Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake,clinically normal cats

Abstract

Objectives

The aim of this study was to compare the effects of multiple once- or twice-daily oral dosage rates of the angiotensin II, type-1 receptor blocker, telmisartan (TEL), or placebo (PLA) on indirect systolic arterial blood pressure (SBP) in awake, clinically normal cats.

Methods

Utilizing an incomplete crossover design and following a 14 day acclimation period, 28 healthy laboratory cats were randomized to undergo treatment with three of the following 14 day treatment protocols, each separated by a 1 week washout period: oral PLA q24h, oral TEL at a dosage of 1, 1.5, 2 or 3 mg/kg q24h, or oral TEL at a dosage of 1 or 1.5 mg/kg q12h. Using the Doppler ultrasound method, indirect SBP was measured daily during each treatment period, and daily during the first 5 days of each washout period, approximately 3 h after administration of the morning treatment.

Results

Each treatment protocol was administered to a total of 12 cats. A statistically significant effect of treatment period was identified for the entire study; therefore, only data from the first treatment period (four cats per treatment group) were used for further analysis. Compared with PLA, during the first treatment period, SBP values were significantly lower in cats treated with TEL at all tested dosages by the second week of treatment. SBP remained significantly lower than in PLA-treated animals for 2 days following administration of the last dose in all TEL treatment groups. No clinical signs of hypotension were noted in any group.

Conclusions and relevance

These results suggest that treatment with TEL at a total daily dose of 1–3 mg/kg – administered as a single dose, or split into two equal doses administered 12 h apart – results in a significant, relatively long-lasting reduction of SBP in clinically normal cats. TEL appears to be well tolerated by normal cats at the dosages tested.

Introduction

Systemic arterial hypertension (HT) is a well-recognized cause of morbidity in aged feline patients, which most frequently develop the disorder in association with other diseases such as chronic kidney disease (CKD) and hyperthyroidism.^1–3 The harmful effects of chronic, persistent HT have been described, and include injury to the kidneys and eyes, and to the cardiovascular and central nervous systems.^4–6 In cats with CKD, HT may accelerate the decline of renal function, worsen glomerulosclerosis and exacerbate proteinuria, the latter a negative prognostic indicator in spontaneous feline CKD.^7–9

The pathogenesis of HT is believed to be multifactorial, and likely varies with the underlying disorder. In people, HT of renal origin is attributed to impaired renal sodium handling, excessive activation of the renin–angiotensin–aldosterone system (RAAS), sympathetic nervous system hyperactivity and endothelial dysfunction, among other factors.¹⁰ The results of multiple clinical trials have demonstrated the renoprotective effects and reduction in cardiovascular risk that attend pharmacologic blockade of the RAAS in people with CKD.^11–13

Antihypertensive drugs that act via RAAS inhibition include angiotensin-converting enzyme inhibitors (ACEi), angiotensin II receptor blockers (ARBs) and renin inhibitors. Of these, ACEi (eg, benazepril) have been evaluated with the greatest depth in cats. However, a prospective, blinded, placebo-controlled, randomized clinical trial of benazepril – the only such study performed to date – was unable to demonstrate a survival benefit in cats with naturally occurring CKD.¹⁴ Further, studies of spontaneous HT in clinical patients describe disappointing antihypertensive efficacy of ACEi in this species.^3,15

An ARB (eg, telmisartan [TEL]) directly and selectively antagonizes the angiotensin II subtype 1 (AT₁) receptor, the latter mediating the adverse effects of angiotensin II on the cardiovascular system and kidneys. In a preclinical study of healthy cats, TEL more effectively attenuated the rise in systolic blood pressure in response to exogenous angiotensin I than did benazepril, suggesting that the former may have advantages in the treatment of cardiovascular and renal diseases in this species.¹⁶ However, limited information exists regarding the use of ARBs in feline patients. The results of a prospective, multicenter, blinded clinical trial evaluating the antiproteinuric effects of TEL in cats with spontaneous CKD found that the drug was non-inferior to benazepril and, unlike benazepril, significantly decreased proteinuria relative to baseline at all assessment points; however, this study was not designed to assess antihypertensive efficacy.¹⁷

The major objective of the present study was to compare the short-term effects of various once- or twice-daily oral dosage rates of oral TEL or placebo (PLA) on indirectly measured systolic arterial blood pressure (SBP) in awake, clinically normal laboratory cats, in anticipation of applying this information to future studies involving cats with naturally occurring HT. We also sought to identify TEL dosage rates that would be associated with measurable reductions in SBP within 1–2 weeks of treatment initiation. We hypothesized that approximately 3 h following an oral dose of TEL, cats would experience a dose-dependent reduction in SBP, and that this reduction would be significantly greater than that noted in cats treated with PLA.

