Chlorthalidone-Telmisartan The New Renaissance

Chlorthalidone: The Renaissance
Risk of hypertension (%)
Lifetime Risk of Developing

Hypertension Beginning at Age 65
100
80
Men
Women
60
40
20
0
10 12
Years
Residual lifetime risk of developing hypertension

among people with blood pressure <140/90 mmHg
Vasan RS, et al. JAMA. 2002; 287:1003-1010.
Copyright 2002, American Medical Association.
14
16 18
20
Ratio (%) of actual to

expected mortality
Mortality According to Blood Pressure

in Men Age 50 to 69
250
200
150
68-82
83-87
88-92
93-97
98-102
100
50
0
158167
148157
138147
128137
98127
Systolic blood pressure (mmHg)

Society of Actuaries. Blood Pressure Study, 1939.
Age-adjusted annual
incidence of CHD per 1000
Blood Pressure and Risk for

Coronary Heart Disease in Men
60
60
50
50
40
40
Age 65-94
30
30
20
20
Age 35-64
10
10
<120 120- 140- 160- 180+

139 159 179
Systolic blood pressure (mmHg)
Age 65-94
Age 35-64
<75
758595- 105+
84
94
104
Diastolic blood pressure (mmHg)
Based on 30 year follow-up of Framingham Heart Study subjects free of coronary heart
disease (CHD) at baseline
Framingham Heart Study, 30-year Follow-up. NHLBI, 1987.
Risk of CHD Death

According to SBP and DBP in MRFIT
Relative risk of
CHD mortality
Systolic blood pressure (SBP)
Diastolic blood pressure (DBP)
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
(lowest 10%)
<112 112- 118<71
71-
76-
121-
125-
129-
132-
79-
81-
84-
86-
CHD=coronary heart disease

He J, et at. Am Heart J. 1999;138:211-219.
Copyright 1999, Mosby Inc.
10
89-
92-
>98
(highest 10%)
137- 142- >151
Relative risk of
stroke death
Risk of Stroke Death According

to SBP and DBP in MRFIT
9
8
7
6
5
4
3
2
1
0
Decile
SBP (mmHg)
DBP (mmHg)
Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)
(lowest 10%)
<112 112- 118<71
71-
76-
121-
125-
129-
132-
79-
81-
84-
86-
He J, et at. Am Heart J. 1999;138:211-219.

Copyright 1999, Mosby Inc.
10
89-
92-
>98
(highest 10%)
137- 142- >151
Age-adjusted annual CVD

event rate per 1000
Isolated Systolic Hypertension

and CVD Risk in Framingham
2.5
100
ISH BP 160/<95 mmHg

BP <140/95 mmHg
80
82
2.4
60
40
20
0
43
33
18
Men
Women
CVD=cardiovascular disease ISH=isolated systolic hypertension

P<0.001 for difference between both men and women with ISH
and blood pressure (BP) <140/95 mmHg
Wilking SV et al. JAMA. 1988;260:3451-3455.
Landmark Clinical Trials
Hypertension Treatment and Cardiovascular Disease Outcomes
1967 VA Cooperative Study on DBP 115-129

1970 VA Cooperative Study on DBP 90-114
1979 HDFP
1980 Australian Trial, Oslo Trial
1985 MRC I, EWPHE
1991 SHEP, STOP-Hypertension
1992 MRC II in the elderly
1997 Syst-Eur
2002 LIFE
2002 ALLHAT
Pharmacologic Treatment in JNC 7

Excellent clinical trial outcome data prove that lowering BP
with several classes of drugs, including ACE inhibitors,
angiotensin receptor blockers (ARBs), b-blockers, calcium
channel blockers (CCBs) and thiazide-type diuretics, will all
reduce the complications of hypertension.
JNC 7 Recommendation for

Initial Drug Therapy
Thiazide-type diuretics should be used as initial therapy for
most patients with hypertension, either alone or in combination
with one of the other classes (ACEIs, ARBs, BBs, CCBs)
demonstrated to be beneficial in randomized controlled outcome
trials.
JNC 7 Algorithm for

Treatment of Hypertension
Initial Drug Choices
Without Compelling
Indications
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)
Inadequate Management of BP in a VA
Hypertensive Population: Clinical Inertia
800 hypertensive men @ 5 VAs in New England over a 2 yr period in
early 1990s.
>6 HTN-related visits/yr; ave age: 65.5 years.
BP control:
40% had BP >160/90 mm Hg

Only 25% had BP <140/90 mm Hg
Increases in therapy: only 6.7% of visits.
More intensive Tx lead to better control of BP (p<.01).
Many physicians are not aggressive enough in their approach to
hypertension.
Berlowitz, et al: NEJM 1998;339:1957-63
Classification and Management

of BP for adults in JNC 7
Initial drug therapy
BP
Classification
Without compelling indication
With compelling
indications
Normal
Prehypertension
No antihypertensive drug indicated
Thiazide-type diuretics for most.

May consider ACEI, ARB, BB, CCB, or
combination
Two-drug combination for most

(usually thiazide-type diuretic and
ACEI or ARB or BB or CCB)
JNC 7. JAMA. 2003;289:2560-2572.
Drug(s) for compelling

indications
Drug(s) for the compelling

indications.
Other antihypertensive
drugs (diuretics, ACEI, ARB,
BB, CCB) as needed.

BP
Classification
With compelling
indications
Normal
Prehypertension

combination

JNC 7. JAMA. 2003;289:2560-2572.

indications

indications.
BB, CCB) as needed.

BP
Classification
With compelling
indications
Normal
Prehypertension

combination

JNC 7. JAMA. 2003;289:2560-2572.

indications

indications.
BB, CCB) as needed.

BP
Classification
With compelling
indications
Normal
Prehypertension

combination

JNC 7. JAMA. 2003;289:2560-2572.

indications

indications.
BB, CCB) as needed.

