when should one initiate successive antihypertensive drugs? henry r. black m.d. rush university...
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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
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