Transcript Hypertension

Hypertension combination
therapy (ACEIs combine CCBs)
聯合醫院忠孝院區
翁紹恩藥師
Outline







Hypertension
JNC 7 (AllHAT trials)
ACEIs CCBs Combine therapy (BP effect)
ACEIs CCBs Vs Beta blockers Thiazides
ACCOMPLISH trials
Discussion
Conclusion
Hypertension


Hypertension: High blood pressure,
defined as a repeatedly elevated SBP,DBP,
or both.
The JNC 7 classification includes normal
BP, prehypertension, stage 1 hypertension,
and stage 2 hypertension.
CVD Risk Factors
 Hypertension*
 Cigarette smoking
 Obesity* (BMI >30 kg/m2)
 Physical inactivity
 Dyslipidemia*
 Diabetes mellitus*
 Microalbuminuria or estimated GFR <60 ml/min
 Age (older than 55 for men, 65 for women)
 Family history of premature CVD
(men
under age
55metabolic
or women
under age 65)
*Components
of the
syndrome.
Classification of hypertension
(JNC 7)
Classification
SBP
(mmHg)
DBP
(mmHg)
＜120
And
＜80
prehypertension
120∼139
Or
80∼89
stage 1 hypertension
140∼159
Or
90∼99
stage 2 hypertension
≧160
Or
≧100
Normal
ESH/ESC 2007 Classification of
hypertension
The term “added” risk indicates that risk is higher than average in patients with compelling
indications – patients with normal BP and established CV or renal disease are at very high added
risk
--- Defines the cut-off for initiating pharmaceutical treatment; for
patients to the right, treatment benefits outweigh the risk of side-effects
ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187
Recommended BP goals (ESH/ESC 2007)


<140/90 mm Hg in all patients with
hypertension
<130/80 mm Hg in patients with diabetes
mellitus and patients with high added risk,
with compelling diseases - stroke,
myocardial infarction (MI), renal
dysfunction or proteinuria
ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187
Treatment guidelines (ESH/ESC
2007)
Average risk
Low added risk
Moderate added risk
High added risk
ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187
Very high added risk
NICE
Lessons from recent large trials
in hypertension



Blood pressure (BP) control helps avoid
cardiovascular (CV) events and the closer BP is
to target, the better the outcome: a difference of
a few mm of Hg can impact on CV events
The earlier that BP control is achieved, the
better the outcome most cases, combinations
are needed to achieve BP control as early as
possible
Antihypertensive therapy can impact on the
metabolic status of patients
Lower BP is associated with
decreased risk of CV events
Stroke and diastolic BP (DBP)
7 prospective observational studies:
843 stroke events
Coronary heart disease (CHD) and DBP
9 prospective observational studies:
4856 CHD events
2.00
1.00
0.50
0.25
0
Category 1
2
3
4
5
mm Hg 76 84 91 98 105
Adapted from Whelton PK. Lancet 1994; 344: 101–106
4.00
Relative risk of CHD
Relative risk of stroke
4.00
2.00
1.00
0.50
0.25
0
Category 1
2
3
4
5
mm Hg 76 84 91 98 105
The JNC 7



(1) In persons older than 50 years, systolic blood pressure
BP) of more than 140 mm Hg is a much more important
cardiovascular disease (CVD) risk factor than diastolic BP
(2) The risk of CVD, beginning at 115/75 mm Hg, doubles
with each increment of 20/10 mm Hg; individuals who are
normotensive at 55 years of age have a 90% lifetime risk
for developing hypertension;
(3) Individuals with a systolic BP of 120 to 139 mm Hg or
a diastolic BP of 80 to 89 mm Hg should be considered as
prehypertensive and require health-promoting lifestyle
modifications to prevent CVD
The JNC 7

(4) Thiazide-type diuretics should be used
in drug treatment for most patients with
uncomplicated hypertension, either alone or
combined with drugs from other classes.
Certain high-risk conditions are compelling
indications for the initial use of other
antihypertensive drug classes (angiotensinconverting enzyme inhibitors, angiotensinreceptor blockers, -blockers,calcium
channel blockers)
The JNC 7


