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 55 or women under age 65)*Components of the metabolic syndrome.

Classification of hypertension(JNC 7)

ClassificationSBP

(mmHg)

DBP

(mmHg)

Normal ＜ 120 And ＜ 80

prehypertension 120 139 ∼ Or 80 89∼

stage 1 hypertension 140 159∼ Or 90 99∼

stage 2 hypertension ≧160 Or ≧100

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 Very high added risk

ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

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

0

4.00

0.250.50

1.00

2.00

Categorymm Hg

176

284

391

498

5105

Rel

ativ

e ris

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CH

D

0

4.00

0.250.50

1.00

2.00

Categorymm Hg

176

284

391

498

5105

Rel

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oke

Stroke and diastolic BP (DBP)7 prospective observational studies:843 stroke events

Coronary heart disease (CHD) and DBP9 prospective observational studies:4856 CHD events

Adapted from Whelton PK. Lancet 1994; 344: 101–106

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 i

n 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 (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, -blockers,calcium channel blockers)

The JNC 7 (5) Most patients with hypertension will req

uire 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

ACC/AHA Heart Failure Guideline, MERIT-HF, COPERNICUS, CIBIS, SOLVD, AIRE, TRACE, ValHEFT, RALES

ACC/AHA Post-MI Guideline, BHAT, SAVE, Capricorn, EPHESUS

ALLHAT, HOPE, ANBP2, LIFE, CONVINCE

THIAZ, BB, ACEI, ARB, ALDO ANT

BB, ACEI, ALDO ANT

THIAZ, BB, ACE, CCB

Heart failure

Postmyocardialinfarction

High CAD risk

Diabetes

Chronic kidney disease

Recurrent stroke prevention

Compelling Indications for Individual Drug Classes

Compelling Indication Initial Therapy Options

Clinical Trial Basis

NKF-ADA Guideline, UKPDS, ALLHAT

NKF Guideline, Captopril Trial, RENAAL, IDNT, REIN, AASK

PROGRESS

THIAZ, BB, ACE, ARB, CCB

ACEI, ARB

THIAZ, ACEI

Possible combinations of different classes of antihypertensive agents

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

Diuretics

AT1-receptorblockers

β-blockers

α-blockers CCBs

ACE inhibitorsACE, angiotensin-converting enzymeAT, angiotensinCCB, calcium-channel blocker

ESH – ESC Guidelines Committee. J Hypertens 2007; 25: 1105–1187

Target BP (mm Hg)Average number of antihypertensive agents

1Trial 2 3 4

Multiple antihypertensive agents are often needed to achieve target BP

UKPDS DBP<85

MDRD MAP<92

ABCD DBP<75

HOT DBP<80

AASK MAP<92

IDNT SBP/DBP 135/85

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 rece

ive 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 toa 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

P:Hypertension I:ACEIs combine CCBs C:Placebo O:Cardiovascular disease

Outline

Combine therapy (BP effect) Two trials

ACEIs and CCBs Randomised, double-blind, placebo-controll

ed, 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

43

Effect of ramipril plus felodipine on SBP in patients with hypertensionRamipril–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

Ramipril–felodipine – antihypertensive efficacy

Adapted from Cvetković R and Plosker G. Drugs 2005; 65: 1851–1868; Herlitz H et al. Nephrol Dial Transplant 2001; 16: 2158–2165

Ch

ang

e f r

om

ba

sel in

e

i n S

BP

(%

)

Ramipril/Felodipine5 mg/5 mg

**

** **

**p<0.001

0

-16

-2-4-6-8

-10

-12

-14

Ramipril10 mg

Felodipine9 mg

*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

BP reduction

-20

-15

-10

-5

0

-9.8-9.1

-11.4

**

**

*

Mea

n ch

ange

in D

BP

(m

m H

g)

Ramipril2.5 mg

Felodipine2.5 mg

Ramipril/Felodipine

2.5 mg/2.5 mg

Responder rate compared with monotherapy

*p<0.0001 for fixed-dose combination vs. ramipril monotherapy**p=0.0035 for fixed-dose combination vs. felodipine monotherapyResponder = 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

0

20

40

60

80

100

28.6

41.2

71.4

***

Res

pond

er r

ate

(%)

Ramipril2.5 mg

Felodipine2.5 mg

Ramipril/Felodipine

2.5 mg/2.5 mg

Adverse event (AE)

Patients (%)

Felodipinen=213

Ramipriln=213

Ramipril–Felodipine

n=216Headache 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

Adverse event

All treatment regimens were well tolerated Peripheral oedema was less frequent with combination therapy than

with felodipine monotherapy

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

1.2%

1.7%

兩邊並無太大差異

Moderate risk patients

ACEIs CCBs 能更快達到 Goal Bp

Area of square is proportional to the amount of statistical information available

