Use of amlodipine in the treatment of cats with systemic hypertension in Japan

Abstract

An increase in systemic blood pressure causes bleeding and ischemia owing to peripheral vascular breakdown, leading to various forms of organ damage. The brain, eyes, kidneys, and cardiovascular system are known target organs for hypertension. To our knowledge, no reports in Japan describe, in detail, the types of antihypertensive drugs used to treat hypertension in cats or its underlying causes. Therefore, we aimed to investigate the use of antihypertensive drugs in domestic cats with hypertension in Japan, the causes of hypertension, and the vital prognosis of these patients. In the present survey, we found that amlodipine was used alone (60/80 cats) or concomitantly (20/80 cats) in all cat patients with hypertension in Japan. We also determined that blood pressure measurements were not yet routinely performed on cats at veterinary clinics in Japan. Furthermore, we have new information suggesting that amlodipine administration in cats with hypertension, which lowers systolic arterial pressure levels to within the normal range (<140 mmHg), may have a negative impact on their survival. Routine blood pressure measurements for cats during their regular health checkups can help identify hypertension, and proper interpretation of blood pressure readings can facilitate suitable treatment measures.

Systemic hypertension is a pathological condition that is defined as a persistent increase in arterial blood pressure [1]. The condition can be broadly classified into the following three types: cases that are caused by an underlying disease that causes an increase in blood pressure (secondary), those that are not associated with an underlying disease (idiopathic), and those that are caused by changes in autonomic nervous system activity due to excitement or anxiety (situational) [1]. Hypertension in cats is defined as systolic arterial pressure (SAP) ≥160 mmHg, which is often encountered in clinical practice. Most occurrences are thought to be cases of secondary hypertension in middle-aged and older cats with underlying diseases [2, 3, 14, 28].

An increase in systemic blood pressure causes bleeding and ischemia owing to peripheral vascular breakdown, leading to various forms of organ damage. In particular, the brain, eyes, kidneys, and cardiovascular system are known target organs for hypertension [1]. Therefore, there is a need for treatments that can sustainably protect these target organs while controlling blood pressure.

The American College of Veterinary Internal Medicine (ACVIM) guidelines list calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) as therapeutic agents for cats with hypertension [1]. Among these, amlodipine, which is a dihydropyridine CCB, is the most commonly recommended for use.

Amlodipine is characterized by slow action onset and long-lasting effects. It also specifically binds to voltage-gated L-type calcium channels and reduces calcium influx into cells. This relaxes the smooth muscles of the coronary and peripheral blood vessels, causing them to dilate. ACEIs dilate blood vessels by inhibiting the enzyme that converts angiotensin (ANG) I in the body to ANG II, a potent endovascular substance [19, 24]. Additionally, ARBs inhibit the effects of ANG II by binding to ANG II type 1 receptors, which leads to blood vessel dilation [24].

To date, there have been several epidemiological reports on the use of amlodipine, ACEIs, or ARBs in cats with hypertension in the West [2, 4, 7, 8, 10, 12, 14, 26].

It has become clear in human medicine that there are country-based differences in the prevalence rates of hypertension as well as the response to treatment. Accordingly, it has been stated that the treatment and control rates for hypertension are higher in middle- and high-income countries, that is, the level and awareness of concerns about hypertension in the population is important [21]. Meanwhile, in veterinary medicine, very few country-specific reports exist on cats with hypertension, and even in Japan, there are many unknown aspects regarding the extent to which diagnosis and treatment are being conducted with awareness of the ACVIM guidelines. Additionally, as far as we are aware, there have not been any prior Japanese reports that have described the underlying diseases that cause hypertension as well as their prognoses.

Therefore, we aimed to investigate the use of antihypertensive drugs in domestic cats with hypertension in Japan, the causes of hypertension, and the vital prognosis of these patients.

MATERIALS AND METHODS

Study participants

In this retrospective study, the participants were domestic cats whose owners visited Tokyo University of Agriculture and Technology or 50 domestic veterinary hospitals between January 2010 and March 2023, and who were diagnosed with hypertension, and treated with antihypertensive drugs. The timing of re-examination after antihypertensive drug administration and changes in drugs used were determined by the clinic and attending veterinarian.

