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Recent Advances in Hypertension Treatment

Recent Advances in Hypertension Treatment

Contents Current status in B-blockers

Combination therapy

New classes of antihypertensives

Recently published clinical trials and new concepts

– Accomplish

– Ontarget

– Hyvet

– Immunnotherapy; Vaccines

CURRENT STATUS IN B-BLOCKERS

-blockers vs. placebo or no treatment Outcomes

End pointEnd point-blocker-blocker

n/Nn/NPlaceboPlacebo

n/Nn/NRRRR

(95% CI)(95% CI)Test for Test for

heterogeneityheterogeneity

StrokeStroke 325/11025325/11025 518/16408518/16408 0.810.81(0.71-0.93)(0.71-0.93) p p = 0.23= 0.23

Myocardial Myocardial infarctioninfarction 413/11025413/11025 639/16408639/16408 0.930.93

(0.83-1.05)(0.83-1.05) p p = 0.85= 0.85

Mortality forMortality forall causesall causes 606/11025606/11025 932/16408932/16408 0.950.95

(0.86-1.04)(0.86-1.04) p = 0.13p = 0.13

Lindholm LH Lindholm LH et al.et al. Lancet 2005 Lancet 2005

-blockers vs. other drugs Outcomes

End pointEnd point-blocker-blocker

n/Nn/NOther drug Other drug

n/Nn/NRRRR

(95% CI)(95% CI)Test for Test for

heterogeneityheterogeneity

StrokeStroke 1650/519631650/51963 1594/538821594/53882 1.161.16(1.04-1.30)(1.04-1.30) p p = 0.02= 0.02

Myocardial Myocardial infarctioninfarction 1935/519631935/51963 2042/538822042/53882 1.021.02

(0.93-1.12)(0.93-1.12) p p = 0.04= 0.04

Mortality forMortality forall Causesall Causes 3525/520163525/52016 3766/539353766/53935 1.031.03

(0.99-1.08)(0.99-1.08) p = 0.20p = 0.20

Lindholm LH Lindholm LH et al.et al. Lancet 2005 Lancet 2005

Incident diabetes (long-term)Result (revised) of network meta-analysis of 22 clinical trials. Different drug classes

compared with diuretics

0.50 0.70 0.90 1.26

Odds ratio for incident diabetes

Elliot Lancet, 2007

0.62 (0.51-0.77) p<0.0001

0.67 (0.57-0.79) p<0.0001

0.75 (0.63-0.89) p=0.001

0.79 (0.67-0.92) p=0.004

0.93 (0.78-1.11) p=0.43

Referent

ARB

ACE inhibitor

Placebo

CCB

Beta-blocker

Diuretic

Treatment of newly diagnosed hypertension: NICE (UK)*

NICE, 2006

<55 yrs<55 yrs 55 yrsor black at any age

55 yrsor black at any age

A*A* C or DC or D

A* + C or A* + DA* + C or A* + D

A* + C + DA* + C + D

Consider 4th line Drug:• alpha-blocker• further diuretic therapy• beta-blocker

Consider seeking specialist advice

Consider 4th line Drug:• alpha-blocker• further diuretic therapy• beta-blocker

Consider seeking specialist advice

A=ACE inhibitor(* consider ARB if ACE-intolerant)

C=calcium channelblocker

D=thiazide-type diuretic

A=ACE inhibitor(* consider ARB if ACE-intolerant)

C=calcium channelblocker

D=thiazide-type diuretic

*National Institute for Health and Clinical Excellence (in the UK)

Strength of Evidence for the Use of BBs in CVD

COMBINATION THERAPY

- WHICH COMBINATION

IS BETTER

2007 ESH/ESC Guidelines Position Statement:

Monotherapy vs. Combination Therapy

Regardless of the drug employed, monotherapy allows to achieve BP target in only a limited number of hypertensive patients

Use of more than one agent is necessary to achieve target BP in the majority of patients.

