WHEN SHOULD ONE INITIATE WHEN SHOULD ONE INITIATE

SUCCESSIVE ANTIHYPERTENSIVE SUCCESSIVE ANTIHYPERTENSIVE

DRUGS?DRUGS?

Henry R. Black M.D.Henry R. Black M.D.RUSH University Medical CenterRUSH University Medical Center

Chicago, ILChicago, ILJune 15, 2005June 15, 2005

Treatment of HypertensionTreatment of Hypertension19371937

“The treatment of hypertension itself is a difficult and almost hopeless task in the present state of knowledge, and in fact for aught we know...the hypertension may be an important compensation mechanism which should not be tampered with, even were it certain that we could control it.”

—Paul Dudley White, 1937

AnimasaAnimasa MistletoeMistletoe

Benzyl BenzoateBenzyl Benzoate “Natheim” Bath“Natheim” Bath

Benzyl SuccinateBenzyl Succinate NitroscleranNitroscleran

Calcium DiuretinCalcium Diuretin Potassium Potassium SulphocyanateSulphocyanate

Calcium Salts and low Protein DietCalcium Salts and low Protein Diet Radiation to the SkullRadiation to the Skull

Corpus LuteumCorpus Luteum Radium WaterRadium Water

DesecinDesecin SubtoninSubtonin

DiathermyDiathermy Sodium SulphocyanateSodium Sulphocyanate

Irradiation of the Suprarenal RegionIrradiation of the Suprarenal Region TheominalTheominal

Liver ExtractLiver Extract Thyroid and PotassiumThyroid and Potassium

Lumbar SympathectomyLumbar Sympathectomy PermanganatePermanganate

LuminalLuminal Watermelon Extract Watermelon Extract

TREATMENT OF ESSENTIAL HYPERTENSION: 1930TREATMENT OF ESSENTIAL HYPERTENSION: 1930Drug or Method UsedDrug or Method Used

Ayman, JAMA 1930; 95:246.Ayman, JAMA 1930; 95:246.

Development ofDevelopment ofAntihypertensive TherapiesAntihypertensive Therapies

Effective but poorly Effective but poorly toleratedtolerated

As effective and As effective and better toleratedbetter tolerated

As effective and even better As effective and even better toleratedtolerated

MoreMoreeffective for effective for

SBPSBP

DirectDirectvasodilatorsvasodilators

ACEACEinhibitorsinhibitors

-blo-blockersckers

ARBsARBs VPIsVPIs

OthersOthersPeripheralPeripheral

sympatholyticssympatholytics

Ganglion Ganglion blockersblockers

VeratrumVeratrumalkaloidsalkaloids

Central Central 22

agonistsagonists

CalciumCalciumantagonists-antagonists-

non DHPsnon DHPs

-blockers-blockers

ThiazidesThiazidesdiureticsdiuretics

CalciumCalciumantagonists-antagonists-

DHPsDHPs

1940’s 1950 1957 1960’s 1970’s 1980’s 1990’s 2001

Combination Antihypertensive TherapiesCombination Antihypertensive Therapies

1950’s 1960’s 1970’s 1980’s1990’s-2000s

Butiserpine (reserpine/butalbital)Hyphex (hexamethonium/hydralazine)Hypotensin A, B, & C

(pentolinium/hydralazine/resperine)Renir (reserpine/ephedrine)Verapene (rauwolfia/veratrum)

Ser-Ap-Es(reserpine/hydralazine/

hydrochlorothiazide)Methyldopa/thiazide

Thiazide/K+-sparing diuretic

blocker/thiazideClonidine/thiazide

ACE inhibitor/thiazide

ACE inhibitor/CCBARB/thiazideLow-dose blocker/thiazide

KEY QUESTIONSKEY QUESTIONS

1.1. How and when should you titrate or add How and when should you titrate or add additional agents?additional agents?

2.2. When should you start with more than one When should you start with more than one drug?drug?

How and when should you titrate or add How and when should you titrate or add additional agents?additional agents?

Any schedule for dose titration is arbitrary and based on the Any schedule for dose titration is arbitrary and based on the pharmacodynamics and pharmacokinetics of the individual pharmacodynamics and pharmacokinetics of the individual drugs used.drugs used.