Survey items

We collected information such as breed, sex, age (at treatment initiation), weight, body condition score (BCS), dietary content, blood pressure measurement method and measurement location (including reasons), blood pressure level before and after antihypertensive drug administration, rate of decrease in SAP after antihypertensive drug administration (%), presence or absence of target organ damage, blood biochemistry levels, and echocardiography test results.

The rate of decrease in SAP (%)=(1-SAP after administration/SAP before administration) × 100 (1)

We also surveyed the drug name, dosage, administration period, concomitant medications, and the presence or absence of side effects during antihypertensive drug use.

Blood biochemistry tests included plasma urea nitrogen (BUN) levels, plasma creatinine concentration (CRE), and symmetrical dimethylarginine (SDMA) levels before and after drug administration. Furthermore, comparisons between the SAP <140 mmHg group and the SAP≥140 mmHg group were performed to assess the percentage change after antihypertensive drug administration.

Echocardiography measurements included left ventricular end-diastolic diameter (LVIDd), left ventricular end-systolic diameter (LVIDs), left ventricular fractional shortening (FS), left atrial diameter (LA), aortic diameter (Ao) and left atrial-aortic diameter ratio (LA/Ao).

A resting SAP ≥160 mmHg was defined as hypertension [1].

We also investigated the causes of hypertension, including the presence or absence of underlying disease [1]. Furthermore, in the case of chronic kidney disease (CKD), we used the International Renal Interest Society (IRIS) classification to determine the disease stage.

Endpoint settings

The primary endpoint was hypertension-related death. Hypertension-related death was defined when a patient was assigned codes I10–I15 according to the International Classification of Diseases (ICD-10) [17].

The secondary endpoint was all-cause death, including hypertension-related death, and patients who discontinued treatment partway through the regimen or those who continued treatment were censored. Survival time was defined as the number of days from the initiation of amlodipine administration to the endpoint or censoring.

Statistical analysis

Each measurement was expressed as the mean ± standard deviation. Time until re-evaluation for each measurement item was expressed as median value and interquartile range (IQR). A normal probability plot was created to confirm whether the measurements were normally distributed, and the normality of the distribution was tested using the Kolmogorov–Smirnov test. Thereafter, a paired t-test or Wilcoxon signed rank test was conducted to compare each item before and after drug administration in the same individual. Comparisons between groups were performed using an unpaired t-test or Mann–Whitney U test. Comparisons of the effects of antihypertensive drugs were performed using the Kruskal–Wallis test, followed by the Steel–Dwass test.

Survival time analysis was conducted as follows: for the primary and secondary endpoints, univariate Cox proportional hazards analysis was first conducted to evaluate whether each variable was associated with the time to the endpoint, after which the hazard ratio (HR) and 95% confidence interval (95% CI) were calculated. The following seven variables were set: age (at which amlodipine treatment was initiated), body weight, sex (male and neutered male, or female and spayed female), presence of concomitant drugs, amlodipine dosage (commonly used dose: ≤0.25 mg/kg/day and high dose: >0.25 mg/kg/day), presence or absence of CKD complications at the time of diagnosis, and SAP after antihypertensive drug treatment (<140 mmHg and ≥140 mmHg).

Next, we conducted multivariate Cox proportional hazards analysis using the variables with P-values <0.1 in the univariate analysis. A reduction method was used for multivariate Cox proportional hazards analysis, and the final model was selected if the P-values of all remaining variables were <0.1. We calculated the HR and 95% CI for variables that remained in the final model.

Furthermore, we stratified the variables that were predicted to be strongly associated with prognosis using uni- and multivariate analysis. Survival rates were compared using the log-rank test (Cochran–Mantel–Haenszel test), and Kaplan–Meier survival curves were created.

All statistical analyses were conducted using SPSS Statistics software ver. 25 (IBM Japan, Tokyo, Japan), and P<0.05 was considered statistically significant.

RESULTS

Overview of survey target patients

Of the 51 hospitals where a survey request was made, 38 (75%) provided responses. We then collected the data of 100 cats. Of these, 80 cats were diagnosed with hypertension and were targeted for study. The remaining 20 were excluded from the study because their SAP levels before antihypertensive drug administration were <160 mmHg (9 patients) or blood pressure measurements were not conducted (11 patients). The blood pressure measurement methods used for the cats in this survey were the oscillometric method in 88/89 patients (98.9%) and the Doppler method in 1 patient (1.1%). The measurement locations were the forelimb in 23/89 patients (25.8%), hindlimb in 2/89 patients (2.2%), and the tail in 64/89 patients (71.9%). Regarding the reason respondents chose the tail as the measurement location, the majority of respondents (80%) said that the tested cat appeared more comfortable with this location than with other measurement locations. Another comment was that cats showed a dislike of the application of the pressure cuff when measurements were taken on the forelimbs, and shaking of the forelimbs was observed.