Initial treatment can make use of monotherapy or combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed.

Monotherapy could be the initial treatment for a mild BP elevation with a low or moderate total CV risk. A combination of two drugs at low doses should be preferred as first step treatment when initial BP is in the grade 2 or 3 range or total CV risk is high or very high.

Fixed combination of two drugs can simplify treatment schedule and favour compliance.

2007 ESH/ESC Guidelines:

Possible Combinations

2003 ESH-ESC 2007 ESH-ESC

Blocker

α Blocker

ACE inhibitor

CCB

ARB

Thiazide diuretics

changes

CCB

ARB

Diuretics

Blocker

α Blocker

ACE inhibitor

2007 ESH/ESC Guidelines:

Fixed-Dose Combination

Limits the flexibility of upward and downward treatment strategies.

Reduces the number of tablets to be taken by the patient, and has some advantage for compliance to treatment.

Favors free combinationsFavors fixed-dose combinations Bangalore S et al. Am J Med. 2007:120;713

Avoiding Cardiovascular Events throughCombination Therapy in Patients Living with Systolic Hypertension

50% Obese

60% DM

67% Lipid-lowering agents (Mean LDL = 101.6 mg/dL)

63% Antiplatelet therapy

97% Treated previously for HT

74% Treated with ≥ 2 antihypertenive agents

78% ACEI or ARB

37.5% Controlled to <140/90 mmHg

ACCOMPLISH patients were receiving significant medical ACCOMPLISH patients were receiving significant medical management at baseline.management at baseline.

ACCOMPLISH will test a new strategy for the treatment of HT – the first outcomes trial to compare initial therapy with two different combinations.

ACCOMPLISH: Design

Jamerson KA et al. Am J Hypertens. 2003;16(part2)193A

*Beta blockers; alpha blockers; clonidine; (loop diuretics).*Beta blockers; alpha blockers; clonidine; (loop diuretics).

14 Days14 Days Day 1Day 1 Month 1Month 1 Month 2Month 2 Year 5Year 5

ScreeningScreening

Amlodipine 5 mg +Amlodipine 5 mg +benazepril 20 mgbenazepril 20 mg

Ran

do

miz

atio

nR

and

om

izat

ion

Benazepril 40 mg + Benazepril 40 mg + HCTZ 12.5 mgHCTZ 12.5 mg

Benazepril 40 mg + Benazepril 40 mg + HCTZ 25 mgHCTZ 25 mg

Free add-on Free add-on antihypertensive antihypertensive agents*agents*

Month 3Month 3

Free add-on Free add-on antihypertensive antihypertensive agents*agents*

Amlodipine 5 mg +Amlodipine 5 mg +benazepril 40 mgbenazepril 40 mg

Amlodipine 10 +Amlodipine 10 +benazepril 40 mgbenazepril 40 mg

Benazepril 20 mg + Benazepril 20 mg + HCTZ 12.5 mgHCTZ 12.5 mg

Titrated to achieve BP<140/90 mmHg; <130/80 mmHg in patients with diabetes or renal insufficiency

Age≥ 55 years

SBP≥160mmHg or current antiHT therapy

Evidence of CVD or renal disease or TOD

N=5741

N=5721

Systolic Blood Pressure Over Time

mm

Hg

Month

5731 5387 5206 4999 4804 4285 2520 10455709 5377 5154 4980 4831 4286 2594 1075

Patients

ACEI / HCTZN=5733

CCB / ACEIN=5713

*Mean values are taken at 30 months F/U visit

129.3 / 71.1 mmHg

130.0 / 72.8 mmHg

p<0.05

DBP: 71.1 DBP: 72.8

Baseline Control Rates37.2 37.9

ACEI / HCTZN=5733

Co

ntr

ol

rate

(%

)

