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 Center RUSH University Medical Center Chicago, IL Chicago, IL June 15, 2005 June 15, 2005
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WHEN SHOULD ONE INITIATE SUCCESSIVE ANTIHYPERTENSIVE DRUGS? Henry R. Black M.D. RUSH University Medical Center Chicago, IL June 15, 2005.
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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.”
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).).
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
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.
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
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
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