies evaluating such dogs for adverse events associated with this combination therapy are needed.
aIvomec, 1% injection, Merial, Duluth, GA
bPanacur, Intervet/Schering-Plough Animal Health, Millsboro, DE
cScience Diet Adult Original, Hills Pet Nutrition Inc, Topeka, KS
dSony Promavica Still Video Recorder, Model MVR5300, Sony Co, Japan
eDip Quick Stain Solution, Jorgenson Laboratories, Loveland, CO
fSAS system, Version 9.12, SAS Institute Inc, Cary, NC
Supported with funding provided by a Virginia Veterinary Medical Association Memorial Grant.