CCB / ACEIN=5713

10

20

30

40

50

60

70

80

9078.5

81.7

P<0.001 at 30 months follow-up Control defined as <140/90 mmHg

ACCOMPLISH: Exceptional Control Rates

with Initial Combination Therapy

Kaplan Meier for Primary EndpointC

umul

ativ

e ev

ent

rate

HR (95% CI): 0.80 (0.72, 0.90)

20% Risk Reduction

Time to 1st CV morbidity/mortality (days)

p = 0

ACEI / HCTZ

CCB / ACEI650

526

.0002

0.5 1.0 2.0

Primary Endpoint and Components

Composite CV mortality/morbidity

Cardiovascular mortality

Non-fatal MI

Non-fatal stroke

Hospitalization for unstable angina

Coronary revascularization procedure

Hard CV endpoint

(CV death, non-fatal MI, non-fatal stroke)

(Intent-to-treat population)Risk Ratio

(95%)

Favors CCB / ACEI

Favors ACEI / HCTZ

0.80 (0.72–0.90)

0.81 (0.62-1.06)

0.81 (0.63-1.05)

0.87 (0.67-1.13)

0.74 (0.49-1.11)

0.85 (0.74-0.99)

0.80 (0.68-0.94)

ACCOMPLISH provide compelling evidence for initial combination therapy with ACEI / CCB and challenge current diuretic-based guidelines.

Capillary bed

Fluid leakage

Vasodilation with CCB

• BP reduction due to arterial vasodilation• Tendency towards edema due to absent venodilation• BP reduction stimulates RAS and increases angiotensin II level

Capillary bed

Complimentary with ACE-I

• Additional venodilation by ACE-I reduces edema• Blockade of RAS inhibits effects of angiotensin II, giving rise to additional BP reduction

NEW CLASSES OF ANTIHYPERTENSIVES

• Vasodilating beta-blockers - Carvedilol, celiprolol, nevibolol

• RAAS blocker - Direct renin Inhibitors : Aliskiren - Aminopeptidase A inhibitor - Chymase inhibitor : TPC-806 - Aldosterone blockers and aldosterone synthase inhibitor

• Endothelin receptor antagonists - Bosentan, darusentan, sitaxsentan, tezosentan

• Vasopeptidase inhibitors (ACE, NEP, ECE) - Omapatrilat, fasidrotril, sampatrilat, gemopatrilat

New Classes of Antihypertensive Drugs

Ang IV

Feedback Loop

AT1 Receptor

ReninAng I

Angiotensinogen

Ang II

Direct renin inhibitor(Aliskiren)

Biological effects

ACE

Non ACE pathways

PRA

Adapted from: Müller DN & Luft FC. 2006

Glomerularvasoconstriction

Inflammation Fibrosis

Kidney

Hypertrophy Fibrosis Vasoconstriction

Heart

Vasoconstriction

Brain

Hyperplasia hypertrophy Inflammation Oxidation Fibrosis

Vessels

Ang III

Aminopeptidase A

Renin-Angiotensin-Aldosterone SystemDirect renin inhibition acts at the point of activation of the Renin System and neutralizes the PRA rise

Chymase Inhibitor

Aliskiren monotherapy provides dose-dependent reductions in DBP and SBP

0

−15

−5

−20

−10

n=133n=129n=130n=127n=130

** *******

p=0.005

p=0.01

Placebo 150 300 600 150

*p<0.02 vs placebo; **p<0.005; ***p<0.0005 vs placebo Gradman AH, et al. 2005 (Study 2201)

n=133n=129n=130n=127n=130

***

******

***

Aliskiren (mg)

DBP SBP

Irbesartan(mg) Aliskiren (mg)

Irbesartan(mg)

Placebo 150 300 600 150

−6.3

−9.3

−11.8 −11.5

−8.9

−5.3

−11.4

−15.8 −15.7

−12.5

Mean change from baseline in mean sitting BP (mmHg)

Molecular Target : ACE2 and Angiotensin (1-7)

Ang (1-7) improve CO and antagonize Ang II-induced vasoconstriction

• Antagonism of AT1R

• Release of NO or other vasorelaxing factors (such as PGI2)

• Affecting other biologically active peptides (such as bradykinin)

RECENTLY PUBLISHED CLINICAL TRIALS

AccomplishOntargetHyvetImmunnotherapy; Vaccines

ONTARGET: The ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial

ONTARGET

Questions:

1.Is telmisartan “non-inferior” to ramipril?