We would generally recommend titration of drugs that are not We would generally recommend titration of drugs that are not given at full dose after 1-4 weeks, or adding additional drugs for given at full dose after 1-4 weeks, or adding additional drugs for those patients those patients not at goal blood pressure.not at goal blood pressure.

The speed with which this is undertaken depends on the stage of The speed with which this is undertaken depends on the stage of

BP (BP (relative riskrelative risk) and the clinician’s judgment of the impact of co-) and the clinician’s judgment of the impact of co-morbidity and other CV risk factors (morbidity and other CV risk factors (absolute riskabsolute risk).).

Antihypertensive Treatment Antihypertensive Treatment RegimenRegimen

Step 1Step 1 Dose 1Dose 1 Dose 2Dose 2 Dose 3Dose 3

ChlorthalidoneChlorthalidone 12.5 mg12.5 mg 12.5 mg12.5 mg 25 mg25 mg

AmlodipineAmlodipine 2.5 mg2.5 mg 5 mg5 mg 10 mg10 mg

LisinoprilLisinopril 10 mg10 mg 20 mg20 mg 40 mg40 mg

Step 2Step 2

ReserpineReserpine 0.05 mg qd0.05 mg qd 0.1 mg qd0.1 mg qd 0.2 mg qd0.2 mg qd

ClonidineClonidine 0.1 mg bid0.1 mg bid 0.2 mg bid0.2 mg bid 0.3 mg bid0.3 mg bid

AtenololAtenolol 25 mg qd25 mg qd 50 mg qd50 mg qd 100 mg qd100 mg qd

Step 3Step 3

HydralazineHydralazine 25 mg bid25 mg bid 50 mg bid50 mg bid 100 mg bid100 mg bid

ALLHATALLHAT

VALUE: DesignElective titration to target BP (<140/90 mmHg)

Month 0.5 0 1 2 3 4 6 * 72

A 10 mg +HCTZ 25 mg

A 5 mg

A 10 mg +HCTZ 12.5 mg

A 10 mg

V 80 mg

V 160 mg

V 160 mg +HCTZ 12.5 mg

V 160 mg +HCTZ 25 mg

Amlodipine -based regimen

V 160 mg +HCTZ 25 mg + "Free" add-on

A 10 mg +HCTZ 25 mg + "Free" add-on

Valsartan-based regimen

ScreeningRandomisation End of treatment adjustment

period

Rolloverfromprevious therapy(92%)

*Patient visits every 6 months for months 6–72.Julius S et al. Lancet. June 2004;363.

When should you start with more than one drug?When should you start with more than one drug?

Adapted from Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1997;157:2413-2446.

JNC VI Treatment Algorithm

Uncomplicated Hypertension Compelling Indications Diuretics Type 1 diabetes ISH Beta blockers -ACE inhibitors -Diuretics

CHF -LA DHP CCBs-ACE inhibitors MI-Diuretics -Beta blockers

-ACE inhibitors

Begin or continue lifestyle modificationsBegin or continue lifestyle modifications

Not at Not at goal BPgoal BP (<140/90 mm Hg) (<140/90 mm Hg)

Not at Not at goal BPgoal BP

No response or troublesome side effects Inadequate response but well tolerated

Substitute another drug fromdifferent class

Add second agent from different class(diuretic if not already used)

Not at Not at goal BPgoal BP

Continue adding agents from other classes Continue adding agents from other classes Consider referral to Consider referral to hypertension specialisthypertension specialist

Initial Drug ChoicesInitial Drug Choices

ACE = angiotensin-converting enzymeLA DHP CCBs = long-actingdihydropyridine calcium-channelblockers

Materson et al. Materson et al. Am J Hypertens.Am J Hypertens. 1993;8:189-192. 1993;8:189-192.

00

2020

4040

6060

8080

Calciumantagonist

Beta-blocker

Diuretic Alpha1

antagonistACEIAlpha2

agonistPlacebo

50% response

Response defined as DBP < 95 mm Hg after one year of treatment

Per

cen

t r

esp

on

se

Monotherapy is Inadequate in 40%–60% of Hypertensive Patients

Not at Goal Blood Pressure

Initial Drug Choices

Uncomplicated

Compelling Indications

Not at Goal Blood Pressure

TREATMENT OF HYPERTENSION – JNC VI

– Start at low dose and titrate upward.– Low-dose combinations may be appropriate.

Specific Indications

MAP=mean arterial pressure.MAP=mean arterial pressure.