The following breeds were included among the 80 patients diagnosed with hypertension: Mixed breeds (60), Scottish Fold (7), American Shorthair (3), Persian (2), Russian Blue (2), and other (6) (Table 1). The average age at the time of diagnosis of hypertension was 14 years (1–20 years).

Table 1. Composition of cat breeds in this study.

Breed	Number
Mixed breeds	60
Scottish Fold	7
American Shorthair	3
Persian	2
Russian Blue	2
Siberian	1
Ragdoll	1
Bengal	1
Siamese	1
Exotic Shorthair	1
Abyssinian	1
Total	80

In terms of sexes, the group included 4 males, 9 females, 33 castrated males, and 34 spayed females. The average body weight was 3.55 ± 0.98 kg. The BCS (evaluated on a five-point scale) was 0% for 1/5, 30.3% for 2/5, 59.1% for 3/5, 7.6% for 4/5, and 3.0% for 5/5. Regarding information about dietary content, we obtained responses for 60/80 cats, confirming that 90% had general diets and 10% had renal therapy diets.

In this survey, 78 of the patients with hypertension had a concurrent disease. The breakdown of these diseases is as follows: chronic kidney disease (69), cardiomyopathy (27), hyperthyroidism (9), malignant tumor (4), third-degree atrioventricular block (3), ureteral stone (2), sinus tachycardia (2), and idiopathic cystitis (2); other diseases included one of each of aortic thromboembolism, cerebellar infarction, renal stones, urachal retention, portal venous hypertension, feline immunodeficiency virus, glaucoma, diabetes mellitus, constipation, and arthritis (Table 2). Of these, 32 patients had two or more diseases. Only two patients did not have an underlying disease.

Table 2. Diseases related to hypertension.

Disease	Number
Chronic kidney disease	69
Cardiomyopathy	27
Hyperthyroidism	9
Malignant tumor	4
Third degree atrioventricular block	3
Ureteral stone	2
Sinus tachycardia	2
Idiopathic cystitis	2
Aortic thromboembolism	1
Cerebellar infarction	1
Renal stones	1
Urachal retention	1
Portal venous hypertension	1
Feline immunodeficiency virus	1
Glaucoma	1
Diabetes mellitus	1
Constipation	1
Arthritis	1
Total	128

*Two cases had no disease.

Additionally, 76 of the 80 patients had target organ damage (TOD) that could be related to hypertension. Organ damage was most common in the following order: the kidneys in 69 patients; eyes in 25; cardiovascular system in 12; and brain in 6 patients. Of these, 27 patients clearly showed damage in multiple organs (Table 3). Of the remaining four patients, two had only hypertension and no underlying disease or organ damage, and one patient each had constipation and arthritis. The median time until re-evaluation of each measurement item before and after amlodipine administration was 17 days (IQR: 12.25–35.75).

Table 3. Target organ damage observed in cats with hypertension.

Target organ damage	Number
Cardiovascular system	6
Eye	1
Cardiovascular system + Eye	1
Kidney	38
Kidney + Eye	14
Kidney + Eye + Cardiovascular system	7
Kidney + Brain	4
Kidney + Cardiovascular system	3
Kidney + Eye + Brain	1
Kidney + Eye + Cardiovascular system + Brain	1

Types of antihypertensive drugs

Of the 80 feline patients with hypertension in this survey, 60 (75%) received amlodipine alone (Amlo only), 11 (14%) concomitantly received amlodipine and telmisartan (Amlo+Telmi), and 9 (11%) concomitantly received amlodipine and benazepril (Amlo+Benaze). In this survey, pimobendan and furosemide were mentioned as cardiovascular-related drugs that were administered before the patient was diagnosed with hypertension. All of these were patients with cardiomyopathy. Other drugs besides antihypertensive drugs, administered alone or concomitantly, were mercazole (9 patients), ursodeoxycholic acid (4 patients), mosapride (3 patients), and others (medicinal activated charcoal, zonisamide, mirtazapine, etc.).