Materials and methods

Cats

Thirty-four adult domestic cats, members of a research colony, were screened for inclusion in the present study. To be eligible, cats had to tolerate daily administration of oral medications and indirect measurement of SBP, and be considered clinically normal based upon the findings of physical examination, complete blood count and serum biochemistry analysis. Cats were excluded if deemed hypotensive (defined by average indirect SBP <80 mmHg, measured as outlined below) or if they had been treated with non-steroidal anti-inflammatory drugs, or any medication expected to affect blood pressure (BP), within the 14 days preceding screening. Of the 35 cats screened, 28 (15 neutered male, six intact females, seven neutered female) met the criteria for participation in the study and were selected for inclusion based on favorable behavior characteristics.

Cats were housed individually, had access to water at all times and were fed a commercially available dry cat food (Science Diet Adult – Optimal Care; Hill’s Pet Nutrition) to which they were accustomed prior to the acclimation phase of the study. Food was administered once daily, following SBP measurement, and any uneaten portion was removed after approximately 4 h. Cats were exposed to a cycle of 12 h of light and 12 h of darkness each day.

Acclimation phase

For 14 days prior to the start of the study (days −14 to −1), cats were acclimated to study procedures by undergoing daily SBP measurement, as described below. Prior to this, cats were handled regularly in an effort to acclimate them to gentle restraint. On days −7 to −3, PLA was administered once daily in the morning, and SBP measured 3 ± 1 h later. For the purposes of statistical analyses, baseline, pretreatment SBP for each cat (SBP_baseline) was defined as the average of these five consecutive daily mean SBP determinations.

Study design

After completion of the acclimation period, cats were block randomized according to SBP_baseline to one of seven treatment groups (n = 4 cats/group): once-daily PLA; oral TEL (Semintra oral solution for cats [telmisartan 4 mg/ml]; Boehringer Ingelheim) at a dosage of 1, 1.5, 2 or 3 mg/kg q24h; or oral TEL at a dosage of 1 or 1.5 mg/kg q12h. For 14 consecutive days, each treatment was administered once in the morning for once-daily dosing protocols, and once in the morning and once in the evening, approximately 12 ± 1 h apart, for twice-daily dosing protocols. Doses as total volume administered were based upon each individual cat’s body mass, as determined to the nearest half pound, on the first day of the treatment period using a calibrated scale. During the 14 day treatment period, SBP was measured and recorded once daily, as described below, 3 ± 1 h following the morning treatment.

A 1 week washout period was allowed after completion of the treatment period. During the first 5 days of this period, PLA was administered once daily in the morning and SBP was recorded once daily, as described below, 3 ± 1 h following PLA administration. No treatment or manipulation was performed on days 6 and 7 (weekends) of the washout period.

Following the washout period, each cat was assigned to a different treatment group according to an incomplete square crossover design, and the procedures described above were repeated. Over the course of the study, all cats underwent three 14 day treatment periods, each separated by a 7 day washout period. Therefore, each treatment protocol was administered to a total of 12 cats.

During all periods, trained personnel observed each cat at least once daily for signs suggestive of adverse treatment effects, and recorded any abnormalities.

Indirect BP determination

At all time points, indirect BP was determined using a single Doppler ultrasonic device (Model 811-B; Parks Medical Electronics) in a manner in keeping with the guidelines set forth by the American College of Veterinary Internal Medicine.¹⁸ This device was chosen to reflect the standard of care for companion animal practice based on the information available at the time of study completion. One of three trained individuals obtained BP measurements at each time point.

Cats were taken to a quiet room and allowed a minimum of 10 mins to acclimate to the surroundings prior to BP measurement. Traffic into, or within, this room was not allowed during the acclimation or measurement periods. Cats were gently restrained in sternal recumbency. An inflatable BP measurement cuff (SoftCheck Cuff; Parks Medical Electronics), the width of which was approximately 40% of the circumference of the cuff site, was applied to the antebrachium, distal to the elbow. The cuff was connected to a sphygmomanometer (1517-100 ri-san; Riester) and positioned at the level of the heart. Hair was clipped from the skin of the palmar aspect of the foot distal to the carpal pad, over the area of the common digital artery.