BP
Classification
With compelling
indications
Normal
Prehypertension

combination

JNC 7. JAMA. 2003;289:2560-2572.

indications

indications.
BB, CCB) as needed.
Hypertension Treatment by Drug Class

% of Treated Patients on Medication
60
Calcium Channel Blockers

Beta Blockers
Diuretics
ACE Inhibitors
ARBs
Diuretics
50
40
-Blocker
30
20
ACE Inhibitors
10
CCBs
ARBs
0
1978
1981
1984
1987
1990
Year
1993
1996
1999
2002
IMS Health NDTI, 1978-2002
JNC 7 Algorithm for Treatment of Hypertension

Initial Drug Choices
Without Compelling
Indications
(SBP 140159 or DBP 9099 mmHg)

May consider ACEI, ARB, BB, CCB,
or combination.
Chlorthalidone: Relationship
with Blood Pressure and

Cardiovascular Disease Risk reduction
Thiazide diuretics in the

management of Hypertension
Thiazide diuretics
Thiazide diuretics became available in the late 1950s and were the first
effective oral antihypertensive agents with an acceptable side-effect profile.
These agents reduce blood pressure when administered as monotherapy,
enhance the efficacy of other antihypertensive agents, and reduce
hypertension-related morbidity and mortality.
Thiazide-type diuretics, especially HCTZ, have been used as a cornerstone of
antihypertensive treatment for years.
There is substantial evidence that low doses of Chlorthalidone (25 mg daily) are effective
reducing CVD morbidity and mortality.
Recent outcome trials showing CVD benefits with thiazide-type diuretics have
primarily used chlorthalidone or indapamide
(Lancet. 1985;1:1349-1354., BMJ. 1992;304:405-412.)
Major Diuretic Trials

VA Coop (1967)
PHS trial (1977)
HDFP (1982)
MRFIT (1990)
EWPHE (1985)
MRC (1992)
SHEP (1991)
TOMHS (1993)
ALLHAT (2002)
ACCOMPLISH (2008)
HCTZ 50-100 mg
Chlorothiazide 500-1000 mg
Chlorthalidone 25-100 mg
HCTZ 50-100 mg (BID) or
HCTZ 25-50 mg
HCTZ 25-50 mg
Chlorthalidone 12.5-25 mg
Chlorthalidone 12.5-25 mg
HCTZ 12.5-25 mg
Chlorthalidone has been the preferred diuretic in NHLBI

hypertension trials but is infrequently used.
Diuretics by Molecule
4,500
4,000
3,500
BENDROFLUMETHIAZIDE
CHLOROTHIAZIDE
TRx (000s)
3,000
CHLORTHALIDONE
HYDROCHLOROTHIAZIDE
2,500
HYDROFLUMETHIAZIDE
INDAPAMIDE
2,000
METHYCLOTHIAZIDE
METOLAZONE
1,500
POLYTHIAZIDE
QUINETHAZONE
1,000
500
Fe
b0
M 1
ay
-0
Au 1
g0
No 1
v0
Fe 1
b0
M 2
ay
-0
Au 2
g0
No 2
v0
Fe 2
b0
M 3
ay
-0
Au 3
g0
No 3
v0
Fe 3
b0
M 4
ay
-0
Au 4
g0
No 4
v0
Fe 4
b0
M 5
ay
-0
Au 5
g0
No 5
v0
Fe 5
b0
M 6
ay
-0
Au 6
g0
No 6
v06
IMSIMS
Health
NDTI,
Data Source:
NPA - 72
months2001-06.
ending January 2007
TRICHLORMETHIAZIDE
ABPM Differences
Week 2
Change in Ambulatory Systolic

Blood Pressure (mm Hg)
Week 8Week 0
Office
Blood
Pressure*
4.5 2.1
15.7 2.2
p = 0.001
Week 4
7.6 2.8
17.4 2.9
p = 0.069
Week 6
9.3 3.2
19.6 3.4
p = 0.109
Week 8
10.8 3.5
17.1 3.7
p = 0.842
6
2
-2
-6
-10
-14
-18
Hydrochlorothiazide 50 mg daily
-22
Chlorthalidone 25 mg daily
-26
-30
Hours
6am
8am
10am
12pm
2pm
4pm
6pm
8pm
*All values are expressed as means the standard deviation. The p values
reported are Bonferroni adjusted p values (unadjusted p value 4 tests).
Ernst ME, et al. Hypertension. 2006;47:352-358,
10pm
12am
2am
4am
Hydrochlorothiazide Vs Chlorthalidone
BP lowering effect of Hydrochlorothiazide and Chlorthalidone
SBP reduction
Chlorthalidone
25mg/day
HCTZ 50mg/day
15.7 2.2 mm
4.5 2.1 mm Hg
(Hypertension. 2006;47:352-358.)
P value
P=.001
Diuretics and CVD Events

5 trials have demonstrated the benefit of chlorthalidone-based
regimen in reducing CVD events. No comparator has proven
superior.
Some trials of HCTZ-based regimens have shown benefit;
they used 25-50 mg/day
2 trials of low-dose (12.5-25 mg/day) HCTZ regimens

(ACCOMPLISH, ANBP-2) were found not as effective in
reducing CVD events as the comparator.
BP differences between groups were similar in ACCOMPLISH study
MRFIT
The Multiple Risk Factor Intervention Trial
Hypertension. 2011;57:689694.
MRFIT
Men ages 35-57 years, upper 10%-15% of CHD
risk, randomization to Special Intervention (SI)
or Usual Care (UC), stratified by clinical center
Choice of diuretic allowed to initiate treatment
in SI group; some clinics predominantly used
HCTZ (50 or 100 mg) while others used
predominantly chlorthalidone (50 or 100 mg)
Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-1628.
MRFIT: H and C Clinics
No. Clinics
No. Participants
% Hypertensive at entry
No. SI
No. UC
Baseline BP
SBP (mm Hg)
DBP (mm Hg)
H Clinics
C Clinics
9
5,466
6
3,193
62.2 %
1725
1674
66.1%
1046
1066
141.5
95.5
142.0
95.8
H- Hydrochlorothiazide C- Chlorthalidone
MRFIT
Four years into the study the DSMB
requested all SI participants on HCTZ be
converted to chlorthalidone.
MRFIT
Probability of event-free cardiovascular events with thiazide-type diuretic
In a retrospective cohort analysis, significantly fewer CV events were

noted with chlorthalidone compared with HCTZ (P=.0016)
Hypertension. 2011;57:689694
Conclusion: Chlorthalidone is the preferred thiazide-type diuretic for

treating those patients with hypertension who are at high risk for CV events.
MRFIT
Leading up to protocol change
H clinics: 44% more CHD, 16% more death
(vs UC patients)
C clinics: 58% less CHD, 41% less death
(vs UC patients; majority of diuretic use in
UC remained HCTZ)
After switch to C
H clinics: 28% less CHD, 26% less death vs
UC (P = 0.04, 0.06)
Multiple Risk Factor Intervention Trial Research Group. Circulation. 1990;82:1616-1628.
Bartsch G et al. Circulation. 1984;70(suppl II):II-1438.
ALLHAT
ALLHAT: Antihypertensive and LipidLowering Treatment to prevent Heart