The mean amlodipine dose was 0.41 ± 0.51 mg/kg/day. For this dose, 2 patients (2.5%) received <0.1 mg/kg, 24 (30.0%) received ≥0.1 mg/kg and <0.2 mg/kg, 25 (31.3%) received ≥0.2 mg/kg and <0.3 mg/kg, and 29 (36.2%) received ≥0.3 mg/kg. The mean administration period was 706 ± 1,423 days. The telmisartan dose was 1.1 ± 0.1 mg/kg/day, and the benazepril dose was 0.6 ± 0.2 mg/kg/day.

Side effects were observed in 3/80 patients, and lightheadedness and hyperplasia were observed in one patient each when amlodipine was administered alone. Additionally, loss of vitality was observed in one patient 1 week after concomitant administration of amlodipine and benazepril.

Blood pressure measurements

The SAP, MAP, and DAP of cats treated with Amlo only, Amlo+Telmi, and Amlo+Benaze all decreased significantly after treatment (P<0.01) (Table 4).

Table 4. Changes in blood pressure levels and heart rate before and after the administration of combinations of antihypertensive drugs.

	Amlo only			Amlo + Telmi			Amlo + Benaze			Amlodipine (Total cases)
	Pre	Post		Pre	Post		Pre	Post		Pre	Post
SAP (mmHg)	197 ± 25	155 ± 23	**	231 ± 28	160 ± 25	**	195 ± 28	156 ± 26	*	201 ± 28	156 ± 24	**
MAP (mmHg)	152 ± 22	117 ± 23	**	176 ± 24	121 ± 19	**	153 ± 30	121 ± 28	*	155 ± 24	118 ± 23	**
DAP (mmHg)	131 ± 24	100 ± 23	**	145 ± 24	95 ± 13	**	134 ± 29	106 ± 26	*	134 ± 25	100 ± 22	**
Heart rate (bpm)										191 ± 30	196 ± 34

Amlo only, administration of amlodipine only; Amlo+Telmi, administration of amlodipine with telmisartan; Amlo+Benaze, administration of amlodipine with benazepril; Amlodipine (total patients), total number of patients treated with amlodipine. SAP, systolic arterial pressure; MAP, mean arterial pressure; DAP, diastolic arterial pressure. Pre, before administration; Post, after administration. Pre vs. Post *P<0.05, **P<0.01.

The rate of decrease in SAP before and after administration with Amlo only was 21 ± 10%, the rate of decrease with Amlo+Telmi was 30 ± 13%, and the rate of decrease with Amlo+Benaze was 20 ± 8%. The rate of decrease in blood pressure was significantly greater with Amlo+Telmi than with Amlo only (P<0.05). No significant difference was observed between Amlo only and Amlo+Benaze (Fig. 1).

Fig. 1.

Rate of decrease in systolic arterial pressure according to the combination of antihypertensive drugs. Amlo only, after administration of amlodipine only; Amlo+Telmi, after administration of amlodipine with telmisartan; Amlo+Benaze, after administration of amlodipine with benazepril. The rate of decrease in blood pressure was significantly larger with Amlo+Telmi than with Amlo only. *P<0.05.

The SAP, MAP, and DAP of all cats treated with amlodipine decreased significantly after treatment (P<0.01). We surveyed the rate of decrease in SAP by separating patients with blood pressures above and below 140 mmHg (the upper limit of normal SAP levels for cats), into two groups, and results showed that the SAP <140 mmHg group had a rate of decrease in SAP of 33.3 ± 10.2%, while that for the SAP≥140 mmHg group after amlodipine administration was 18.5 ± 8.3%. The SAP <140 mmHg group had a significantly higher rate of decrease in blood pressure than the SAP ≥140 mmHg group (P<0.01). There was also no significant difference in the rate of SAP reduction between amlodipine doses (≤0.25 mg/kg/day vs. >0.25 mg/kg/day).

The heart rate was 191 ± 30 bpm before administration and 196 ± 34 bpm after administration, and no significant difference was observed (Table 4).

Blood biochemistry tests

The BUN, CRE, and SDMA results for all cats treated with amlodipine are shown in Table 5. No significant changes were observed in these levels after drug administration. Additionally, the percentage change after antihypertensive drugs were as follows: for BUN, 9.5 ± 29.6% for SAP <140 mmHg group and 1.0 ± 27.2% for SAP≥140 mmHg group; and for CRE, 0.8 ± 32.7% for SAP <140 mmHg group and 0.7 ± 20.4% for SAP≥140 mmHg group. No significant differences were found between the two groups for either drug.