Following appropriate positioning of the Doppler ultrasound probe with coupling gel, the cuff was inflated to a pressure that was approximately 20–30 mmHg greater than that at which the Doppler signal became inaudible. The cuff was slowly deflated, and SBP was taken to be the pressure at which the Doppler signal was first detected again. This procedure was repeated five times, and consecutive measurements were recorded. For the purposes of statistical analysis, SBP for each measurement session was determined by discarding the highest and lowest BP values and taking the arithmetic mean of the remaining three measurements.

Statistical analysis

Analyses were performed with the assistance of two commercial software packages (SAS version 9.2 and Prism version 6). The SBP data collected during the first three treatment periods were analyzed using the MIXED procedure. The mixed model included fixed effects of sequence, period, treatment, time, treatment by time, sequence by time and period by time. Random effects included block, animal within sequence and block, and residual. The appropriate covariance structure was determined by fitting at least the compound symmetry, unstructured and autoregressive structures. The structure with the smallest Akaike information criterion was used for the final model. Using this model, period effect was found to be significant; therefore, further analysis was conducted utilizing data from the first treatment period alone.

For the first treatment period, in individual cats, mean SBP was calculated for the entire 14 day treatment period (SBP_week1+2) and for the first or second treatment week only (SBP_week1 and SBP_week2, respectively). The model for the first treatment period included the fixed effects of treatment, time, and treatment by time interaction. The random effects included block, animal within block and residual. Comparisons between treatments were conducted using two-sided tests with an alpha level of 0.05.

Where appropriate, data were tested for normality of distribution by means of a D’Agostino and Pearson omnibus test. Data are reported as mean ± SD. A P value <0.05 was considered statistically significant.

Results

At the time of inclusion, mean ± SD body weight for the 28 cats was 4.5 ± 1.3 kg. Cats were approximately 2–6 years of age. Blood pressure cuffs of sizes 3, 4 and 5 were used in six, 20 and two cats, respectively; cuff size for each cat was kept constant over the course of the study. SBP_baseline was similar between treatment groups (Table 1).

Table 1

Mean ± SD for indirectly measured systolic arterial blood pressure (SBP) in 28 awake, clinically normal cats (n = 4 cats/treatment group) administered various dosages of telmisartan (TEL) or placebo (PLA) orally for 14 days

Variable (mmHg)	Placebo	Telmisartan
Variable (mmHg)	Placebo	1 mg/kg q24h	1.5 mg/kg q24h	2 mg/kg q24h	1 mg/kg q12h	3 mg/kg q24h	1.5 mg/kg q12h
Baseline SBP	131 ± 15	130 ± 15	130 ± 19	130 ± 12	131 ± 19	127 ± 13	130 ± 15
SBP_{week 1+2}	125 ± 14	108 ± 9	112 ± 30	100 ± 6**	98 ± 19**	97 ± 8**	103 ± 4*
SBP_{week 1}	125 ± 17	111 ± 10	119 ± 35	103 ± 4*	104 ± 21*	103 ± 9*	108 ± 5
SBP_{week 2}	124 ±13	105 ± 10*	105 ± 26*	97 ± 8**	91 ± 18**	90 ± 10***	97 ± 6**

All values were obtained 3 ± 1 h following the morning dose of TEL or PLA. Within rows, values marked with asterisk are significantly (*P <0.05; **P <0.01; ***P <0.001) different compared with placebo

Abnormal observations – including diarrhea, vomiting, and vomiting or regurgitating after dosing – were recorded in 18/28 animals (nine PLA-treated and nine TEL-treated) over the course of the entire study; all were considered mild in severity and none required treatment. Similar numbers of cats vomited or regurgitated within 30 mins of dosing when treated with TEL (n = 3) or PLA (n = 3), whereas slightly more cats treated with PLA (n = 4) vomited at other time points vs those treated with TEL (n = 2). It was not necessary to alter dosing for any animal, and all animals received their doses as scheduled. No overt clinical signs of hypotension, including, but not limited to, ataxia, abnormal mentation and/or weakness, were observed in-cage or during daily exercise in any cat.

A statistically significant effect of period was found across all treatments (P = 0.035), confounding interpretation of data from the second and third treatment periods. Therefore, data from these treatment periods were not considered further.

Figure 1 illustrates mean SBP by study day for each treatment group during the first treatment period. When mean SBP was calculated for the entire 14 day treatment period (SBP_week1+2), treatment with TEL at all but the two lowest dosages, 1 mg/kg q24h and 1.5 mg/kg q24h, was associated with significantly lower SBP at 3 ± 1 h post-administration compared with treatment with PLA. However, by the second treatment week (SBP_week2), at all tested dosages, TEL administration resulted in a significantly lower SBP at 3 ± 1 h post-administration compared with PLA (Table 1).