(5) Most patients with hypertension will
require 2 or more antihypertensive
medications to achieve goal BP (140/90 mm
Hg, or 130/80 mm Hg for patients with
diabetes or chronic kidney disease)
(6) If BP is more than 20/10 mm Hg above
goal BP, consideration should be given to
initiating therapy with 2 agents, 1 of which
usually should be a thiazide-type diuretic
With Compelling
Indications
Classification of antihypertension
drugs







Diuretics
Beta-blockers
Angiotensin-converting enzyme inhibitors, ACEI
Angiotensin II receptor blockers , ARBs
Calcium channel blockers ,
α blockers
Direct vasodilators
Compelling Indications for
Individual Drug Classes
Compelling Indication
Initial Therapy Options
Clinical Trial Basis
Heart failure
THIAZ, BB, ACEI, ARB,
ALDO ANT
ACC/AHA Heart Failure
Guideline, MERIT-HF,
COPERNICUS, CIBIS,
SOLVD, AIRE, TRACE,
ValHEFT, RALES
Postmyocardial
infarction
BB, ACEI, ALDO ANT
ACC/AHA Post-MI
Guideline, BHAT, SAVE,
Capricorn, EPHESUS
High CAD risk
THIAZ, BB, ACE, CCB
ALLHAT, HOPE, ANBP2,
LIFE, CONVINCE
Compelling Indications for
Individual Drug Classes
Compelling Indication
Initial Therapy Options
Clinical Trial Basis
Diabetes
THIAZ, BB, ACE, ARB, CCB
NKF-ADA Guideline,
UKPDS, ALLHAT
Chronic kidney disease
ACEI, ARB
NKF Guideline, Captopril
Trial, RENAAL, IDNT,
REIN, AASK
Recurrent stroke prevention
THIAZ, ACEI
PROGRESS
Possible combinations of different
classes of antihypertensive agents
Diuretics
β-blockers
AT1-receptor
blockers
α-blockers
CCBs
ACE, angiotensin-converting enzyme
AT, angiotensin
CCB, calcium-channel blocker
ACE inhibitors
The preferred combinations in general hypertensive population are represented
as thick lines. The frames indicate classes of agents proven to be beneficial
in controlled interventional trials
ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187
Multiple antihypertensive agents are often
needed to achieve target BP
Average number of antihypertensive agents
Trial
Target BP (mm Hg)
UKPDS
DBP<85
ABCD
DBP<75
MDRD
MAP<92
HOT
DBP<80
AASK
MAP<92
IDNT
SBP/DBP 135/85
1
2
3
4
ALLHAT trials
ALLHAT trials

Setting and Participants
A total of 33357 participants aged 55 years
or older with hypertension and at least 1
other CHD risk factor.
ALLHAT trials

Interventions
Participants were randomly assigned to
receive
Chlorthalidone, 12.5 to 25 mg/d (n=15255)
Amlodipine, 2.5 to 10 mg/d (n=9048)
Lisinopril, 10 to 40 mg/d (n=9054)
planned follow-up of approximately 4 to 8
years.
ALLHAT trials

Main Outcome Measures
The primary outcome was combined fatal CHD
or nonfatal myocardial infarction
Secondary outcomes were all cause mortality,
stroke, combined CHD (primary outcome,
coronary revascularization,or angina with
hospitalization), and combined CVD (combined
CHD, stroke, treated angina without
hospitalization, heart failure
Thiazide類的表現與Amlodipine lisinopril無太大差異
ALLHAT trials

Conclusion
Thiazide-type diuretics are superior in
preventing 1 or more major forms of CVD
and are less expensive. They should be
preferred for first-step antihypertensive
therapy.
ACEIs Combine CCBs



Better Compliance
Less adverse events
Synergistic effect
Poor Compliance and Persistence
with Antihypertensive Treatment
時間越久病患的順從度越差
Better Compliance with Antihypertensive
Drugs Leads to
a Lower Risk of Hospitalization
鈣離子通道阻斷劑/腎素血管收縮素系統抑
制劑的互補療效：減低與CCB有關的水腫
Adverse events
增加Amlodipine劑量的水腫不良反應
ACEIs
ACEIs Combine CCBs


ACE inhibitors and dihydropyridine
calcium channel blockers each exhibit
vascular protective effects.
ACE inhibitors and CCBs each stimulate
nitric oxide production appears to produce a
synergistic effect
PICO
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P:Hypertension
I:ACEIs combine CCBs
C:Placebo
O:Cardiovascular disease
Outline
Combine therapy (BP effect)
 Two trials