Table 5. Changes in renal function measurements before and after amlodipine administration.

	Pre	Post
BUN (mg/dL)	51.7 ± 27.7	53.1 ± 32.6
CRE (mg/dL)	2.81 ± 1.41	2.81 ± 1.8
SDMA (μg/dL)	12.9 ± 3.6	12.5 ± 4.9

BUN, plasma urea nitrogen; CRE, plasma creatinine concentration; SDMA, symmetrical dimethylarginine. Pre, before administration; Post, after administration.

The IRIS stage classifications of the 69 patients with CKD were as follows: stage 1 (5 patients), stage 2 (35 patients), stage 3 (25 patients), and stage 4 (4 patients). Blood biochemical tests, including BUN and CRE measurements, were performed multiple times, and CKD was identified based on these results.

Echocardiography

Following amlodipine administration, no significant differences were observed in LVIDd, LVIDs, and Ao levels among all cats. However, FS showed an increasing tendency (P<0.08), and LA showed a significant decrease after drug administration (P<0.01). Furthermore, a significant decrease was noted in La/Ao (P<0.05) (Table 6).

Table 6. Echocardiographical indicators before and after amlodipine administration.

	Pre	Post
LVIDd (mm)	14.2 ± 2.8	14.1 ± 2.5
LVIDs (mm)	6.8 ± 2.2	6.2 ± 1.9
FS (%)	52.1 ± 10.9	55.8 ± 12
LA/Ao	1.51 ± 0.41	1.37 ± 0.3	*
LA (mm)	13.2 ± 2.5	11.9 ± 2.6	**
Ao (mm)	8.9 ± 1.1	8.8 ± 1.0

LVIDd, left ventricular end-diastolic diameter; LVIDs, left ventricular end-systolic diameter; FS, left ventricular diameter fractional shortening; LA/Ao, left atrial-aortic diameter ratio; LA, left atrial diameter; Ao, aortic diameter. Pre, before administration; Post, after administration. Pre vs. Post *P<0.05, **P<0.01.

Endpoint

Of the 80 targeted patients, 36 had reached the primary endpoint at the end of the survey. Seventy-two patients reached the secondary endpoint (hypertension-related death, 36 patients; death due to causes other than hypertension, 3 patients; discontinued treatment, 2 patients; ongoing treatment, 31 patients). The causes of death other than hypertension-related death were as follows: lung tumors, 2 patients; and lymphoma, 1 patient.

Survival time analysis

Regarding the univariate Cox proportional hazards analysis of the primary endpoint, the following variables were significant (P<0.1): age, body weight, amlodipine dosage, CKD complications, and SAP level after antihypertensive drug treatment. No significance was observed for sex (P=0.941) and presence of concomitant drugs (P=0.354) (Table 7).

Table 7. Hazard ratio of reaching primary and secondary endpoints according to univariate Cox proportional hazards analysis.

Variable	Primary endpoint			Secondary endpoint
	HR	95% CI	P value	HR	95% CI	P value
Age	1.102	1.024–1.186	0.009	1.110	1.033–1.193	0.005
Body weight	0.732	0.513–1.045	0.086	0.743	0.528–1.045	0.088
Sex	1.026	0.524–2.006	0.941	0.949	0.499–1.803	0.872
Presence of concomitant drugs	0.688	0.312–1.518	0.354	0.829	0.401–1.710	0.612
Amlodipine dose >0.25 mg/kg/day	1.832	0.931–3.605	0.080	1.731	0.904–3.315	0.098
With CKD	2.658	0.987–7.160	0.053	2.827	1.058–7.549	0.038
Post SAP <140 mmHg	3.050	1.532–6.073	0.002	2.714	1.391–5.296	0.003

HR, hazard ratio; 95% CI, 95% confidence interval; CKD, chronic kidney disease; SAP, systolic arterial pressure.

Regarding the univariate Cox proportional hazards analysis of the secondary endpoint, the following variables had significance (P<0.1): age, body weight, amlodipine dosage, CKD complications, and SAP level after antihypertensive drug treatment. No significance was observed for sex (P=0.872) and presence of concomitant drugs (P=0.612) (Table 7).