CCB ACE inhibitor better β-blocker diuretic better

0.50 0.70 1.00 1.45

Primary Non-fatal MI (inc. silent) + fatal CHD

SecondaryNon-fatal MI (exc. silent) + fatal CHDTotal coronary endpointTotal CV event and proceduresAll-cause mortalityCV mortalityFatal and non-fatal strokeFatal and non-fatal heart failure

2.00

Unadjusted hazard ratio0.90; p=0.1052

0.87; p=0.04580.87; p=0.00700.84; p<0.00010.89; p=0.02470.76; p=0.00100.77; p=0.00030.84; p=0.1257

ASCOT

Reprinted from The Lancet, 366, Dahlof B et al., 895–906, copyright (2005), with permission from Elsevier

NNT=100

NNT=33

NNT=100

NNT=100

NNT=100

Tertiary Silent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset type 2 diabetesNew-onset renal impairment

Post-hoc Primary endpoint + coronary revascularisation proceduresCV death + MI + stroke

ASCOTUnadjusted hazard ratio

1.27; p=0.30890.68; p=0.01150.98; p=0.83230.65; p=0.00011.07; p=0.80090.70; p<0.00010.85; p=0.0187

0.86; p=0.0058

0.84; p=0.0003

CCB ACE inhibitor better β-blocker diuretic better

0.50 0.70 1.00 1.45 2.00

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 β-blockers 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 atenolol-hydrochlorothiazide–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 hyperte

nsion is not established. Current U.S. guidelines recommend inclusion of a

diuretic. We hypothesized that treatment with the combinat

ion of an angiotensin-converting–enzyme (ACE) inhibitor and a dihydropyridine calcium-channel 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 gr

oups Combination of 20 mg of benazepril and 5 mg of a

mlodipine, once daily. Combination of 20 mg of benazepril and 12.5 mg

of hydrochlorothiazide, once daily. (Benazepril can increase to 40 mg daily) (Amlodipine dose to 10 mg daily) (Hydrochlorothiazide dose to 25 mg daily)

The addition of other antihypertensive agents was permitted (excluding any calcium-channel blockers, any ACE inhibitors, any angiotensin II–receptor blockers, and any thiazide diuretics but including beta-blockers, alpha-blockers, clonidine, and spironolactone). Loop diuretics taken once daily were permitted for volume management.

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 The primary end point was measured

as the time to the first event (which was defined as the composite of a cardiovascular event and death from cardiovascular causes)

Death from cardiovascular causes was defined as a death attributed to sudden death from cardiac causes, myocardial infarction, stroke, coronary intervention, congestive heart failure, or other cardiovascular causes.

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 TimeSystolic Blood Pressure Over Timem

m H

g

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 mmHg

130mmHg

Difference of 0.7 mmHg p<0.05*

DBP: 71.1 DBP: 72.8 Presented at ACC 2008. http//www.cardiosource.com/iamerson-accomplish.ppt

150

145

140

135

130

125 0 6 12 18 24 30 36 42

Baseline Control Rates37.2 37.9

Exceptional Control Rates with Exceptional Control Rates with Initial Combination TherapyInitial Combination Therapy

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

Presented at ACC 2008. http//www.cardiosource.com/iamerson-accomplish.ppt

NNT=45

NNT=166

NNT=111

SummarySummary

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

0

5

10

15

20

25

30

≤ 90 ≤ 85 ≤ 80

11.9

18.6

p=0.005 for

–51%

Ma

j or

CV

ev e

nts

pe r

1

0 00

pa

t ien

t -y e

ars

Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762

DBP(mm Hg)

p=0.005 for trend

18.6

24.4

11.9

The HOT study C

V m

ort

al i t

y p

e r 1

000

pa

t ien

t -ye

ars

0

2

4

6

8

10

12

14

16

≤ 90 ≤ 85 ≤ 80

3.7

11.2

p=0.016 for trend–67%

Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762

DBP(mm Hg)

11.1 11.2

3.7

p=0.016 for trend

The HOT study T

ota

l nu

mb

er

of s

t ro

kes

Adapted from Hansson L et al. Lancet 1998; 351: 1755–1762

0

5

10

15

20

25

30

35

40

≤ 90 ≤ 85 ≤ 80

20

30

p=0.046 for–43%

DBP(mm Hg)

p=0.046 for trend3530

20

Lower BP is associated with decreased risk of CV events

0

4.00

0.250.50

1.00

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Categorymm Hg

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498

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0.250.50

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Categorymm Hg

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498

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Stroke and diastolic BP (DBP)7 prospective observational studies:843 stroke events

Coronary heart disease (CHD) and DBP9 prospective observational studies:4856 CHD events

Adapted from Whelton PK. Lancet 1994; 344: 101–106

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。