ACEIs and CCBs
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Randomised, double-blind, placebocontrolled, parallel-group, multicentre trial.
Treatment with
amlodipine 5 mg/benazepril 10 mg
amlodipine 5 mg
benazepril 10 mg, or placebo for 8 weeks.
ACEIs and CCBs
BP
Goal
Ramipril–felodipine
– antihypertensive efficacy
Ramipril/Felodipine Ramipril
5 mg/5 mg
10 mg
0
-2
-4
-6
-8
-10
**
-12
**
-14
Felodipine
9 mg
**p<0.001
**
-16
Effect of ramipril plus felodipine on SBP in patients with hypertension
Ramipril–felodipine 5 mg/5 mg, ramipril 10 mg and felodipine 9 mg groups all had a
significant reduction from baseline in median SBP at study endpoint
43
Adapted from Cvetković R and Plosker G. Drugs 2005; 65: 1851–1868; Herlitz H et al. Nephrol Dial Transplant 2001; 16: 2158–2165
BP reduction
Mean change in DBP
(mm Hg)
Ramipril
2.5 mg


Ramipril/
Felodipine
2.5 mg/2.5 mg
0
-5
-10
-9.8
-15
*
-20

Felodipine
2.5 mg
-9.1
*
-11.4
*
**
*p<0.0001 vs. baseline
**p=0.02 for fixed-dose combination vs. felodipine monotherapy
Patients with hypertension; intention-to-treat population
Poisson P et al. Curr Med Res Opin 1996; 14: 445–456
Responder rate (%)
Responder rate compared with
monotherapy
*
100
**
71.4
80
60
41.2
40
28.6
20
0
Ramipril
2.5 mg
Felodipine
2.5 mg
Ramipril/
Felodipine
2.5 mg/2.5 mg
*p<0.0001 for fixed-dose combination vs. ramipril monotherapy
**p=0.0035 for fixed-dose combination vs. felodipine monotherapy
Responder = BP <140/90 mm Hg or a reduction in BP of >15/10 mm Hg
Scholze J et al. Int J Clin Pract 2006; 60: 265–274
Adverse event


All treatment regimens were well tolerated
Peripheral oedema was less frequent with combination therapy than
with felodipine monotherapy
Patients (%)
Adverse event
(AE)
Felodipine
n=213
Ramipril
n=213
Ramipril–
Felodipine
n=216
Headache
3.8
2.3
4.6
Cough
0.9
3.3
4.6
Vasodilatation
3.3
1.9
3.7
Peripheral oedema
3.8
0.9
1.9
Poisson P et al. Curr Med Res Opin 1996; 14: 445–456
Summary



Achieve ‘’Goal BP’’ easier
Better Compliance
Adverse events was less frequent with
combination therapy than monotherapy
Outline
Combine ACEIs CCBs Vs Beta
Blockers Thiazides
 Two trials

1.7%
1.2%
Moderate risk patients
兩邊並無太大
差異
ACEIs CCBs能更快達到Goal Bp
ASCOT
Primary
Non-fatal MI (inc. silent) + fatal CHD
Unadjusted hazard ratio
0.90; p=0.1052
Secondary
Non-fatal MI (exc. silent) + fatal CHD
NNT=100
Total coronary endpoint
Total CV event and proceduresNNT=33
All-cause mortality
NNT=100
CV mortality
NNT=100
Fatal and non-fatal stroke
NNT=100
Fatal and non-fatal heart failure
0.50
0.87; p=0.0458
0.87; p=0.0070
0.84; p<0.0001
0.89; p=0.0247
0.76; p=0.0010
0.77; p=0.0003
0.84; p=0.1257
0.70
CCB  ACE inhibitor better
1.00
1.45
2.00
β-blocker  diuretic better
Area of square is proportional to the amount of statistical information available
Reprinted from The Lancet, 366, Dahlof B et al., 895–906, copyright (2005), with permission from Elsevier
ASCOT
Tertiary
Silent MI
Unstable angina
Chronic stable angina
Peripheral arterial disease
Life-threatening arrhythmias
New-onset type 2 diabetes
New-onset renal impairment
Unadjusted hazard ratio
1.27; p=0.3089
0.68; p=0.0115
0.98; p=0.8323
0.65; p=0.0001
1.07; p=0.8009
0.70; p<0.0001
0.85; p=0.0187
Post-hoc
Primary endpoint + coronary
revascularisation procedures
CV death + MI + stroke
0.50
0.86; p=0.0058
0.84; p=0.0003
0.70
CCB  ACE inhibitor better
1.00
1.45
2.00
β-blocker  diuretic better
Area of square is proportional to the amount of statistical information available
Reprinted from The Lancet, 366, Dahlof B et al., 895–906, copyright (2005), with permission from Elsevier
ASCOT