For the primary endpoint, multivariate Cox proportional hazards analysis that incorporated age, body weight, amlodipine dosage, CKD complications, and SAP level after antihypertensive drug treatment showed that the following variables were significant: age and SAP level after the start of antihypertensive drugs. No significance was found for body weight, amlodipine dosage (P=0.694), and CKD complications (P=0.471) (Table 8).

Table 8. Hazard ratio of reaching primary and secondary endpoints according to multivariate Cox proportional hazards analysis.

Variable	Primary endpoint			Secondary endpoint
	HR	95% CI	P value	HR	95% CI	P value
Age	1.106	1.013–1.208	0.025	1.109	1.017–1.209	0.019
Body weight	0.698	0.459–1.062	0.093	0.706	0.470–1.062	0.095
Amlodipine dose >0.25 mg/kg/day	1.160	0.555–2.425	0.694	1.189	0.583–2.425	0.634
With CKD	1.483	0.508–4.332	0.471	1.500	0.515–4.369	0.457
Post SAP <140 mmHg	2.994	1.436–6.246	0.003	2.662	1.307–5.420	0.007

HR, hazard ratio; 95% CI, 95% confidence interval; CKD, chronic kidney disease; SAP, systolic arterial pressure.

For the secondary endpoint, multivariate Cox proportional hazards analysis that incorporated age, body weight, amlodipine dosage, CKD complications, and SAP level after the administration of antihypertensive drugs showed that the following variables were significant: age and SAP level after antihypertensive drug administration. No significance was found for body weight (P=0.095), amlodipine dosage (P=0.634), and CKD complications (P=0.457) (Table 8).

For the primary and secondary endpoints, we compared survival rates by stratifying using the following variables that had P<0.1 in the univariate analysis: amlodipine dosage (conventional use vs. high dose), CKD complications (present vs. absent), and SAP level after initiation of antihypertensive drugs (<140 mmHg vs. ≥140 mmHg) (Fig. 2).

Fig. 2.

Kaplan–Meier curves for the primary and secondary endpoints. For the primary and secondary endpoints, the survival rate was significantly higher in the systolic arterial pressure ≥140 mmHg group than in the SAP <140 mmHg group after amlodipine administration. SAP, systolic arterial pressure.

For the primary endpoint, the survival rate was significantly higher in the patient group without CKD complications than in the patient group with CKD complications (P=0.046). Furthermore, the survival rate was significantly higher in the group with SAP levels ≥140 mmHg after the administration of antihypertensive drugs than in the group with SAP levels <140 mmHg after the administration of antihypertensive drugs (P=0.001). For the amlodipine dosage, there was no significant difference in the survival rate between the conventional use and high dose groups (P=0.075).

For the secondary endpoint, the survival rate was significantly higher in the patient group without CKD complications than in the patient group with CKD complications (P=0.032). Furthermore, the survival rate was significantly higher in the group with SAP levels ≥140 mmHg after the administration of antihypertensive drugs than in the group with SAP levels <140 mmHg after the administration of antihypertensive drugs (P=0.002). In terms of amlodipine dosage, there was no significant difference in the survival rate between the conventional use and high dose groups (P=0.094).

DISCUSSION

The present study describes the results of a survey on blood pressure measurement methods, underlying diseases, and treatments for cats with hypertension. To the best of our knowledge, this is the first such report published by a Japanese group and is possibly the first among all Asian countries.

In the present survey, only two cats were thought to have idiopathic hypertension, while the others had an underlying disease that was thought to be related to hypertension [1]. Additionally, in the present survey, 76 of the 80 patients had TOD that could be related to hypertension. Of these, 69 patients had kidney damage (i.e., CKD). There have been many reports on the association between hypertension and CKD in cats [2, 3, 5, 28]. In humans, prolonged hypertension is thought to cause sclerosis and degeneration of renal blood vessels, leading to renal dysfunction [15]. Meanwhile, dysfunctional kidneys do not properly excrete sodium and urine, causing hypertension owing to increased circulating blood volume [15]. Reduced renal blood flow increases renin secretion, which leads to an increase in blood pressure [15]. However, in this survey, we targeted cats diagnosed with hypertension during a preliminary examination, so we cannot ascertain the symptoms and condition of the cats before the onset of hypertension. Additionally, not all of the clinical facilities that participated in the present survey conducted special tests to differentiate between idiopathic hypertension and secondary hypertension. It is extremely difficult for owners and veterinarians to judge the subjective symptoms of animals, so most occurrences are of cats being brought to a veterinary hospital after showing clinical symptoms of hypertension. Therefore, it was not possible to clearly distinguish between idiopathic or secondary hypertension in the cats used in the present survey. For the same reason, it could not be determined whether the organ damage was the result or the cause of the hypertension. Clarification of these issues will require regular blood pressure monitoring and early detection of diseases through health examinations.