Figure 1

Mean indirectly measured systolic arterial blood pressure in 28 awake, clinically normal cats (n = 4 cats/treatment group) administered various dosages of telmisartan (TEL) or placebo (PLA) orally for 14 days. All values were obtained 3 ± 1 h following the morning dose of TEL or PLA. For ease of interpretation, error bars are not included

For all TEL treatment groups, mean SBP_week2 was numerically lower than SBP_week1; however, this difference was statistically significant for dosages of 1.5 mg/kg q24h (P = 0.0002), 1 mg/kg q12h (P = 0.0004), 3 mg/kg q24h (P = 0.0002) and 1.5 mg/kg q12h (P = 0.0022) only. No significant differences were detected in SBP parameters among TEL treatment groups, although compared with cumulative dosage rates <2 mg/kg/day, those ⩾2 mg/kg/day were associated with a greater reduction in mean SBP (Figure 2).

Figure 2

Group means for indirectly measured systolic arterial blood pressure (SBP) in 28 awake, clinically normal cats (n = 4 cats/treatment group) administered various dosages of telmisartan (TEL) or placebo (PLA) orally for 14 days. For each treatment, mean SBP for all four cats at baseline and during the first and second weeks of treatment period 1 are depicted. All values were obtained 3 ± 1 h following the morning dose of TEL or PLA. Error bars represent SD

Discussion

In the present study, compared with PLA, treatment of healthy adult cats with oral TEL was associated with measurable reductions in SBP approximately 3 h following the morning treatment. A goal of this study was to identify TEL dosage rates that would be associated with measurable reductions in SBP within the clinically relevant time period of 1–2 weeks following treatment initiation. Although only statistically significant for the highest tested dosages (ie, those ⩾2 mg/kg/day) during the first week of treatment, this effect was statistically significant by the second week of treatment for all tested dosages of TEL. The decline in mean SBP relative to baseline appeared to be clinically significant as well, with decreases of approximately 25–37 mmHg noted for the range of TEL dosages tested, compared with a decrease of only 6 mmHg in the PLA group during the same period (Table 1). Although direct comparison between studies is challenging, the effect of TEL on mean SBP in the present study was greater than that noted for the combination of dietary sodium restriction and the ACEi, lisinopril, on mean arterial pressure in conscious, unrestrained cats from a previous report.¹⁹

While SBP reduction was not significantly different among the tested dosages of TEL, given the small number of animals (n = 4) per treatment group in the final analysis, it is possible, if not likely, that this study was underpowered to detect relatively small differences, possibly resulting in type II error.

In general, for TEL-treated cats, mean SBP measured during the second week of treatment was lower than that measured during the first week of treatment. In the present study, determination of the maximum BP-lowering effect of TEL is likely limited by the duration of the treatment period. In hypertensive rats treated with oral dosages of 1–3 mg/kg/day of TEL, maximum BP reduction was identified at the end of a 9 week study period,²⁰ and unpublished data (AM Traas, 2016, personal communication) generated in cats suggests that the maximum antihypertensive effect of the drug plateaus approximately 12–14 weeks following initiation of oral therapy.

Although indirectly measured mean SBP measurements <80 mmHg were documented in individual cats during this study, no cat exhibited clinical signs consistent with systemic hypotension. An expert consensus panel advises that ‘a BP <120/60 mmHg combined with clinical findings of weakness, syncope or tachycardia indicate systemic hypotension and therapy should be adjusted accordingly’.¹⁸ Given the tendency of Doppler ultrasonography techniques to systematically underestimate SBP in conscious cats,²¹ documentation of clinical signs compatible with hypotension would seem valuable for defining this state in animals for which BP is being estimated by indirect means. That said, as cats are sedentary creatures by nature, subtle signs of systemic hypotension may have gone unnoticed, despite careful monitoring in the present study.