Attack Trial
Heart Attack Trial. JAMA 2002;288:298197.
ALLHAT
Purpose
To determine whether, in hypertensive patients, the calcium channel
blocker amlodipine or the angiotensin converting enzyme inhibitor
lisinopril reduces coronary heart disease and other cardiovascular
disease compared with the thiazide diuretic chlorthalidone
The ALLHAT Officers and Coordinators for the ALLHAT
Collaborative Research Group.
Heart Attack Trial. JAMA 2002;288:298197.
ALLHAT Study Design

Doxazosin
n=9,062
YEAR 1
YEAR 5
Intent-toTreat
Analysis
Discontinued
early at 3.3 yrs
Randomized
n=42,418
Chlorthalidone
n=15,255
Amlodipine
n=9,048
Lisinopril
n=9,054
n=13,854
n=8,215
n=8,158
2,235 (16.1%)
stopped drug
1,357 (16.5%)
stopped drug
1,842 (22.6%)
stopped drug
n=6,210
n=3,769
n=3,605
1,873 (30.2%)
stopped drug
1,052 (27.9%)
stopped drug
1,399 (38.8%)
stopped drug
n=15,255
n=9,048
n=9,054
339 (2.2%) lost to follow-up

80 (0.5%) refused follow-up

ALLHAT Research Group. JAMA. 2002;288:2981-2997.

www.hypertensiononline.org
ALLHAT Endpoints
Primary endpoint
Composite of fatal coronary heart disease (CHD) or nonfatal
myocardial infarction (MI)
Other predefined endpoints
all-cause mortality
stroke
combined CHD nonfatal MI, CHD death, coronary
revascularization, hospitalized angina
combined cardiovascular disease combined CHD, stroke,
lower extremity revascularization, treated angina, fatal/
hospitalized/treated congestive heart failure, hospitalized or
outpatient peripheral arterial disease
other renal
ALLHAT Mean Systolic and Diastolic Blood

Pressure During Follow-up
Chlorthalidone
Amlodipine
150
Lisinopril
145
Compared to chlorthalidone:
SBP significantly higher in
amlodipine (~1 mmHg) and
lisinopril (~2 mmHg) groups.
140
135
130
Diastolic BP (mmHg)
Systolic BP (mmHg)
Chlorthalidone
90
Amlodipine
Lisinopril
85
Compared to chlorthalidone:
DBP significantly lower in
amlodipine group (~1 mmHg).
80
75
70
6
0
1
Follow-up, yrs
SBP=systolic blood pressure DBP=diastolic blood pressure

ALLHAT BP Controlled
to <140/90 mmHg
Chlorthalidone
Amlodipine
% Patients with
BP <140/90 mmHg
70
60
*
50
Lisinopril
Year 4
Year 5
40
30
20
10
0
Baseline
Year 1
Year 2
Year 3
*P<0.001 for amlodipine vs chlorthalidone

P<0.001 for lisinopril vs chlorthalidone
ALLHAT Primary Outcome

by Treatment Group
Fatal CHD and nonfatal MI
Cumulative
event rate
(%)
20
16
12
8
Chlorthalidone
Amlodipine
Lisinopril
0
0
Years after randomization

ALLHAT Officers and Coordinators.
JAMA 2002; 288 :2981 97.
ALLHAT Combined CV Disease

Relative Risk Favors
Relative Risk
Favors
(95% CI) amlodipine chlorthalidone (95% CI)
TOTAL
1.04
(0.99-1.09)
1.10
(1.05-1.16)
Age <65
1.03
(0.94-1.12)
1.05
(0.97-1.15)
Age 65
1.05
(0.99-1.12)
1.13
(1.06-1.20)
Men
1.04
(0.98-1.11)
1.08
(1.02-1.15)
Women
1.04
(0.96-1.13)
1.12
(1.03-1.21)
Black
1.06
(0.96-1.16)
1.19
(1.09-1.30)
Nonblack
1.04
(0.97-1.10)
1.06
(1.00-1.13)
Diabetic
1.06
(0.98-1.15)
1.08
(1.00-1.17)
Nondiabetic
1.02
(0.96-1.09)
1.12
(1.05-1.19)
0.5

Favors
Favors
lisinopril chlorthalidone
0.5
ALLHAT Stroke
Relative Risk
Favors
TOTAL
0.93
(0.82-1.06)
1.15
(1.02-1.30)
Age <65
0.93
(0.73-1.19)
1.21
(0.97-1.52)
Age 65
0.93
(0.81-1.08)
1.13
(0.98-1.30)
Men
1.00
(0.85-1.18)
1.10
(0.94-1.29)
Women
0.84
(0.69-1.03)
1.22
(1.01-1.46)
Black
0.93
(0.76-1.14)
1.40
(1.17-1.68)
Nonblack
0.93
(0.79-1.10)
1.00
(0.85-1.17)
Diabetic
0.90
(0.75-1.08)
1.07
(0.90-1.28)
Nondiabetic
0.96
(0.81-1.14)
1.23
(1.05-1.44)
0.5

Favors
Favors
0.5
Cumulative event rate (%)
ALLHAT Heart Failure

by Treatment Group
No. at Risk
Chlorthalidone
Amlodipine
Lisinopril
15
Chlorthalidone
Amlodipine
12
P<0.001 for chlorthalidone vs

amlodipine and chlorthalidone
vs lisinopril
Lisinopril
9
6
3
0
15255
9048
9054
14528
8535
8496
13898
8185
8096
3
4
5
Time to event, yrs
13224
7801
7689
11511
6785
6698

6369
3775
3789
3016
1780
1837
384
210
313
ALLHAT Heart Failure

Relative Risk
Favors
TOTAL
1.38
(1.25-1.52)
1.20
(1.09-1.34)
Age <65
1.51
(1.25-1.82)
1.23
(1.01-1.50)
Age 65
1.33
(1.18-1.49)
1.20
(1.06-1.35)
Men
1.41
(1.24-1.61)
1.19
(1.03-1.36)
Women
1.33
(1.14-1.55)
1.23
(1.05-1.43)
Black
1.47
(1.24-1.74)
1.32
(1.11-1.58)
Nonblack
1.33
(1.18-1.51)
1.15
(1.01-1.30)
Diabetic
1.42
(1.23-1.64)
1.22
(1.05-1.42)
Nondiabetic
1.33
(1.16-1.52)
1.20
(1.04-1.38)
0.5

