State of the art treatment

of hypertension:

established and

new drugs

Prof. M. BurnierService of Nephrology and HypertensionLausanne, Switzerland

ACE inhibitorsAT1-receptor blockers Calcium antagonists

Diureticsß-blockers

Adapted from the 2009 Reappraisal of ESH/ESC Hypertension Guidelines

First-line therapies

First line therapies in hypertension

Law et al, BMJ 2003

Standard

dose

Twice

standard

dose

Half

standard

dose

-blockers

ACE inhibitors

Thiazides

Calcium antagonists

AT1-receptor blockers

0

-5

-10

-15

Ch

an

ge

s in

SB

P, m

mH

g

Placebo-corrected changes in SBP

Law et al, BMJ 2003

Pe

rce

nta

ge

of p

atie

nts

with

AE

Standard

dose

Twice

standard

dose

Half

standard

dose

-blockers

ACE inhibitors

Thiazides

Calcium antagonists

AT1-receptor blockers

20

15

10

5

0

-5

N° of trials :

59

96

62

9644

Isolated systolic hypertension

Hypertension in blacks

Angina pectoris

Post-myocardial infarction

Left ventricular hypertrophy

Atrial fibrillation

Heart failure

Carotid/coronary atherosclerosis

Metabolic syndrome

Non diabetic nephropathy

Diabetic nephropathy

Proteinuria/microalbuminuria

Blockers of the RAS

Dihydropyridines

Thiazides

Adapted from ESH/ESC Hypertension Guidelines

Baseline Control Rates

37.2 37.9

ACCOMPLISH: Exceptional Control Rates

with Initial Combination Therapy

ACEI / HCTZN=5733

Co

ntr

ol r

ate

(%

)

CCB / ACEIN=5713

10

20

30

40

50

60

70

80

90

78.581.7

P<0.001 at 30 months follow-up

Control defined as <140/90 mmHg

One topic of debate: ACEI or ARB ?

Arguments regarding:

Impact on morbidity and mortality

Tolerability profile and risk of SAE

ONTARGETRamipril vs Telmisartan

Time to Primary Outcome

Years of Follow-up

Cu

mu

lative

Ha

za

rd R

ate

s

0.0

0.0

50

.10

0.1

50

.20

0.2

5

0 1 2 3 4

Telmisartan

Ramipril

# 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

N Engl JMed 2008;358:1547-59

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 line

is the 95% CI representing 1.96 SD for each outcome

CV Death

MI

Stroke

CHF Hosp

All Death

Telmisartan better Ramipril better

ONTARGET

N Engl JMed 2008;358:1547-59

Angiotensin receptor blockers and all cause mortality,

stratified by comparison group (placebo v active treatment).

Bangalore S et al. BMJ 2011;342:bmj.d2234

Angiotensin receptor blockers and myocardial infarction,

stratified by comparison group (placebo v active treatment).

Bangalore S et al. BMJ 2011;342:bmj.d2234

Angiotensin receptor blockers and stroke,

stratified by comparison group (placebo v active treatment).

Bangalore S et al. BMJ 2011;342:bmj.d2234

ONTARGETReasons for Permanently

Stopping Study Medications

Ram

N=8576

Tel

N=8542

Tel vs. Ram

RR P

Hypotension 149 224 1.51 0.0001

Syncope 15 18 1.20 0.593

Cough 359 93 0.26 <0.0001

Diarrhea 12 19 1.59 0.20

Angioedema 25 10 0.40 0.0115

Renal

Impairment

59 68 1.16 0.41

Any

Discontinuation

2098 1962 0.94 0.02

N Engl JMed 2008;358:1547-59

Risk of angioedema : ARBs vs ACEIs

Makani et al, Am J Cardiol 2012; 110:383

Incidence of angioedema is higher in patients with heart failure

Losartan

Eprosartan

Telmisartan

Irbesartan

Candesartan

Valsartan

Olmesartan

0 2 6 10 124 8

Standardised discontinuation rate(100 patients/month)

ARBs

Captopril

Moexipril

Spirapril

Fosinopril

Quinapril

Benazepril

Trandolapril

Delapril

Cilazapril

Lisinopril

Enalapril

Perindopril

Zofenopril

Ramipril

0 10 20 30 40

Standardised discontinuation rate(100 patients/month)

ACEIs

The importance of tolerability is reflected by within-class differences in discontinuation rates

Mancia et al. J Hypertens 2011;29:1012-1018.

Another question: which calcium antagonist ?