Adapted from Bakris et al, Brenner et al,Adapted from Bakris et al, Brenner et al, and Lewis et al.and Lewis et al.

Number of BP Medications

Antihypertensive Therapy: Number of Agents Antihypertensive Therapy: Number of Agents Required to Achieve BP Goal Required to Achieve BP Goal

UKPDS (<85 mm Hg, diastolic)

4321

MDRD (92 mm Hg, MAP)

HOT (<80 mm Hg, diastolic)

AASK (<92 mm Hg, MAP)

RENAAL (<140/90 mm Hg)

IDNT (135/85 mm Hg)

Adapted from Hansson L et al for the HOT Study Group. Lancet. 1998;351:1755-1762.

Enrollment Final

161/98 142/83

<90 mm Hg

144/85

<85 mm Hg

142/93

<80 mm Hg

140/81

SBP/DBP mm Hg

SBP/DBPmm Hg

37%63%

32%68%

25%75%

60%40% 32%

68%

Monotherapy

CombinationTherapy

Combination Therapy Needed Combination Therapy Needed to Achieve Target Blood Pressureto Achieve Target Blood Pressure

CLINICAL TRIALS IN HYPERTENSIONCLINICAL TRIALS IN HYPERTENSIONHOT STUDYHOT STUDY

80

85

90

95

100

105

0 3 6 12 24 36 Final

Target <90Target <85Target <80

Hansson L et al, Lancet 1998;351:1755

DB

P in

mm

Hg

DB

P in

mm

Hg

MonthsMonths

24.4

18.6

11.9

0

5

10

15

20

25

30

Major CV Events/1000 Patient-yrMajor CV Events/1000 Patient-yr

90 mm Hg90 mm Hg 85 mm Hg85 mm Hg 80 mm Hg 80 mm Hg (target DBP)(target DBP)

Hansson et al. Lancet 1998;351:1755Hansson et al. Lancet 1998;351:1755

PP = 0.005 for trend = 0.005 for trend

Significant Benefits From Intensive BP Significant Benefits From Intensive BP Reduction in Diabetic PatientsReduction in Diabetic Patients

PROGRESSPROGRESS Combination (ACEI Combination (ACEI ++ Diuretic) lowered BP by12/5 mm Hg Diuretic) lowered BP by12/5 mm Hg Single-drug (ACEI) lowered BP by 5/3 mm Hg) Single-drug (ACEI) lowered BP by 5/3 mm Hg)

Tests for homogeneity (combination vs single drug): both <0.001.PROGRESS Collaborative Group. Lancet. 2001;358:1033-1041.

Events (No.) Risk reduction(95% CI)Active Placebo

Stroke

Single drug 227 237 4% (-15%-20%)

Favorsactive

Favorsplacebo

0.5 2.0 Hazard ratio

1.0

Combination 150 255 43% (30%-54%)

Combination 231 367 40% (29%-49%)

Total 458 604 26% (16%-34%)

Single drug 157 165 5% (-19%-23%)

Total 307 420 28% (17%-38%)

Major vascular events

Randomized DesignRandomized Designof ALLHATof ALLHAT

ALLHAT Collaborative Research Group. ALLHAT Collaborative Research Group. JAMAJAMA. 2002;288:2981-2997.. 2002;288:2981-2997.ALLHAT Collaborative Research Group. ALLHAT Collaborative Research Group. JAMAJAMA. 2000;283:1967-1975.. 2000;283:1967-1975.

High-risk High-risk hypertensive hypertensive patientspatients

Consent/ Consent/ RandomizeRandomize

(42,418)(42,418)

Amlodipine 2.5-10 mg (n=9048)Amlodipine 2.5-10 mg (n=9048)

Chlorthalidone 12.5-25 mg (n=15,255)Chlorthalidone 12.5-25 mg (n=15,255)

Doxazosin 2-8 mg (n=9067)Doxazosin 2-8 mg (n=9067)

Lisinopril 10-40 mg (n=9054)Lisinopril 10-40 mg (n=9054)

Amlodipine 2.5-10 mg (n=9048)Amlodipine 2.5-10 mg (n=9048)

Chlorthalidone 12.5-25 mg (n=15,255)Chlorthalidone 12.5-25 mg (n=15,255)

Doxazosin 2-8 mg (n=9067)Doxazosin 2-8 mg (n=9067)

Lisinopril 10-40 mg (n=9054)Lisinopril 10-40 mg (n=9054)

Eligible for Eligible for lipid-loweringlipid-lowering

Not eligible for Not eligible for lipid-loweringlipid-lowering

Consent/Randomize (10,355)Consent/Randomize (10,355)

Pravastatin Pravastatin Usual careUsual care

Follow for CHD and other outcomes until death or end of study (up to 8 years).Follow for CHD and other outcomes until death or end of study (up to 8 years).Follow for CHD and other outcomes until death or end of study (up to 8 years).Follow for CHD and other outcomes until death or end of study (up to 8 years).