Favors
Favors
0.5
ALLHAT
ALLHAT Conclusions
Better control of systolic BP was achieved with

chlorthalidone than with amlodipine or lisinopril
There were no differences in risk for CHD
death/nonfatal MI between chlorthalidone and
amlodipine or lisinopril
In secondary endpoints, chlorthalidone was
associated with lower risk for
stroke, combined CVD, and HF compared with
lisinopril
HF compared with amlodipine
MI=myocardial infarction
CHD=coronary heart disease
HF=heart failure
ALLHAT
ALLHAT Implications
Unless contraindicated, or unless specific indications

are present that would favor use of another drug
class, diuretics should be the initial drug of choice in
antihypertensive regimens
Only 30 percent of patients achieve both systolic BP
<140 mmHg and diastolic BP <90 mmHg on
monotherapy
Many high-risk hypertensive patients will require 2

or more drugs for BP control
The Systolic Hypertension

in the Elderly Program, 1991 (SHEP)
The Systolic Hypertension in

the Elderly Program, 1991
Cohort
4,736; 43% men
Age
60 yrs old; mean 71.6 yrs old
Eligibility
Systolic BP 160219 mmHg and

Diastolic BP <90 mmHg
Design
Double blind; placebo control
Therapy
Chlorthalidone (atenolol as step 2)
Duration
4.5 years
BP change
Systolic BP 12 mmHg
BP=blood pressure
SHEP Research Group. JAMA. 1991;265:3255-3264.
SHEP
Change in Blood Pressure
Diastolic BP
Change in BP (mmHg)
Systolic BP
80
180
170
Placebo (n=2,371)
75
Placebo (n=2,371)
160
70
150
Active Rx (n=2,365)
Active Rx (n=2,365)
65
140
2 3
Years
SHEP=Systolic Hypertension in the Elderly Program

2 3
Years
BP=blood pressure
Blood pressure (mmHg)
SHEP
Average Blood Pressure During Follow-up
200
185
170
155
140
125
110
95
80
65
50
0
12
24
36
Months of follow-up
48
60
Cumulative stroke rate

per 100 persons
SHEP
Cumulative Stroke Rate
10
9
8
7
6
5
4
3
2
1
0
P=0.0003
Placebo
(n=2,371)
Active Rx
(n=2,365)
12
24
36
48
Months of follow-up
60
72
Relative risk (95% CI)
SHEP
Cardiovascular Disease Endpoints
Active Therapy vs. Placebo
1.60
1.40
1.20
1.00
0.80
0.60
0.87
0.63
0.68
0.75
0.46
0.40
0.20
Stroke
CHD
CHF
CVD
Death
CHD=coronary heart disease; CHF=congestive heart failure; CVD=cardiovascular disease

SHEP
Conclusions
SHEP was the first clinical trial to demonstrate that
reduction of blood pressure in patients with isolated
systolic hypertension reduced cardiovascular (CV)
mortality
The relative risk of stroke was reduced by 36% with
chlorthalidone compared to placebo (P=0.0003)
The 5-year absolute benefits were a reduction in 30
strokes and 55 major CV disease events per 1,000
persons
The Australian National

Blood Pressure (ANBP) Study, 1980
The Australian National

Blood Pressure Study, 1980
Cohort
Age
Eligibility
Design
3,427; 80% men

3069 yrs old
Diastolic BP 95109 mmHg

Single blind; placebo control
Therapy
Chlorothiazide (methyldopa, beta blocker)
Duration
4 yrs
BP
difference
-6 mmHg
The Australian Study Committee. Lancet. 1980;1:1261-1267.
The Australian Study

Mean Diastolic Blood Pressure
Diastolic blood
pressure (mmHg)
104
Placebo
100
Active
96
92
88
84
80
At Screening
During Trial

Incidence of Trial Endpoints (TEP)*
Intention-to-treat
Placebo (n=1,706)
Active (n=1,721)
No.
Rate
No.
Rate
35
5.1
25
3.6
Cardiovascular
18
2.6
1.1
Non-cardiovascular
17
2.5
17
2.4
Non-fatal TEP
133
19.4
113
16.2
All TEP
168
24.5
138
19.7
Total Fatal TEP
*Rates per 1,000 person-years exposure to risk.

P<0.05
P<0.025

Intention-to-Treat Trial Endpoints
No. of events
Placebo
n=1,706
Active
n=1,721
Fatal
11
Nonfatal myocardial infarction
22
28
Nonfatal other
76
65
16
10
Other fatal
18
17
Other nonfatal
10
Ischemic heart disease
Cerebrovascular events
Fatal
Nonfatal
Hemorrhage or thrombosis
Transient cerebral ischemic attacks

On-Treatment Trial Endpoints (TEP)
Number of trial endpoints
140
120
Active (n=1,721)
All TEP
P<0.01
Placebo (n=1,706)
100
80
60
All Fatal TEP
40
P<0.05
20
0
400
600
1200
Days in trial

Reprinted with permission from Elsevier Science.
1600
2000

Conclusions
The actively treated compared to placebo
group experienced 30 fewer trial endpoints
endpoints (P<0.05)
There was a significant reduction in mortality

in the actively treated group, mostly due to a
reduction in death from cardiovascular
disease (P<0.025)
Association between chlorthalidone treatment of

systolic hypertension and long-term survival
22 years of follow-up after chlorthalidone stepped-care
therapy for 4.5 years in the SHEP trial.
Study Design: A national death index ascertainment of
death in the long-term follow up of SHEP trial of patient
aged 60 years or older with isolated systolic hypertension
Main outcome measures: cardiovascular death and allcause mortality
JAMA. 2011;306(23):2588-2593.