ACCOMPLISH: RAS-blocker/CCB combined

therapy offers benefits in higher-risk patients

20% lower

The primary cardiovascular composite end point was significantly lower with an ACEI/CCB than an ACEI/diuretic combination

Jamerson et al. N Engl J Med 2008;359:2417-28

16

14

12

10

8

6

4

2

0

Pati

ents

wit

h p

rim

ary

even

ts (

%)

No. at risk:

Benazepril / AML

Benazepril / HCTZ

Benazepril plus hydrocholorthiazide

Benazepril plus amlodipine

0 6 12 18 24 30 36 42Months

5512 5317 5141 4959 4739 2826 1447

5483 5274 5082 4892 4655 2749 1390

Incidence of adverse responses to different

classes of drugs as reported by physicians

0

5

10

15

20

25

Diur ß-block CCB ACEi Alpha-

block

other

E.Ambrosioni et al, J Hypertens ;18 , 2000

%

**

Adherence to cardiovascular drugs in primary prevention

Naderi et al, The American Journal of Medicine (2012) 125, 882-887

Peripheral edema:

Adverse events in the VALUE trial

Valsartan

(n=7622)

Amlodipine

(n=7576)P

Pre-specified adverse events

Peripheral edema 1135 (14.9%) 2492 (32.9%) <0.0001

Dizziness 1257 (16.5%) 1083 (14.3%) <0.0001

Headache 1120 (14.7%) 947 (12.5%) <0.0001

Fatigue 739 (9.7%) 674 (8.9%) 0.0750

Additional common adverse events

Diarrhea* 670 (8.8%) 515 (6.8%) <0.0001

Edema other* 243 (3.2%) 462 (6.1%) <0.0001

Hypokaliemia* 266 (3.5%) 469 (6.2%) <0.0001

*With an incidence >3% and a difference between treatment groups >1%

Julius et al. Lancet. 2004;363:2022-2031.

Adverse events in the ASCOT trial

Adverse event*

Amlodipine

perindopril

n (%)

Atenolol

thiazide

n (%)

p-value

Bradycardia 34 (0.4) 536 (6) <0.0001

Chest pain 740 (8) 849 (9) 0.0040

Cough 1859 (19) 782 (8) <0.0001

Diarrhoea 377 (4) 548 (6) <0.0001

Dizziness 1183 (12) 1555 (16) <0.0001

Dyspnoea 599 (6) 987 (10) <0.0001

Eczema 493 (5) 383 (4) 0.0002

Erectile

dysfunction556 (6) 707 (7) <0.0001

Fatigue 782 (8) 1556 (16) <0.0001

Joint swelling 1371 (14) 308 (3) <0.0001

Lethargy 202 (2) 525 (6) <0.0001

Oedema peripheral 2188 (23) 588 (6) <0.0001

Peripheral coldness 81 (1) 579 (6) <0.0001

Vertigo 642 (7) 745 (8) 0.0039

37 % of edema

PREVALENCE OF DRUG-SPECIFIC AE’s IN THE

LERCANIDIPINE CHALLENGE STUDY.

96

52

87

0

20

40

60

80

100

CCB Lercanidipine CCB

yesno

% p

atie

nts

wit

h

S.E

.s

P<0.001

P<0.001

Ankle edema

Borghi C et al, Blood Pressure, 2003

% o

f pa

tient

s

02468

101214161820

Baseline 1 month 2 months 3 months 6 months End of

study

Lercanidipine

Amlodipine

Lacidipine

% OF PTS WITH ANKLE EDEMA OVER TIME

COHORT Study, Am J Hypertens, 2002

P<0.001

Initiation

(n=683)

Add-on

(n=844)

Substitution

(n=672)

Premature treatment

interruption due to

adverse events4.4 7.8 8.8

Ankle edema

Headache

Flush

Others

0.6

0.6

0.4

2.8

1.9

1.1

1.3

3.8

3.0

1.1

0.6

4.3

Impact of lercanidipine on peripheral edema in 2199 patients

followed by GPs in Switzerland

Burnier and Gasser, 2007

Last question: which diuretic ?

Hydrochlorothiazide

Chlorthalidone

Indapamide

Dose-response relationships for thiazides vs BP (A and B)

(C) serum potassium; and (D) serum urate.

Peterzan M A et al. Hypertension 2012;59:1104-1109

Risk of cardiovascular events in patients receiving HCTZ or chlorthalidone

according to the changes in systolic BP

Roush G C et al. Hypertension 2012;59:1110-1117

Antihypertensive Efficacy of Hydrochlorothiazide vs ChlorthalidoneCombined with Azilsartan Medoxomil

Bakris et al, The American Journal of Medicine 2012, 125; p1229.e1-e10

Cushman W C et al. Hypertension 2012;60:310-318

Azilsartan + CLD vs olmesartan + HCTZ

Change in systolic blood pressure by ABPM at week 12.

Cushman W C et al. Hypertension 2012;60:310-318

Over one year, compliance and persistence with

anti-hypertensive therapy typically falls to <50%

Vrijens et al. BMJ 2008;336:1114-7.

• Study of hypertensive patients in clinical studies

• 4783 patients in 21 Phase IV trials

• Evaluated by medication event monitoring system

Fall in persistencebecause of discontinuation of treatment

Fall in adherencebecause of

poor execution of dosing regimen

100

90

80

70

60

50

00 50 100 150 200 250 300 350

Time (days)

3108 980 828 618 474 400 331No of patientsremaining in study

Pe

rce

nta

ge o

f p

atie

nts

PersistenceAdherence/compliancePerfect adherence

Adherence to cardiovascular drugs

Naderi et al, The American Journal of Medicine (2012) 125, 882-887