ALLHAT

SBP Distribution at Baseline SBP Distribution at Baseline and 36 Months of Follow-upand 36 Months of Follow-up

0

10

20

30

40

<100 100-109

110-119

120-129

130-139

140-149

150-159

160-169

170-179

180+

Baseline:Baseline:31% <31% < 140 mm Hg 140 mm Hg14% 14% 160 mm Hg 160 mm Hg

36 Months:36 Months:64% <64% < 140 mm Hg 140 mm Hg 8% 8% 160 mm Hg 160 mm Hg

SBP (mm Hg)

Per

cen

tALLHATALLHAT

Cushman, et al. J Clinical Hypertens 2002; 4:393-404Cushman, et al. J Clinical Hypertens 2002; 4:393-404

Blood Pressure ControlBlood Pressure Control

31

58 60 64 67 67

92%91%90%88%86%

68% 66656258

27

55

0

20

40

60

80

100

0 1 2 3 4 5

Years of Follow-up

Per

cent

DBP<90 SBP<140 BP<140/90

ALLHATALLHAT

1.41.6 1.7

1.82.0

1.6 = mean number of drugs1.6 = mean number of drugs

Cumulative Combined CVD Event Rate

Years to Combined CVD Event0 1 2 3 4 5 6 7

0

.1

.2

.3

.4

.5

Number at risk:

Chlor 15,255 13,752 12,594 11,517 9,643 5,167 2,362 288 Amlo 9,048 8,118 7,451 6,837 5,724 3,049 1,411 153 Lisin 9,054 7,962 7,259 6,631 5,560 3,011 1,375 139

Cumulative Event Rates for Combined CVD by ALLHAT Treatment Group

RR (95% CI) p value

A/C 1.04 (0.99-1.09) 0.12

L/C 1.10 (1.05-1.16) <0.001

ALLHAT

ChlorthalidoneAmlodipineLisinopril

Cumulative Stroke Rate

Years to Stroke0 1 2 3 4 5 6 7

0

.02

.04

.06

.08

.1

Number at risk: Chlor 15,255 14,515 13,934 13,309 11,570 6,385 3,217 567 Amlo 9,048 8,617 8,271 7,949 6,937 3,845 1,813 506 Lisin 9,054 8,543 8,172 7,784 6,765 3,891 1,828 949

Cumulative Event Rates for Stroke by ALLHAT Treatment Group

RR (95% CI) p value

A/C 0.93 (0.81-1.06) 0.28

L/C 1.15 (1.02-1.30) 0.02

ALLHAT

ChlorthalidoneAmlodipineLisinopril

Stroke – Subgroup Comparisons – RR (95% CI)

Amlodipine Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 0.96 (0.81, 1.14)

Diabetic 0.90 (0.75, 1.08)

Non-Black 0.93 (0.79, 1.10)

Black 0.93 (0.76, 1.14)

Women 0.84 (0.69, 1.03)

Men 1.00 (0.85, 1.18)

Age >= 65 0.93 (0.81, 1.08)

Age < 65 0.93 (0.73, 1.19)

Total 0.93 (0.82, 1.06)

Lisinopril Better Chlorthalidone Better

0.50 1 2

Non-Diabetic 1.23 (1.05, 1.44)

Diabetic 1.07 (0.90, 1.28)

Non-Black 1.00 (0.85, 1.17)

Black 1.40 (1.17, 1.68)

Women 1.22 (1.01, 1.46)

Men 1.10 (0.94, 1.29)

Age >= 65 1.13 (0.98, 1.30)

Age < 65 1.21 (0.97, 1.52)

Total 1.15 (1.02, 1.30)

ALLHAT

P = .01 for interaction

BP Results by Treatment Group

Compared to chlorthalidone:

SBP significantly higher in the amlodipine group (~1 mm Hg) and the lisinopril group (~2 mm Hg).