The majority of cats included in this survey were fed a general diet, and there were no changes in this following amlodipine administration. Previous reports have shown that a renal therapy diet for cats with spontaneous chronic kidney disease can significantly reduce renal-related mortality [23]. As few cats in this survey were fed therapeutic diets, it is likely that diet did not have a significant effect on survival time.

In this study, 27 cases of hypertension were associated with cardiomyopathy, of which 14 cases were due to non-obstructive hypertrophic cardiomyopathy. We excluded from the analysis four cases with obstructive hypertrophic cardiomyopathy for which the use of vasodilators was contraindicated. Both hypertension and hypertrophic cardiomyopathy are characterized by hypertrophy of the ventricular muscle, so there are many morphological similarities in the heart between the two. Myocardial tissue biopsies were not conducted on all cats in this study, so it is highly likely that non-obstructive hypertrophic cardiomyopathy was not accurately differentiated from hypertension.

Amlodipine is thought to be highly safe to administer to cats with hypertension, and few side effects have been reported [1]. In this survey, we observed gingival hyperplasia in one case following amlodipine administration. The incidence of gingival hyperplasia has been reported to be in the range of 1.7–5% in humans [9, 11, 20] and 8.5% in dogs [29], with its incidence in cats thought to be similarly low [8]. Other side effects included lightheadedness (one case) and decreased vitality (one case), both of which were expected to occur following the administration of vasodilators.

Blood pressure measurements showed that SAP, mean blood pressure, and diastolic blood pressure were all significantly lower after administration than before administration in all cats receiving amlodipine. Additionally, compared to administration of amlodipine alone, concomitant administration of amlodipine and telmisartan further reduced SAP. To date, research using rats and domestic dogs with spontaneous hypertension reported that concomitant administration of amlodipine and telmisartan had a synergistic effect on hypertension [6, 31]. This is thought to be due to the fact that CCBs and ARBs have different mechanisms of action for lowering blood pressure [31]. Therefore, a similar mechanism may have operated in cats in the present survey, resulting in a high antihypertensive effect. However, no significant difference was observed between the concomitant administration of amlodipine and benazepril and that of amlodipine alone. Although reported in healthy cats, benazepril has been shown to have less antihypertensive effects than telmisartan [13]. These results suggest that the differences in antihypertensive effects of benazepril and telmisartan may have been reflected in the present survey.

Blood biochemistry testing confirmed no changes in BUN, CRE, and SDMA levels following amlodipine administration. Similar to the present survey, a previous report on domestic cats showed that serum creatinine levels did not change following amlodipine administration [26]. SDMA levels have been reported to increase several months earlier than CRE levels when glomerular filtration rate is reduced by about 40% on average [22]. Meanwhile, research on biological variations in SDMA levels in healthy cats showed clear intra-individual, but little inter-individual, variation [25]. Additionally, the IRIS guidelines stated that it is preferable to judge SDMA levels through multiple measurements. Therefore, SDMA measurements in this survey may not have detected changes in renal blood flow affected by amlodipine administration due to intra-individual variation and the single measurement conducted in this study.

In this study, echocardiography revealed that the LA and LA/Ao measurements before amlodipine administration tended to be larger than in the healthy cats described in the report by Snyder et al. on hypertensive cats [27]. Meanwhile, amlodipine administration caused a significant decrease in LA/Ao, possibly due to a decrease in LA. Factors that may have reduced LA/Ao include a decrease in circulating blood volume (preload) due to dehydration or bleeding, and an increase in forward pumping due to a decrease in afterload. In this study, the blood biochemistry test results and cardiac ultrasound test results were negative for a decrease in circulating blood volume, and the decrease in LA/Ao was thought to be due to an increase in forward ejection as a result of decreased afterload, which is a recognized pharmacological effect of amlodipine.