Results: Blood pressure
Active treatment group
Placebo
Reduction in SBP from baseline

(mmHg)
-26
-15
Reduction in DBP from baseline

(mmHg)
-9
-4
Lowering in mean SBP (mmHg)
- 11-14
Lowering in mean DBP (mmHg)
- 3-4
Goal BP achievement(%)
65-72
32-40

Results: Life expectancy at 22 years
Active treatment
group
P-value
Life expectancy gain from Cardio-vascular

death
158 d
P=.009
Life expectancy gain from All-cause mortality
105 d
P=.07
Life expectancy free of cardiovascular death

If controlled at first year
215.2 d
If controlled at the second year
130.7 d
If controlled at the end of study
215.3 d
Life expectancy free of all-cause mortality

If controlled at first year
195.6 d

Conclusion:
The active treatment group was associated with
higher survival free from cardiovascular death
compared with the placebo group
The gain in life expectancy free from cardiovascular death

corresponds with approximately 1 day gained for each month of
treatment.
JAMA. 2011;306(23):2588-2593.
Chlorthalidone: Pleiotropic effects

Reduce epinephrine-mediated platelet aggregation.
Increase transcription of vascular endothelial growth
factor C and transforming growth factor-beta3
Thereby lead to reduced vascular permeability to
albumin and increased angiogenesis
These properties explain the ability of chlorthalidone
to reduce cardiovascular morbidity.
Hypertension. 2010 Sep;56(3):463-70. Epub 2010 Jul 12.
Chlorthalidone
Head-to-head studies favor chlorthalidone as a more
effective blood pressure lowering agent compared with
HCTZ
CTD produce superior 24-hour blood pressure control
compared with HCTZ
When comparing the 2 drugs, CTD had significantly fewer
CVEs compared with HCTZ.
SHEP trial: Chlorthalidone treatment was associated with
36% reduction in total stroke incidence
27% lower incidence of nonfatal MI and coronary death
32% reduction in all cardiovascular event
Hypertension. 2011; 57: 689-694
Chlorthalidone
Each month of chlorthalidone therapy associated with an
additional day free from risk of cardiovascular death
CTD displayed significantly lower SBP, total cholesterol,
low-density lipoprotein cholesterol, potassium, and higher
uric acid compared with HCTZ.
Given the documented irregular intake of antihypertensive
drugs, the prolonged efficacy of chlorthalidone makes this
agent a "forgiving drug" with a definite advantage over
hydrochlorothiazide.
Combining Antihypertensive Drugs
Most drug classes can be combined safely in most patients.
Diuretic will combine well with any other class.
Non-DHP CCBs and clonidine should not be combined with bblockers (DHPs combine well).
b-blockers add little BP efficacy to ACEIs, ARBs, or other

adrenergic inhibitors except a-blockers.
ESH 2003: Possible Combinations of Different Classes of

Antihypertensive Agents
The most rational combinations are represented as thick lines
Diuretics
b-blockers
AT1-receptor
blockers
a-blockers
Calcium
antagonists
ACE inhibitors
ESH/ESC Guidelines Committee. J Hypertens. 2003;21:1011-1053.
Example of an Effective Combination

Regimen:
Diuretic + ACEI or ARB + CCB
Could add reserpine or aldosterone

antagonist
Examples of Combination Regimens
Diuretic + ACEI (or ARB) + CCB and/or reserpine
Diuretic + b-blocker + DHP CCB and/or a-blocker
Diuretic + b-blocker + vasodilator + aldosterone antagonist
For rare patient who cannot take a diuretic:

ACEI (or ARB) + CCB + reserpine
Angiotensin II
Non-ACE pathways
escape
(e.g. chymase, tPA,
cathepsin)
Angiotensinogen
Vasoconstriction
Cell growth
Sodium/water retention
Sympathetic activation
Angiotensin I
AT1 receptor
ACE
Bradykinin
ACE
Angiotensin II
Inactive fragment
Aldosterone
Sodium/water
retention
Adapted with permission from Dzau. J Hypertens Suppl. 2005;23(1):S9S17.
AT2 receptor
Vasodilation
Antiproliferation
Tissue regeneration
Natriuresis
RAAS
Renal
Sodium
Retention
Sympathetic
Nerve
Activity
Preload
Contractility
Heart Rate
Vasoconstriction
Blood Pressure = C.O. X Peripheral Resistance
Oxidative Stress
Inflammation
NAD(P)H oxidase activity
Vascular permeability Leucocyte infiltration
Reactive oxygen species
Activation of signalling pathways
LDL peroxidation
LOX-1 expression
Angiotensin II
Production of
inflammatory mediators
Nitric oxide
Proliferation of VSMCs
Vasoconstriction
PAI-1 activation
Platelet aggregation
Endothelial dysfunction
Schmieder et al. Lancet 2007;369:12081219
Matrix deposition
MMP activation
Tissue remodelling
Myocardial infarction
and stroke
Atherosclerosis
and
left ventricular
hypertrophy
Risk factors
Remodelling
CV High-Risk
Ventricular dilation/
cognitive dysfunction
Congestive heart failure/

secondary stroke
Hypertension
Angiotensin II
Adapted from
Dzau VJ, et al. Circulation 2006;114:28502870; Figure adapted from Dzau V, Braunwald E.
Am Heart J 1991;121:12441263; Yusuf S, et al. Lancet 2004;364:937952
HF
Death
Death
Angiotensin converting
enzyme inhibitors (ACE)
Captopril,
Enalapril,
Lisinopril
Ramipril
Perindopril
Angiotensin II receptor
Blockers (ARBs)
Losartan
Irbesartan
Olmesartan
Candesartan
Valsartan
Telmisartan
Azilsartan
Bradykinin/NO
Angiotensin I
ACEACE
Inhibitor
Inactive fragments
ACE-independent
ANG II formation
by Chymase, etc.
Angiotensin II
ARB
AT1 RECEPTOR
Vasoconstriction
Sodium retention
SNS activation
Inflammation
Growth-promoting effects
Aldosterone
Apoptosis
AT2 RECEPTOR
Vasodilation
Natriuresis
Tissue regeneration
Inhibition of inappropriate cell growth
Differentiation
Anti-inflammation
Apoptosis
SNS = sympathetic nervous system

Hanon S, et al. J Renin Angiotensin Aldosterone Syst 2000;1:147150;
Chen R, et al. Hypertension 2003;42:542547; Hurairah H, et al. Int J Clin Pract 2004;58:173183;
Steckelings UM, et al. Peptides 2005;26:14011409
Percent (%)
P value*
<0.001
<0.001
* ARB p value vs each of the other classes (Chi-Square)