2.Is the combination superior to ramipril?

Outcome:

1.Primary: CV death, MI, stroke, CHF hosp

2.Key secondary: CV death, MI, stroke (HOPE trial outcome)

Design:

Single blind run-in (n=29,018)

Randomized, double blind, double dummy study conducted in 733 centers in 41 countries (n=25,620)

56 months follow-up with 99.8% outcome ascertainment

Time to Primary Outcome

Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es

TelmisartanRamipril

0.0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

TelmisartanRamipril

# at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5

T 8542 8177 7778 7420 7051 4575R 8576 8214 7832 7472 7093 4562

ONTARGET

Rami

Telmi

ONTARGET Non-Inferiority Comparison

0.6 0.7 0.8 0.9 1.0 1.1 1.2 1.3 1.4

RR (95% CI)

Note that the outcomes are presented as point estimates with confidence intervals. The solid lineis the 95% CI representing 1.96 SD for each outcome

CV Death

MI

Stroke

CHF Hosp

All Death

Telmisartan better Ramipril better

Telmi Rami

Time to Primary Outcome

Years of Follow-up

Cum

ulat

ive

Haz

ard

Rat

es

0.0

0.05

0.10

0.15

0.20

0.25

0 1 2 3 4

RamiprilTel. & Ram.

# at Risk Yr 1 Yr 2 Yr 3 Yr 4 Yr 4.5

R 8576 8214 7832 7472 7093 4562T&R 8502 8133 7738 7375 7022 4467

ONTARGET

Telmi & Rami vs Rami

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Composite (p = 0.8522)

CV Death

MI

Stroke

CHF Hosp

Ramipril + Telmisartan better Ramipril better

RR (95% CI)

Note that the outcomes are presented as point estimates with confidence intervals. The solid lineis the 95% CI for each outcome

Efficacy Comparison ONTARGET

Telmi & Rami vs Rami

Renal Dysfunction Dialysis & Related Death

Ram

(n=8576)

%

Ram + Tel (n=8502)

%

Ram + Tel v Ram

RR (95% CI)

P value

Any renal dysfunction* 10.04 13.35 1.33 (1.22-1.45) <0.0001

Creatinine x 2 1.84 2.12 1.15 (0.93-1.42) 0.197

Potassium >5.5 mmol/L

3.32 5.67 1.71 (1.48-1.98) <0.0001

SAE renal failure 0.28 0.64 2.27 (1.40-3.67) 0.0006

Need for dialysis 0.55 0.78 1.42 (0.98-2.06) 0.066

Death after renal dysfunction

1.84 2.21 1.20 (0.97-1.48) 0.087

*local definition

Ontarget; Conclusions

1. Telmisartan is clearly “non-inferior” to ramipril

2. Telmisartan exhibits slightly superior tolerability

3. Telmi & Rami Combination therapy does not reduce the primary outcome to a greater extent compared to ramipril alone

Higher rates of adverse events:-hypotension related, including syncope-renal dysfunction, including dialysis

The HYpertension in the Very Elderly Trial

BP & The Very Elderly (Aged 80 or More)

Epidemiologic population studies suggest better survival with higher levels of blood pressure

Clinical trials recruited too few.