Compared to chlorthalidone:

DBP significantly lower in the amlodipine group (~1 mm Hg).

ALLHAT

Algorithm for Treatment of HypertensionAlgorithm for Treatment of Hypertension

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Not at Goal Blood Pressure (<140/90 mmHg) (<130/80 mmHg for those with diabetes or chronic kidney disease)

Initial Drug ChoicesInitial Drug Choices

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

Drug(s) for the compelling indications

Other antihypertensive drugs (diuretics, ACEI, ARB, BB, CCB)

as needed.

With Compelling Indications

With Compelling Indications

Lifestyle ModificationsLifestyle Modifications

Not at Goal Blood Pressure

Not at Goal Blood Pressure

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Optimize dosages or add additional drugs until goal blood pressure is achieved.

Consider consultation with hypertension specialist.

Stage 2 Hypertension (SBP >160 or DBP >100

mmHg) 2-drug combination for most

(usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 2 Hypertension (SBP >160 or DBP >100

mmHg) 2-drug combination for most

(usually thiazide-type diuretic and

ACEI, or ARB, or BB, or CCB)

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for

most. May consider ACEI, ARB, BB,

CCB, or combination.

Stage 1 Hypertension(SBP 140–159 or DBP 90–99

mmHg) Thiazide-type diuretics for

most. May consider ACEI, ARB, BB,

CCB, or combination.

Without Compelling Indications

Without Compelling Indications

VALUE: Fatal and Non-fatal Stroke

Julius S et al. Lancet. June 2004;363.

Number at risk

Valsartan

Amlodipine 7596

7649

7499

7494

7455

7448

7334

7312

7195

7170

6918

6877

7055

7022

6744

6692

6163

6093

3846

3859

1532

1516

6587

6515

6

5

4

3

2

1

0

Time (months)0 6 12 18 24 30 36 42 48 54 60 66

Pro

port

ion

of

Pati

en

ts W

ith

Fir

st

Even

t (%

)

Valsartan-based regimen

Amlodipine-based regimen

HR = 1.15; 95% CI = 0.98–1.35; P = 0.08

VALUE: Outcome and SBP Differencesat Specific Time Periods: Stroke

Julius S et al. Lancet. June 2004;363.

Odds Ratios and 95% CIs

favors valsartan favors amlodipine1.0 2.00.5

Time Interval(months)

Overall study

36–4824–3612–246–12

0–3

Study end

SBP(mmHg)

1.41.61.82.0

3.8

1.7

2.2

3–6 2.3

0.25 4.0

STROKE

VALUE: Systolic Blood Pressure in Study

Julius S et al. Lancet. June 2004;363.

Valsartan (N= 7649)

Amlodipine (N = 7596)

135

140

145

150

155

mm

Hg

Months (or final visit)

Sitting SBP by Time and Treatment Group

Baseline 1 24 482 3 4 6 12 18 30 36 42 54 60 66

01.02.03.04.0

1 24 48

mm

Hg

2 3 4 6 12 18 30 36 42 54 60 66Months (or final visit)

5.0Difference in SBP Between Valsartan and Amlodipine

–1.0

VALUE: Analysis of Results Based on VALUE: Analysis of Results Based on Immediate ResponseImmediate Response

Outcomes were compared in:

Immediate responders

– patients not on previous treatment, with BP response of ≥10 mmHg SBP at 1 month, OR

– patients on previous treatment, with BP ≤ baseline at 1 month

WITH:

Non-immediate responders

– those who failed to meet above criteria

Weber MA et al. Lancet. 2004;363:2047–49.

VALUE: Analysis of Results Based on VALUE: Analysis of Results Based on Immediate Response*Immediate Response*

Fatal/Non-fatal cardiac events

Fatal/Non-fatal stroke

All-cause death

Myocardial infarction

Heart failure hospitalizations

0.4 0.6 0.8 1.0 1.2 1.4Immediate responders*

(n = 9336)Non-immediate responders

(n = 5663)

Odds Ratio 95% CI*Those not on previous tx: SBP ≥10 mmHg at one month; those on previous tx: SBP ≤ baseline at one month.**P < 0.05; †P < 0.01.