Chaput AJ. Can J Cardiol 2000;16(suppl F):194A
<0.001
0.060
Telmisartan- The Uniqueness
Telmisartan is an angiotensin II receptor antagonist

that is highly selective for Type1 angiotensin II
receptors

Onset of action : 3 hours
Longer elimination half-life of 24 hrs
High affinity towards AT1 receptor (telmisartan > olmesartan > candesartan >
valsaratan > losartan)
Very slow dissociation rate
These unique properties of Telmisartan ensure improved 24- hr control of blood

pressure as compared to other ARBs
24-hour action of Telmisartan covers the early morning risk- hours
when the need for the BP control is the greatest

Longest elimination Half-Life
Range
Burnier M., Lancet 2000;355:637645

Brunner HR., J Hum Hypertens 2002;16(Suppl 2):S13S16
Liters
500
450
400
350
(Index of the Ability of a Drug to Enter Tissues

Throughout the Body)
300
250
200
150
100
50
Candesartan Valsartan
Olmesartan
Losartan
Losartan
Metabolite
Irbesartan
Telmisartan
Telmisartan most potently activates the PPAR-y

Fold activation
16
14
12
10
8
6
4
2
Losartan
Olmesartan
Eprosartan
Irbesartan
5 micromolar
Valsartan
Candesartan
Telmisartan
Implication of activating PPAR-
Improves insulin sensitivity

Decreases adipocyte cell size
Decrease hepatic fat storage

Decreased serum glucose
and serum triglyceride levels, and increased

glucose uptake and GLUT4 protein expression
These effects improve metabolic syndrome and reduce the risk of
atherosclerosis
Hypertension
Indicated for treatment of hypertension
May be used alone or in combination with other antihypertensive agents
Cardiovascular Risk Reduction

Indicated for risk reduction of myocardial infarction, stroke, or death from
cardiovascular causes in patients 55 years of age or older at high risk of developing
major cardiovascular events who are unable to take ACE inhibitors.
High risk for cardiovascular events can be evidenced by a history of coronary artery
disease, peripheral arterial disease, stroke, transient ischemic attack, or high-risk
diabetes (insulin-dependent or non-insulin dependent) with evidence of end-organ
damage
Telmisartan is particularly useful in following groups of

hypertensive patients:
Intolerance to ACE inhibitor
Diabetics
Patients with heart failure.
Elderly
Renal impairment
90
Ambulatory DBP
(mm HG)
85
80
75
70
Baseline
65
Final Visit
60
8:00 AM
n=1628
12:00 PM
4:00 PM
8:00 PM
12:00 AM
4:00 AM
Time of day
White WB, et al. Blood Press Monit. 2005;10:157-163.
8:00 AM
Change in mean ABPM blood pressure during the first 4

hours after awakening2
Blood Pressure Reduction (mm

HG)
SBP
DBP
-5
-7.08.9
-10
-11.513.2
-15
White WB, et al. Blood Press Monit. 2005;157:157-161.
Early-morning BP control:
Telmisartan Vs existing therapy
Additional DBP reductions (mm HG) when telmisartan is added to
patients uncontrolled on current therapy at the end of the dosing period
Beta Blockers
CCBs
-4.8
n=56
-0.2
n=56
-5.8
n=35
ACE Inhibitors
-2.3
n=36
Telmisartan 40mg 80mg plus current therapy
-6.8
n=49
HCTZ
-5.2
n=50
-10.6
n=14
1.9
n=15
Placebo plus current therapy
Gil-Extremera B, et al. Int J Clin Pract. 2003;57:861-866.
Change in BP in Last 6
Hours of the Dosing Period
(mm HG)
Reduction in SBP in elderly patients

treated with telmisartan
0
SBP
-5
-10
-15
n=448
-20
-18.3
No overall differences in effectiveness and safety of telmisartan was observed in elderly patients
compared with younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Neldam S, Edwards C, on behalf of the ATHOS Study Group. Am J Geriatr Cardiol. 2006;15(3):151-160.
Percentage of patients achieving

BP control
A large percentage of patients

achieved blood pressure control
Office (n=1627)
100
90
80
90
90%
91%
80
82%
79%
70
70
60
60
50
SBP
<140
ABPM (n=1628)
100
DBP
<90
SBP/DBP
<140/90
71%
70%
50
SBP
<130
White WB, et al. Am Heart J. 2006;151:176-184.
DBP
<85
SBP/DBP
<130/85
In Combination with Other

Antihypertensive Agents
Adjunctive therapy with Telmisartan
calcium channel antagonist
a -blocker
a diuretic agent
Was effective in controlling Blood Pressure
Drugs 2006; 66 (1)
Comparison of Telmisartan with

other Anti-hypertensive Drugs
Comparison with other ARBs

Versus Losartan :Telmisartan monotherapy (40 or 80mg OD)
demonstrated superior anti-hypertensive efficacy to Losartan
monotherapy (50mg or 100mg OD)
Versus Valsartan: Telmisartan monotherapy (4080mg OD)
demonstrated better anti-hypertensive efficacy than Valsartan
monotherapy (80160mg once daily)
Drugs 2006;66(1) 51-83
Comparison with other ARBs

Parameter
Telmisartan
Olmesartan
24 hrs
13 hrs
Trough Peak Ratio
66 -100 %
60 -80%
24 hr control of BP*
Complete 24 hr control of
BP covers early morning
Hour
Incomplete 24 hr control
of BP
More Lipophilic so better

tissue penetration and hence
better inhibition of tissue
RAAS
Less lipophilic so less

inhibition of tissue RAAS.
1% urine
99% stools
35-50% urine
50% stools
No dosage adjustment
20 mg maximum in severe
disease
Present therefore Improves

insulin sensitivity and lipid
profile
Absent
Elimination
Half- life (hr)
Lipophilicity
Elimination
Renal Insufficiency
PPAR Agonistic activity
Telmisartan Vs Losartan
Aim: Anti-hypertensive efficacy & tolerability of Telmisartan and
Losartan compared with placebo in a
6-week study
Patients: 223 patients with mild-to moderate Hypertension
Treatment: Telmisartan 40 mg, telmisartan 80 mg, losartan 50 mg, or
placebo
J Hum Hypertens. 1999 Oct;13(10):657-64.
Telmisartan Vs Losartan
Telmisartan more effective anti-hypertensive during
18-24 hour peroid after dosing( P<0.05)
Reduction in Blood
Pressure
Telmisartan 40mg
-5
Telmisartan 80mg
-6/3.7 mm Hg
-10
-10.7/6.8mm Hg
-12.2/7.1 mm Hg
Losartan 50mg
-15
J Hum Hypertens. 1999 Oct;13(10):657-64
Patients: 533 patients with mild- moderate hypertension