Univariate Cox proportional hazards analysis showed that older patients, with lower body weights, CKD complications, amlodipine dosage of ≥0.25 mg/kg/day, and SAP level <140 mmHg after amlodipine administration tended to have a higher risk of reaching the primary and secondary endpoints. Meanwhile, multivariate Cox proportional hazards analysis showed that only older age and SAP level <140 mmHg after initiation of amlodipine administration increased the risk of reaching the primary and secondary endpoints. Increased age and increased hazard risk are non-specific events that apply to many diseases, so it was judged that secondary factors were a major contributor.

In veterinary medicine, the ACVIM guidelines recommend lowering SAP in cats with hypertension to SAP <140 mmHg as a treatment objective. Mishina et al. reported that the SAP level measured using the oscillometric method in 60 healthy cats was 115 ± 10 mmHg [18]. The measurements taken in this survey indicate that approximately 95% of healthy cat SAP levels fall within the 95–135 mmHg range. Therefore, the treatment strategy was to bring the blood pressure levels of the cats with hypertension back to the normal range. Before starting the survey, we also expected that keeping the blood pressure levels of cats with hypertension low would prolong their survival time. In the present survival time analysis, we stratified patients based on the SAP level after amlodipine administration (SAP <140 mmHg vs. SAP≥140 mmHg) and compared survival rates based on the ACVIM guidelines. Results showed that when the blood pressure level of cats with hypertension was reduced to SAP <140 mmHg, which was the treatment objective level, using amlodipine, the survival rate was conversely decreased. In human medicine, Kurasawa et al. reported that an excessive decrease in the SAP level in patients with CKD was associated with worsening renal function and poor prognosis. In human medicine, it is said that the normal SAP level is ≤120 mmHg [30], but this report stated that the preservation of renal function requires the objective lower limit of SAP to be 110 mmHg, and that blood pressure should not be excessively lowered [16]. In our present survey, 86% of the cats that reached the primary endpoint had CKD. Furthermore, the SAP <140 mmHg group contained 70% of the patients that were administered amlodipine at a dose of ≥0.25 mg/kg/day, which is higher than the commonly used dose. Additionally, the SAP <140 mmHg group had a significantly higher rate of decrease in SAP after amlodipine administration than the SAP ≥140 mmHg group. Due to these factors, blood pressure is maintained within the normal range; however, because the degree of blood pressure reduction was large, it is thought that sufficient renal blood flow could not be achieved for each individual. Therefore, similar to the report by Kurasawa et al. on human CKD patients, it is thought that an excessive blood pressure reduction could worsen the prognosis, at least for cats with hypertension and CKD.

This survey had several limitations. The first is that veterinarians from multiple institutions participated and cooperated in data collection, and procedures such as blood pressure measurements and ultrasound examinations were not uniform. However, since the evaluations before and after amlodipine administration were conducted by the same veterinarian, it is thought that the evaluation of the effects of amlodipine were less affected. The second is that the survey was retrospective, so the time between amlodipine administration and the evaluation differed for each patient. The variation in results could have been minimized if the time between drug administration and evaluation had been set. The third is that it was not possible to trace information on whether the patient was still alive or dead in some instances. This may have influenced the survival curve results. The fourth is that the presence and severity of proteinuria, which is thought to affect survival time, was not consistently reported by the veterinarians who cooperated with this survey due to the low rate of testing. This aspect is thought to be one of the reasons for the low level of awareness regarding hypertension treatment in Japan. Therefore, it is strongly recommended that veterinarians and owners make conscious improvements in the treatment of hypertension in cats.

Fifth, there was the issue of the number of entries. Increasing the number of patients analyzed may have resulted in statistically significant differences in items such as heart rate and FS. In the future, we would like to measure renal blood flow to evaluate the effect on life expectancy.

In the present survey, we found that amlodipine was used alone or concomitantly in all cat patients with hypertension in Japan. We also determined that blood pressure measurements were not yet routinely performed on cats at medical clinics in Japan. Furthermore, we have new information suggesting that amlodipine administration in cats with hypertension, which lowers SAP levels to within the normal range, may have a negative impact on their survival.

Routine blood pressure measurements should be recommended for cats during their regular health checkups to help identify hypertension. Proper interpretation of the blood pressure readings can facilitate the implementation of suitable treatment measures.

CONFLICTS OF INTEREST

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.