Meta-analysis (n=1670) (Gueyffier et al. 1997)

– 36% reduction in the risk of stroke (BENEFIT)

– 14% (p=0.05) increase in total mortality (RISK)

Hypertension in the Very Elderly Trial (HYVET) pilot results (n=1273) similar to meta-analysis (Bulpitt et al. 2003)

International, multi-centre, randomized double-blind placebo controlled

Inclusion Criteria: Exclusion Criteria:Aged 80 or more Standing SBP < 140mmHgSystolic BP 160 -199mmHg Stroke in last 6 monthsDiastolic BP <110 mmHg Dementia / Need daily nursing care

Primary Endpoint: All strokes (fatal and non-fatal)

Target BP 150/80 mmHg

Placebo Active (n=1912) (n=1933)

Age 83.5 yrs 83.6 yrs

Female 60.3% 60.7%

BP 173.0/90.8 173.0/90.8

ISH 32.6% 32.3%

CVD 12.0% 11.5%

Stroke 6.9% 6.7%

HF 2.9% 2.9%

Anti-HT 65.1% 64.2%

70

80

90

100

110

120

130

140

150

160

170

180

0 1 2 3 4 5

Follow-up (years)

Blo

od P

ress

ure

(mm

Hg)

Placebo

Indapamide SR +/- perindopril Median follow-up 1.8 years

15 mmHg

6 mmHg

Blood Pressure Separation Over TimeBlood Pressure Separation Over Time

0 20.50.2

HR 95% CI

0.70 (0.49-1.01)

0.61 (0.38-0.99)

0.79 (0.65-0.95)

0.81 (0.62-1.06)

0.77 (0.60-1.01)

0.71 (0.42-1.19)

0.36 (0.22-0.58)

0.66 (0.53-0.82)

All Stroke

Stroke Death

All cause mortality

NCV/Unknown death

CV Death

Cardiac Death

Heart Failure

CV events

Primary Endpoint and Components(Intent-to-treat population)

Vaccine for Hypertension

• Key factors affecting adherence

- Presence of side effects

- Concerns over taking long-term medication in the absence of symptoms

• Active immunization to induce antibodies against angiotensin II

- A few injections per year

• Age : 18-65 years

• Mild-to-moderate HT - Supine BP(WHO criteria) 140-179/90-109mmHg

• Vaccination schedule - SC injection - 0, 4, and 12 weeks

• Phase IIa study - Safety and tolerability

Summary of Adverse Events

HR,12-lead ECG data, and laboratory indices were unchanged.

• IgG antibody titers are expressed as geometric mean titers±SE.

• Concentration of immune complexes containing C1, C3, and C3a and the population of activated T cells did not show any changes.

Average half-life : 3.2 wks (95% CI 2.8–3.7, n=43)

Average half-life : 17 wks (95% CI 15–19, n=42)

Profile of IgG Antibody Titers Against Angiotensin II

Change from Baseline in Ambulatory BP

100 μg 300 μg

Placebo AngQb Placebo AngQb (n=12) (n=22) (n=12) (n=21)

SBP day –3.4±2.3 –1.5±1.7 3.4±2.8 –5.5±2.1*

DBP day –1.6±1.8 0.0±1.3 1.1±1.7 –2.9±1.2†

SBP night –2.6±3.2 1.1±2.3 –2.5±4.0 –1.2±3.0

DBP night 1.7±2.0 1.3±1.5 –1.8±2.3 –0.8±1.7

• In the 300 μg group, there was a reduction from baseline in mean daytime ABP at week 14 by -9.0/-4.0 mmHg compared with placebo (p=0.015 for SBP and 0.064 for DBP).

• Change from supine to standing position did not lead to orthostatic HoT.

• Significant increase in mean renin from baseline at week 14 in the 300 μg group (from 5.1 to 6.3 pg/mL, p=0·02) : Coincident with BP reduction

Effects on Early Morning BP Surge

Profiles of mean hourly ABP measurements of the 300 μg AngQb(n=21) and corresponding placebo group(n=12) at week 14. BP surge between 5AM and 8AM was reduced compared with placebo (p=0.012 and p=0.036, respectively; BP change at 8AM was –25/–13 mmHg, p<0.005)

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