Duration: 26-week
Treatment :
- Telmisartan (40 mg titrated to 80 mg titrated to 120 mg)
- Atenolol (50 mg titrated to 100 mg)
- Hydrochlorothiazide (HCTZ) 12.5 or 25 mg was added if needed
Clin Ther. 2001 Jan;23(1):108-23.
Telmisartan more effective than Atenolol in Controlling

Systolic Blood Pressure(p=0.003)
80%
% of
Patient
showing
Reduction
of SBP >
or =
80
70
68%
Telmisartan
Atenolol
60
Reduction from baseline in SBP of > or = 10 mm Hg achieved by 80% of

Telmisartan-treated and 68% of Atenolol-treated patients (P = 0.003)
Clin Ther. 2001 Jan;23(1):108-23.
Result
Final SBP/DBP reductions of 20.9/14.4 mm Hg for Telmisartan versus
16.7/13.3 mm Hg for Atenolol
Difference in SBP was significant (P = 0.005)
Safety Profile:
Incidence of mild to moderate adverse effect was lower in Telmisartan as
compared to Atenolol. ( 52.7% vs 61.2% )
Incidence of Fatigue and male impotence more common in Atenololtreated patients (3.4% vs 4.0%)
Clin Ther. 2001 Jan;23(1):108-23.
Versus Calcium Channel Blockers:

Comparison of efficacies & duration of action of
Telmisartan and Amlodipine
Patients: 234 patients with hypertension
Treatment:
40 mg Telmisartan increased to 80 and 120 mg as necessary for patients
5 mg Amlodipine titrated to 10 mg as necessary for patients
Placebo (n = 81)
12 weeks of double-blind treatment
Both drugs also significantly reduced 24 h mean systolic blood pressures and DBP
compared with placebo (P < 0.0001)
Blood Press Monit. 1998 Oct;3(5):295-302.
Comparison of efficacies & duration of action of

Telmisartan and Amlodipine
Telmisartan effective in controlling Diastolic Blood
pressure
% patients with
Twenty four-hour
mean ABPM DBP <
85 mmHg
80
71%
55%
60
40
Telmisartan
20
Amlodipine
Twenty four-hour mean ABPM DBP < 85 mmHg were observed in 71% of Telmisartan
patients and in 55% of patients administered Amlodipine
Comparison of efficacies & duration of action

of Telmisartan and Amlodipine
Reductions in DBP with Telmisartan greater (P < 0.05) than with
Amlodipine during the night-time interval and the last 4 h of the dosing
period
Both Telmisartan and Amlodipine well tolerated
Drug-related edema occurred significantly more commonly

(P < 0.05) among the patients administered Amlodipine
than it did among patients administered either Telmisartan
or placebo.
Telmisartan indicated for

reduction of CV morbidity
Hypertension
Losartan
Epro-sartan
Irbe-sartan
Olme-sartan
Valsartan
Cande-sartan
Renal disease with hypertension and T2DM
Prevention of stroke in hypertensive patients with LVH
CV High-Risk
Telmisartan
Telmi-sartan
Type 2 diabetes with target organ damage
Coronary Heart Disease
Peripheral Vascular Disease
Stroke
Product information provided by EMA (http://www.emea.europa.eu) and eMC (http://emc.medicines.org.uk)
Telmisartan is indicated* for the reduction of CV morbidity in

patients with
1. manifest atherothrombotic cardiovascular disease (history of
coronary heart disease or stroke, or peripheral vascular
disease) or
2. diabetes with documented target organ damage
Because telmisartans unique pharmacology leads to proven differences
in organ protection a class effect cannot be assumed
* EMEA: European Medicines Agency

Bakris G, et al. Telmisartan is more effective than losartan in reducing proteinuria in patients
with diabetic nephropathy. Kidney Int 2008:74:364369.
Mechanism of Cardiovascular Protection by

Telmisartan
Expert Opin. Pharmacother. (2008) 9(8):1397-1406
ONTARGET trial
CV High-Risk
patients
ONTARGET: The ONgoing Telmisartan Alone and

in combination with Ramipril Global Endpoint
Trial
ACE-inhibitors (e.g. ramipril in the HOPE trial) reduces
CV death, MI,
stroke and HF hosp in those with CVD or DM in the absence of ventricular
dysfunction or heart failure
ACE-inhibitors are not tolerated by 15% to 25% of patients

Will an ARB (telmisartan) be as effective and better tolerated?
Is the combination superior?
Teo K, et al. Am Heart J 2004;148:5261; The ONTARGET Investigators. N Engl J Med 2008;358:15471559
n=25,620
n=8,542
Telmisartan 80 mg
n=8,576
Ramipril 10 mg
n=8,502
Telmisartan 80 mg + Ramipril 10 mg
5.5 years
Follow-up at 6 weeks and every 6 months

*Age 55 years at high risk of a CVD event
(i.e. with a history of: coronary artery disease, peripheral arterial occlusive disease (PAD),
cerebrovascular event, or diabetes mellitus with end-organ damage)
Teo K, et al. Am Heart J 2004;148:5261; The ONTARGET Investigators. N Engl J Med 2008;358:15471559
Telmisartan 80mg reduces devastating CV events similar to

ramipril 10mg in CV High-Risk patients
Reduction in composite CV risk
Cumulative Hazard Ratio
0.20
0.15
0.10
p< 0.01 vs.