Amlodipine based VS Atenolol besed
Higher mean pulse rate (P<0.001)
Higher HDL-Cholseterol (0.1mmol/L
p<0.001)
Lower BMI, Triglycerides, serum
creatinine, and glucose
No differences LDL, total-cholesterol
ASCOT adverse events
NNH=9
NNH=9
NNH=6
ASCOT conclusions

Antihypertensive therapy based on an ACE
inhibitor and CCB resulted in a 16%
reduction of CV events (NNT=33) and a
30% reduction of new onset of type 2
diabetes (p<0.0001) compared with βblockers and diuretics.
INVEST



Randomized, open label, blinded end point study
of 22576 hypertensive CAD patients aged 50
years or older
Patients were randomly assigned to either
CAS(verapamil sustained release) or NCAS
(atenolol)
The primary outcome was the first occurrence of
death (all-cause), nonfatal MI, or nonfatal stroke
INVEST


The verapamil-trandolapril–based strategy was as
clinically effective as the atenololhydrochlorothiazide–based strategy in
hypertensive CAD patients
CAS group 569 (7.03%) were diagnosed as having
diabetes during follow-up. NCAS group 665
(8.23%) were diagnosed as having diabetes during
follow-up (RR, 0.85; 95% CI, 0.77-0.95).
Summary



BP (ASCOT vs INVEST)
CV events (ASCOT vs INVEST)
Diabetes
Background



The optimal combination drug therapy for
hypertension is not established.
Current U.S. guidelines recommend inclusion of a
diuretic.
We hypothesized that treatment with the
combination of an angiotensin-converting–enzyme
(ACE) inhibitor and a dihydropyridine calciumchannel blocker would be more effective in
reducing the rate of cardiovascular events than
treatment with an ACE inhibitor plus a thiazide
diuretic.
Methods



Multicenter
Double-blind
Randomized control trials
Patients

The broad definition of such patients is that
they are 60 years of age, with a systolic BP
160 mm Hg or currently on
antihypertensive therapy, and in addition
have evidence of cardiovascular or renal
disease or target organ damage.
Inclusion Criteria


Beyond the age and BP criteria already
defined, patients must have evidence of at
least one of cardiovascular diseases or target
organ damage
Patients aged 55 to 59 years are eligible if
they have evidence of two or more of the
cardiovascular diseases or target organ
damage
Exclusion Criteria




Current evidence for angina pectoris
A history of symptomatic heart failure
myocardial infarction, other acute
coronary syndromes, within 1 month
hypertension that is excessively severe
Stroke within 3 months
Procedures
Patients were randomly assigned two treatment
 The
addition of other antihypertensive agents was
groups
permitted
(excluding any calcium-channel blockers,
 Combination of 20 mg of benazepril and 5 mg of
any ACE
inhibitors,
angiotensin II–receptor
amlodipine,
onceany
daily.
blockers, and any thiazide diuretics but including
 Combination of 20 mg of benazepril and 12.5 mg
beta-blockers,
alpha-blockers, clonidine, and
of hydrochlorothiazide, once daily.
spironolactone).
(Benazepril
can
increase
to
40
mg
daily)
 Loop diuretics taken once daily were permitted
(Amlodipine
dose to 10 mg daily)
for volume
management.
(Hydrochlorothiazide dose to 25 mg daily)