Pooled Treatment Groups

**

†

**

0.88 (0.79–0.97)

0.83 (0.71–0.98)

0.90 (0.81–0.99)

0.89 (0.76–1.04)

0.87 (0.75–1.01)

Odds Ratio

Weber MA et al. Lancet. 2004;363:2047–49.

VALUE: Analysis of Results Based on VALUE: Analysis of Results Based on BP Control at 6 MonthsBP Control at 6 Months

Fatal/Non-fatal cardiac events

Fatal/Non-fatal stroke

All-cause death

Myocardial infarction

Heart failure hospitalizations

0.4 0.6 0.8 1.0 1.2 1.4Controlled patients*

(n = 10755)Non-controlled patients

(n = 4490)

Hazard Ratio 95% CI*SBP < 140 mmHg at 6 months.

Pooled Treatment Groups

**

**

**

**

**P < 0.01.

0.75 (0.67–0.83)

0.55 (0.46–0.64)

0.79 (0.71–0.88)

0.86 (0.73–1.01)

0.64 (0.55–0.74)

Odds Ratio

Weber MA et al. Lancet. 2004;363:2047–49.

VALUE: Analysis of Results Based on VALUE: Analysis of Results Based on BP Control at 6 MonthsBP Control at 6 Months

Fatal/Non-fatal cardiac events

Fatal/Non-fatal stroke

All-cause death

Myocardial infarction

Heart failure hospitalizations

*SBP < 140 mmHg at 6 months.**P < 0.01.

Patients Treated With Valsartan Patients Treated With Amlodipine

Hazard Ratio 95% CI

0.4 0.6 0.8 1.0 1.2

Controlled patients*

(n = 5253)

Non-controlled patients

(n = 2396)

**

**

**

**

0.4 0.6 0.8 1.0 1.2

Controlled patients*

(n = 5502)

Non-controlled patients

(n = 2094)

Hazard Ratio 95% CI

**

**

**

**

0.76 (0.66–0.88)

0.60 (0.48–0.74)

0.79 (0.69–0.91)

0.83 (0.66–1.03)

0.62 (0.50–0.77)

Odds Ratio

0.73 (0.63–0.85)

0.50 (0.39–0.64)

0.79 (0.69–0.92)

0.91 (0.71–1.17)

0.64 (0.52–0.79)

Odds Ratio

Weber MA et al. Lancet. 2004;363:2047–49.

ASCOT: Primary Objectives

•To assess and compare the long-term

effects on nonfatal MI and fatal CHD of the

standard antihypertensive regimen (-

blocker +/- diuretic) with a more

contemporary regimen (CCB +/- ACEI)

BP Control at 3 years

• One drug 27%

• Two or more drugs73%

ASCOT = Anglo-Scandinavian Cardiac Outcomes Trial; MI = myocardial infarction; CHD = cardiovascular heart disease; CV = cardiovascular.Sever PS, Dahlöf B. American College of Cardiology 2005 Scientific Sessions; March 6-9, 2005; Orlando, FL.

ASCOT: Primary and Secondary End Points ASCOT: Primary and Secondary End Points –Amlodipine/Perindopril vs Atenolol/Bendroflumethiazide–Amlodipine/Perindopril vs Atenolol/Bendroflumethiazide

FavorsAmlodipine/Perindopril

Favors Atenolol/Bendroflumethiazide

Hazard Ratio

All-cause mortality

Primary end point: nonfatal MI and fatal CHD

Total coronary end point: primary end point + new-onset angina + fatal and nonfatal heart failure

Fatal and nonfatal stroke

All CV events and revascularization procedures

CV mortality

0.5 1 1.5

End point P Value

0.005

0.12

0.0048

0.0007

<0.0001

0.0017

Blood Pressure

• Overall, BP was lowered by 28/16 mm Hg. Early

differences in BP were observed between treatment

groups with lower levels on amlodipine/perindopril. BP

differences reduced over time and mean trial

differences were 2.9 mm Hg systolic and 1.8 mm Hg

diastolic.

PRELIMINARY DATA - ACC – March 8, 2005

BP Reductions as Small as 2 mmHg Reduce the Risk of CV Events by Up to 10%

• Meta-analysis of 61 prospective, observational studies

• 1 million adults

• 12.7 million person-years

Prospective Studies Collaboration. Lancet. 2002;360:1903-1913.