non-inferiority margin (1.13)
0.05
0
No. at risk
Telmisartan
Ramipril
Telmisartan
Ramipril
8,452
8,576
8,177
8,214
7,778
7,832
7,420
7,472
7,051
7,093
Reduction in composite CV risk (Primary endpoint: cardiovascular mortality, non-fatal myocardial infarction,
hospitalisation for congestive heart failure, non-fatal stroke)
The ONTARGET Investigators. N Engl J Med 2008;358:15471559
Years of followup
1,687
1,703
5
Largest ever trial investigating the reduction of cardiovascular morbidity

and mortality
Telmisartan demonstrated long-term CV protection similar to the
reference standard ACE-inhibitor, ramipril in a broad range of high-risk
patients
Results demonstrate the CV protective effects of telmisartan beyond

blood pressure reduction
Telmisartan was better tolerated than ramipril and provided greater
long-term adherence, despite the fact that patients were selected for
ramipril tolerance at start
ONTARGET
Myocardial infarction
and stroke
LIFE
VALUE
Atherosclerosis
and
left ventricular
hypertrophy
Risk factors
Hypertension
CV High-Risk
Remodelling
ValHeFT
VALIANT
CHARM
Ventricular dilation/
cognitive dysfunction
HF
Death
Adapted from
Dzau VJ, et al. Circulation 2006;114:28502870; Figure adapted from Dzau V, Braunwald E.
Am Heart J 1991;121:12441263; Yusuf S, et al. Lancet 2004;364:937952
Congestive heart failure/

secondary stroke
Death
TRANSCEND:
Telmisartan Randomized
AssesmeNt Study in aCE iNtolerant Subjects with Cardiovascular Disease
ONTARGET / TRANSCEND Investigators
Koon K. Teo, MB, PhD, FRCPC
The TRANSCEND Investigators. Lancet 2008; 372:1174-83.
TRANSCEND :
Question:
1. Is telmisartan superior to placebo in patients at high risk of CV events who are intolerant
of ACE-I?
Outcome:
1. Primary: CV death, MI, stroke, CHF hosp
2. Key secondary: CV death, MI, stroke (HOPE trial outcome)
Design:
Single blind run-in (n=6,666)
Randomized, double blind, placebo controlled study conducted in 630 centers in 40
countries (n=5,926)
56 months follow-up with 99.7% outcome ascertainment
Primary and Key - Secondary Outcomes

Telm
Plac
HR (CI)
Primary
CV death, MI,
Stroke
465 (15.7%)
504 (17.0%)
0.92 (0.81-1.05)
0.2158
384 (13.0%)
440 (14.8%)
0.87 (0.76-1.00)
0.0475
227 (7.7%)
223 (7.5%)
1.03 (0.85-1.24)
116 (3.9%)
147 (5.0%)
0.79 (0.62-1.01)
112 (3.8%)
136 (4.6%)
0.83 (0.64-1.06)
134 (4.5%)
129 (4.3%)
1.05 (0.82-1.34)
CV death
MI
Stroke
CHF hosp
Composite endpoint of CV death, MI and stroke in TRANSCEND

confirms protective effect of telmisartan in CV High-Risk patients
Telmisartan + Standard of Care
Standard of Care
Cumulative incidence
(%)
Hazard ratio 0.87 (95% CI 0.76 - 1.00); p = 0.048

13.0%
Years of
follow-up
n at risk
Telmisartan
+ Standard of Care
Standard of Care
2,954
2,839
2,745
2,634
2,344
1,127
2,972
2,866
2,745
2,626
2,306
1,103
Reduction of composite CV risk (Secondary endpoint: CV death, MI, stroke [=HOPE primary endpoint])
Primary endpoint (Composite endpoint of CV death, MI, Stroke and hospitalization for Heart failure)
Hazard ratio 0.92 (not significant)
Conclusions: Telmisartan vs.

Placebo
1. Telmisartan reduces the primary outcome by 8% (P=0.22), but

reduces significantly the main secondary outcome of CV death, MI
or stroke by 13% (P=0.048).
2. Telmisartan is well tolerated and there is no excess of adverse
events
Advantages of Combining Telmisartan and

Chlorthalidone
Head-to-head studies favor chlorthalidone as a more effective
blood pressure lowering agent compared with HCTZ
CTD produce superior 24-hour blood pressure control compared
with HCTZ
CTD displayed significantly lower SBP, total cholesterol, lowdensity lipoprotein cholesterol, potassium, and higher uric acid
compared with HCTZ
Clinical trials and the clinical practice setting indicates that
Telmisartan, either as monotherapy or in combination with
other antihypertensive agents, is effective in a broad spectrum
of hypertensive patients:
Including the elderly
Those with coexisting type 2 diabetes
Metabolic syndrome
Renal impairment
Thus combining the two would give an agent with unsurpassed
advantage of superior BP control and CV protection conferred
by the two agents

Chlorthalidone-Telmisartan The New Renaissance

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Chlorthalidone: The Renaissance

Risk of hypertension (%)

Lifetime Risk of Developing

Residual lifetime risk of developing hypertension

Ratio (%) of actual to

Mortality According to Blood Pressure

Systolic blood pressure (mmHg)

Blood Pressure and Risk for

<120 120- 140- 160- 180+

Risk of CHD Death

Systolic blood pressure (SBP)

Diastolic blood pressure (DBP)

CHD=coronary heart disease

Risk of Stroke Death According

Systolic blood pressure (SBP)

He J, et at. Am Heart J. 1999;138:211-219.

Age-adjusted annual CVD

Isolated Systolic Hypertension

ISH BP 160/<95 mmHg

CVD=cardiovascular disease ISH=isolated systolic hypertension

Landmark Clinical Trials

Hypertension Treatment and Cardiovascular Disease Outcomes

1967 VA Cooperative Study on DBP 115-129

Pharmacologic Treatment in JNC 7

JNC 7 Recommendation for

JNC 7 Algorithm for

(SBP >160 or DBP >100 mmHg)

40% had BP >160/90 mm Hg

Berlowitz, et al: NEJM 1998;339:1957-63

Classification and Management

Without compelling indication

No antihypertensive drug indicated

Thiazide-type diuretics for most.

Two-drug combination for most

JNC 7. JAMA. 2003;289:2560-2572.

Drug(s) for compelling

Drug(s) for the compelling

Classification and Management

Without compelling indication

No antihypertensive drug indicated

Thiazide-type diuretics for most.

Two-drug combination for most

JNC 7. JAMA. 2003;289:2560-2572.

Drug(s) for compelling

Drug(s) for the compelling

Classification and Management

Without compelling indication

No antihypertensive drug indicated

Thiazide-type diuretics for most.

Two-drug combination for most

JNC 7. JAMA. 2003;289:2560-2572.

Drug(s) for compelling

Drug(s) for the compelling

Classification and Management

Without compelling indication

No antihypertensive drug indicated

Thiazide-type diuretics for most.

Two-drug combination for most

JNC 7. JAMA. 2003;289:2560-2572.

Drug(s) for compelling

Drug(s) for the compelling

Classification and Management

Without compelling indication