Procedures

Blood pressures were recorded as the
average of three readings taken at 2-minute
intervals after the patient had remained in a
seated position for 5 minutes.
End points
Thefrom
primary
end point
waswas
measured
cardiovascular
causes
defined as aas
death
sudden
from
cardiacwas
causes,
theattributed
time to to
the
firstdeath
event
(which
myocardial
stroke, coronary
defined infarction,
as the composite
of a intervention,
congestive
heart failure,
or other
cardiovascular
event
andcardiovascular
death from
causes.
cardiovascular causes)
Death
Cardiovascular event was defined as a nonfatal
myocardial infarction, stroke, hospitalization for
unstable angina, coronary revascularization, or
resuscitation after sudden cardiac arrest.
兩邊情況皆相似
Systolic Blood Pressure Over Time
150
ACEI / HCTZ
145
N=5733
CCB / ACEI
N=5713
mm Hg
140
135
130mmHg
130
Difference of 0.7 mmHg p<0.05*
129.3 mmHg
125
Month
Patients
0
6
12
18
24
30
36
5731
5709
5387
5377
5206
5154
4999
4980
4804
4831
4285
4286
2520
2594
42
1045
1075
*Mean values are taken at 30 months F/U visit
DBP: 71.1
DBP: 72.8
Presented at ACC 2008.
http//www.cardiosource.com/iamerson-accomplish.ppt
Exceptional Control Rates with
Initial Combination Therapy
90
Control rate (%)
80
78.5
81.7
70
60
50
40
30
Baseline
Control Rates
37.2
37.9
ACEI / HCTZ
CCB / ACEI
N=5733
N=5713
20
10
P<0.001 at 30 months follow-up
Control defined as <140/90 mmHg
Presented at ACC 2008.
http//www.cardiosource.com/iamerson-accomplish.ppt
NNT=45
NNT=166
NNT=111
Summary

Single tablet combination therapy was initiated in
11,462 high risk hypertensive patients

After mean follow-up of 39 months, The
combination of ACEI / CCB was superior to ACEI /
diuretic CV morbidity / mortality was reduced by
20% (p=0.0002) in patients with high risks
Discussion





Patients all > 65
No Asian
High risk Hypertension
Diabetes mellitus > 60%
Other antihypertensive drugs use >97%
Discussion








No Durgs wash-out period.
Exclusion angina
Blood Pressure measure way.
Chlorthalidone vs Hydrochlorothiazide
Hypokalemia
Outcome
Edema (Loop diuretics use)
Sponsor
The HOT study



18,790 patients with hypertension and DBP
between 100 and 115 mm Hg (mean 105
mm Hg)
Felodipine as baseline treatment. Average
follow up was 3.8 years
Randomly allocated to one of the three DBP
target groups: ≤90 ≤85 ≤80 mm Hg
The HOT study
30
25
p=0.005 for
24.4 p=0.005 for trend
–51%
18.6
18.6
20
15
11.9
11.9
10
5
0
≤90
≤85
DBP
(mm Hg)
Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762
≤80
The HOT study
16
14
12
p=0.016
trend
p=0.016
forfortrend
–67%
11.2
11.1
11.2
10
8
6
3.7
3.7
4
2
0
≤90
≤85
DBP
(mm Hg)
Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762
≤80
The HOT study
40
35
30
35 p=0.046
for trend
p=0.046
for
–43%
30
30
25
20
20
20
15
10
5
0
≤90
≤85
DBP
(mm Hg)
Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762
≤80
Lower BP is associated with
decreased risk of CV events
Stroke and diastolic BP (DBP)
7 prospective observational studies:
843 stroke events
Coronary heart disease (CHD) and DBP
9 prospective observational studies:
4856 CHD events
2.00
1.00
0.50
0.25
0
Category 1
2
3
4
5
mm Hg 76 84 91 98 105
Adapted from Whelton PK. Lancet 1994; 344: 101–106
4.00
Relative risk of CHD
Relative risk of stroke
4.00
2.00
1.00
0.50
0.25
0
Category 1
2
3
4
5
mm Hg 76 84 91 98 105
Discussion


Hot Vs Accomplish trials
Low bp effect vs Drugs effect
衛生署指定適應症

高血壓 vs 高危險病人之高血壓
Conclusion





Better compliance
Better BP control
CV event (Combine therapy)
Diabetes
First line combine therapy
Conclusion

現今高血壓用藥的複方產品越來越多，但哪種
併用方法為第一線使用仍屬未知，但新的JNC
8透露出，應屏除第一線第二線的用藥觀念，
而是以保護病患器官傷害為優先的治療方式，
未來也會有更多新的藥品，像是FDA剛核准的
Aliskeren併用Valsartan這種併用方式，將來該
如何使用，何種時機要使用，都是需要更多的
實驗來證明的，但只要是對病患健康有幫助的，
就不失為一個好方式。