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Jonathan Elliott

MA, vetMB, PhD, certSAC, dipECVPT, MRCVS

Vice Principal, Research Professor of Veterinary Clinical Pharmacology, Royal Veterinary College, London, UK

New findings influencing the management of feline hypertension

Jonathan ElliottRoyal Veterinary CollegeLondon

Importance of feline hypertension

● Known to be a condition affecting cats over theage of 10 years associated most commonly withCKD

● Recent data from our group has:– Provided evidence for a pre-hypertensive

phase – Identified factors associated with/ related to the

dose of amlodipine required to manage hypertension

– Found evidence of biomarkers of cardiac and vascular damage that may help in identifying cats with TOD and indicate adequacy of treatment

Classification of human hypertension

7th JNC Report on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003 Dec. 42(6):1206-52

Classification of human hypertension

Heart Foundation Guide to management of hypertension 2008

Classification of feline hypertension

International Renal Interest Society 2015(based on ACVIM Consensus statement 2007)

Is systemic hypertension a factor in progression of CKD?

● Evidence from human medicine seems clear-cut

● Elevations of BP are a strong independent riskfactor for ESRD

Klag et al., 1996 NEJM, 334, 13-18

Category ESRD RRBP

Incid(105 yr)

Optimal 5.3 1.0120/80

Normal 6.6 1.2129/84

High normal 11.1 1.9139/90

Stage 1 21.0 3.1159/100

Stage 2 43.6 6.0179/110

Stage 3 96.1 11.2209/120

Stage 4 187.1 22.1210/120

What are the risk factors for hypertension in the cat?

• Most reports of hypertension suggest it occurs most frequently in association with underlying disease• Chronic kidney disease• Hyperthyroidism • Hyperaldosteronism (Conn’s Syndrome)• Secondary to use of erythrocyte stimulating agents

• Idiopathic hypertension – unknown aetiology (represents 1 in 6 (c18%) of hypertensive cats we see)

Systolic blood pressure in healthy cats

Does BP increase with age?• 133 normotensive cats (≥10 yrs)• Followed for 700 days (median)• SBP measured every 3-6 mths;

slope 0.4 ± 0.1 mmHg/100 days• 9/133 diagnosed as hypertensive –

these had higher SBP at entry

131.6 (115.0, 143.7) vs. 145.6 (139.5, 154) mmHg

Is this evidence for pre-hypertension?

• Based on 780 cats at a re-homing centre• All healthy on physical exam• Prevalence of hypertension in healthy

cats ≥10 yrs – 12.7 (6.7-18.7)% Jepson et al. 2009 J Vet Intern Med. 23(4):806-13

Bijsmans et al., (2015) JVIM 29:855–861Payne et al., 2013 Vet Cardiovascular Society

Does Blood pressure increase over-time in CKD cats?

• 265 cats dx with CKD and followed for >3 months

• 105 (39 [33-45] %) had concomitant hypertension (or hypertension dx within 3 mths)

• Of the remaining 160 cats➢ 133 remained normotensive (followed 316 [225-512] days) SBP 133.2

[121.2,144.6] mmHgrate of change of SBP 0.5 ± 0.1 mmHg/100 days

➢ 27 (17%) became hypertensive (followed 379 [281-771] days)

SBP 147.2 [140.4 , 156.1] mmHg; rate of change of SBP 1.1 ± 0.3 mmHg/100 days

Bijsmans et al., (2015) JVIM 29:855–861

Development of hypertension over time

Cox’s proportional hazards ratio:0.2 (0.08 – 0.36) – P<0.001)

Bijsmans et al., (2015) JVIM 29:855–861

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Conclusions

• Cats with CKD are at a 2 to 3 fold higher risk of being hypertensive vs. healthy cats of similar age

• Normotensive CKD feline patients are 5 times more likely to develop a blood pressure where treatment is needed to prevent target organ damage than are healthy cats

• A pre-hypertensive stage could be proposed for cats with CKD (140-150 mmHg)

• Does starting antihypertensive interventions at an early stage prevent severe hypertension developing?

• What would this do to progression of CKD?

Antihypertensive treatment

For cats with SABP persistently above 160 mmHg or those with clinical evidence of HT

▪ amlodipine (0.125 – 0.5 mg/kg once daily) consistently lowers SABP by 15% or to <150 mm Hg in two thirds of cats treated (ESCAT study)

▪ Maintaining SBP <160 mmHg protects against retinal and CNS damage and is currently considered to be standard care

▪ Most human hypertensive patients would be managed on combination therapy; many do not reach target BP (target is lower than for the cat)

▪ Logical drugs to use in combination with amlodipine would be benazepril or telmisartan if:➢ Blood pressure remains above 160 mmHg on amlodipine➢ Proteinuria / borderline proteinuria persists on amlodipine

The use of mineralocorticoid receptor antagonists in hypertensive cats remains to be investigated

Mean (± SEM) SBP over time by treatment group –whole study period

Dose escalation from day 14:➢ amlodipine 54%➢ placebo 80%

Note! Placebo group switched to amlodipine on day 28

Moderate risk of TOD

Mean responder rate at Day 28

Responder = a decrease of SBP to < 150 mmHg or a SBP change from baseline of at least 15% from screening to D28

Dose of amlodipine required

• Why do some cats need 2x the dose to achieve the target blood pressure level on treatment?

• Possibilities:➢ Compliance issue➢ Pharmacokinetic difference (ADME)➢ Pharmacodynamic differences (channel affinity; cause of

hypertension more difficult to reverse)

• Measurement of blood concentrations of amlodipine at the point of blood pressure control might provide insights into this

Conclusions

• Cats that require a higher dose are more severely hypertensive

• Higher dose was associated with higher plasma concentrations• Difference in dose is unlikely to be due to individual pharmacokinetics• Owner compliance did not seem to play a role

• Direct relationship between drop in SBP and plasma concentration

• Cats with blood pressure >200 mmHg systolic might need to start on the higher dose of amlodipine?

Markers of target organ damage

• Increased NT-proBNP in human hypertensive patients with target organs damage (TOD)1

• Increased NT-proBNP with poor response to antihypertensive treatment2

• Hypertensive cats with TOD have significantly higher NT-proBNP concentrations than normotensive cats

1. Svensson et al., Blood Pressure, 20052. Welsh et al., Hypertension, 2014

Lalor et al., (2009) J Vet Cardiol; 11, S71-S79

Conclusions to biomarkers

• Show some promise in indicating severity of hypertension • Repeatability, sensitivity and specificity of biomarkers likely to be an

issue (combining biomarkers might be more effective)• Prospective studies with full assessment of target organs are

needed• Normalisation of NT-proBNP might help assess efficacy of

treatment – further prospective studies are necessary

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• Blood pressure increases with age in cats – increasing faster in cats with CKD

• The higher the blood pressure at diagnosis the greater the concentration of amlodpine required to lower the BP to current target level

• Use of biomarkers of cardiac and vascular stress in combination with proteinuria may help in diagnosis of hypertension and assessing the adequacy of treatment

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New findings influencing the management offeline hypertension

AcknowledgementsGraduate students:Hattie SymeRosanne JesponEsther Bisjmans

Veterinary Nurses:Elaine ReubensSam LakehalKim SouttarNicola Lötter

Funding:Waltham Centre for Pet NutritionPetPlan Chartiable TrustZoetis Ltd.