There are limitations to this study. First, a statistically significant effect of period was observed; for this reason, treatment comparisons were limited to data derived from the first treatment period, resulting in a small number of cats per group. Study design dictated that this effect was not exposed until the conclusion of the study, precluding any corrective adjustments a priori. As measurement of SBP was performed at a single time point post-dose (3 ± 1 h), the study reported here was not designed to evaluate duration of BP control over the dosing interval. Finally, this study was performed on normotensive, healthy cats; extrapolation of results to cats with naturally occurring disease should be undertaken with caution. The percentage of an oral dose of TEL undergoing urinary excretion in the cat is not known; however, elimination via this route is considered low (0.1–4%).²²

Conclusions

Based on the results of this study, TEL appears to be well tolerated in normal cats at the dosages tested. Compared with PLA, treatment with oral TEL at dosages of 1 mg/kg q24h or 2–3 mg/kg/day as a single dose or divided twice daily, resulted in statistically and clinically significant BP reduction within the second week of treatment for all dosages, and within the first week of treatment for dosages ⩾2 mg/kg/day. Additional studies are needed to establish the efficacy of this drug for cats with HT.

Footnotes

Accepted: 25 January 2018

Conflict of interest

Lawrence Bryson, Alicia Zimmerman and Anne Traas are employees of Boehringer Ingelheim Vetmedica, and Marcus Stark and Tanja Zimmering of Boehringer Ingelheim Animal Health. Amanda Coleman and Scott Brown have served as consultants for Boehringer Ingelheim Vetmedica. A company representative of Boehringer Ingelheim read and approved the final draft.

Funding

This study was funded by Boehringer Ingelheim Vetmedica.

References

Kobayashi

Peterson

Graves

et al . Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990; 4: 58–62.

Syme

Barber

Markwell

et al . Prevalence of systolic hypertension in cats with chronic renal failure at initial evaluation. J Am Vet Med Assoc 2002; 220: 1799–1804.

Littman

MP.

Spontaneous systemic hypertension in 24 cats. J Vet Intern Med 1994; 8: 79–86.

Chetboul

Lefebvre

Pinhas

et al . Spontaneous feline hypertension: clinical and echocardiographic abnormalities, and survival rate. J Vet Intern Med 2003; 17: 89–95.

Brown

Munday

Mathur

et al . Hypertensive encephalopathy in cats with reduced renal function. Vet Pathol 2005; 42: 642–649.

Maggio

DeFrancesco

Atkins

et al . Ocular lesions associated with systemic hypertension in cats: 69 cases (1985–1998). J Am Vet Med Assoc 2000; 217: 695–702.

Syme

Markwell

Pfeiffer

et al . Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 2006; 20: 528–535.

Chakrabarti

Syme

Elliott

Clinicopathological variables predicting progression of azotemia in cats with chronic kidney disease. J Vet Intern Med 2012; 26: 275–281.

Jepson

Elliott

Brodbelt

et al . Effect of control of systolic blood pressure on survival in cats with systemic hypertension. J Vet Intern Med 2007; 21: 402–409.

10.

Campese

VM.

Pathophysiology of resistant hypertension in chronic kidney disease. Semin Nephrol 2014; 34: 571–576.

11.

The GISEN Group. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: 1857–1863.

12.

Lewis

Hunsicker

Clarke

et al . Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 2001; 345: 851–860.

13.

Maschio

Alberti

Janin

et al . Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med 1996; 334: 939–945.

14.

King

Gunn-Moore

Tasker

et al . Tolerability and efficacy of benazepril in cats with chronic kidney disease. J Vet Intern Med 2006; 20: 1054–1064.

15.

Jensen

Henik

Brownfield

et al . Plasma renin activity and angiotensin I and aldosterone concentrations in cats with hypertension associated with chronic renal disease. Am J Vet Res 1997; 58: 535–540.

16.

Jenkins

Coleman

Schmiedt

et al . Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats. Am J Vet Res 2015; 76: 807–813.

17.

Sent

Gossl

Elliott

et al . Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in cats with chronic kidney disease. J Vet Intern Med 2015; 29: 1479–1487.

18.

Brown

Atkins

Bagley

et al . Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 2007; 21: 542–558.

19.

Brown

Langford

Tarver

Effects of certain vasoactive agents on the long-term pattern of blood pressure, heart rate, and motor activity in cats. Am J Vet Res 1997; 58: 647–652.

20.

Bohm

Lee

Kreutz

et al . Angiotensin II receptor blockade in TGR(mREN2)27: effects of renin-angiotensin-system gene expression and cardiovascular functions. J Hypertens 1995; 13: 891–899.

21.

Haberman

Morgan

Kang

et al . Evaluation of Doppler ultrasonic and oscillometric methods of indirect blood pressure measurement in cats. Intern J Appl Res Vet Med 2004; 2: 279–289.

22.

Wienen

Entzeroth

van Meel

JCA

et al . A review on telmisartan: a novel, long-acting angiotensin II-receptor antagonist. Cardiovasc Drug Rev 2000; 18: 127–156.