2 mmHg decrease in mean SBP 10% reduction in

risk of stroke mortality

7% reduction in risk of IHD mortality

Odds Ratio for CV Events and Systolic BP Odds Ratio for CV Events and Systolic BP Difference: Recent and Older TrialsDifference: Recent and Older Trials

Staessen et al. Staessen et al. J HypertensJ Hypertens. 2003;21:1055-1076.. 2003;21:1055-1076.

Od

ds

Rat

io (

exp

erim

enta

l/re

fere

nce

)O

dd

s R

atio

(ex

per

imen

tal/

refe

ren

ce) 1.501.50

1.251.25

1.001.00

0.750.75

0.500.50

0.250.25

-5-5 00 55 1010 1515 2020 2525

PP<.0001<.0001

Difference (reference minus experimental) Difference (reference minus experimental) in Systolic BP (mm Hg)in Systolic BP (mm Hg)

Recent trialsRecent trials

Older trials placeboOlder trials placebo

STONESTONE

UKPDS L vs. HUKPDS L vs. H

PROGRESSION/ComPROGRESSION/Com

STOP 1STOP 1

RCT70-80RCT70-80

EWPHEEWPHEHEPHEP

MRC2MRC2

SHEPSHEP

Syst-EurSyst-Eur

PART2/SCATPART2/SCAT

HOPEHOPE

STOP2/ACEIsSTOP2/ACEIs

ALLHAT/DoxALLHAT/Dox

UKPDS C vs. AUKPDS C vs. A

MIDAS/NICS/VHASMIDAS/NICS/VHAS

STOP2/CCBsSTOP2/CCBs

HOT M vs. HHOT M vs. HINSIGHTINSIGHT

HOTHOT

PROGRESS/PerPROGRESS/PerPATSPATS

RENAALRENAAL

L vs. HL vs. HMRCMRC

ATMHATMH

Syst-ChinaSyst-China

OlderOlderRecentRecentAASK L vs. HAASK L vs. HABCD/NT L vs. HABCD/NT L vs. H

ALLHAT/Lis BlacksALLHAT/Lis BlacksALLHAT/Lis ALLHAT/Lis 6565ALLHAT/LisALLHAT/LisALLHAT/AmlALLHAT/Aml

CONVINCECONVINCEDIABHYCARDIABHYCAR

ANBP2ANBP2

LIFE/ALLLIFE/ALL

ELSAELSA

LIFE/DMLIFE/DMNICOLENICOLEPREVENTPREVENT

IDNT2IDNT2

SCOPESCOPE

Older trials activeOlder trials active

BP-Lowering Treatment TrialistsBP-Lowering Treatment Trialists

StrokeStroke

Systolic BP Difference Between Systolic BP Difference Between Randomized Groups (mm Hg)Randomized Groups (mm Hg)

Rel

ativ

e R

isk

of

Rel

ativ

e R

isk

of

Str

oke

Str

oke

0.250.25

0.500.50

0.750.75

1.001.00

1.251.25

1.501.50

-10-10 -8-8 -6-6 -4-4 -2-2 00 22 44

Systolic BP Difference Between Systolic BP Difference Between Randomized Groups (mm Hg)Randomized Groups (mm Hg)

Rel

ativ

e R

isk

of

CH

DR

elat

ive

Ris

k o

f C

HD

0.250.25

0.500.50

0.750.75

1.001.00

1.251.25

1.501.50

-10-10 -8-8 -6-6 -4-4 -2-2 00 22 44

CHDCHD

Blood Pressure Lowering Treatment Trialists’ Collaboration. Blood Pressure Lowering Treatment Trialists’ Collaboration. LancetLancet. 2003;362:1527-1535.. 2003;362:1527-1535.

JNC – VI, 7 and ?JNC – VI, 7 and ?(8)(8)S.O.C.O.sS.O.C.O.s

Go For Goal And Don’t Settle For LessGo For Goal And Don’t Settle For Less

It’s not It’s not BEYONDBEYOND the Blood Pressure, IT the Blood Pressure, IT

IS IS THE BLOOD PRESSURE!THE BLOOD PRESSURE!

AND IT’S ALSO HOW AND IT’S ALSO HOW FASTFAST YOU GET TO YOU GET TO

GOALGOAL

S.O.C.O. = Single Overriding Communications ObjectiveS.O.C.O. = Single Overriding Communications Objective