1

• The Recent Treatment Trials,, VALUE --

ASCOT – Trophy -- Should the results of
these studies change the approach to
Hypertension management?
2

WHAT REALLY MATTERS

IN DECIDING ON THERAPY?

It is still the same old question

Is it blood pressure lowering alone that makes the

difference
or specific medications?
3

Another look at the results

of the
placebo/ controlled long-term

hypertension treatment trials?

4
Results of PLACEBO
CONTROLLED TRIALS
Effect of Antihypertensive Drug
Treatment on Cardiovascular Events
in Events **
% Reduction

CHF Strokes LVH CVD CHD events

Fatal/Non-fatal Deaths Fatal/Non-fatal

*Combined results from 17 randomized placebo controlled

treatment trials (48.000 subjects) Diuretic or Beta-blocker based

**All differences are statistically significant

Moser,J Am Coll Cardiol. 1996;27:1214-1218; Arch Intern Med 1993;S76-S71

5

THE VALUE TRIAL

6
Valsartan Antihypertension Long-Term Use
Evaluation Trial (VALUE)
Valsartan (V) Compared to Amlodipine (A) Based Regimen

No. 15,245 high risk - 4.2 years

Rx V - 80-160 mg/qd + HCTZ; A - 5-10 mg + HCTZ

Results:
Cardiac endpoints - no difference
MI: 25.8% lower with (A) (S)
Heart failure: 12.7% greater with (A) (NS)
Stroke: 17.1% lower with (A) (NS)
7

In the VALUE trial:

•MIs were lower in amlodipine compared to

Valsartan-based treatment groups
•BP control better with Amlodipine
•Differences in BP: 4/2 mm Hg at 6 mos.
1.5/1.3 mm Hg at 1 year

Did the differences in BP or specific treatments

determine the outcome?
8

Primary Composite Endpoints

in Value Study

Valsartan-based regimen Amlodipine-based regimen

Proportionof patients with first event

14
12
10
8
(%)

6
4
2
0
0 6 12 18 24 30 36 42 48 54 60 66
9

Valsartan Antihypertension Long-Term Use

Evaluation Trial (VALUE)

Early control of BP appears to make

a difference in outcome
10

ASCOT Trial*

Baseline:
19,339 patients - 77% men; 95% white -
age 63 yrs - 27% diabetics
BP: 164/94 mm Hg + 3 other risk factors
80% on 1 or 2 medications prior to study
*Anglo-Scandinavian Cardiac Outcomes Trial, Lancet 2005;366:895
11

ASCOT Trial* Primary Objectives

To compare the effect on non-fatal

myocardial infarction (MI) and fatal
CHD of an antihypertensive regimen
based on a B-blocker +/- diuretic with a
regime based on a CCB +/- an ACE inhibitor

, Lancet 2005;366:895
12
ASCOT Trial
BP Targets <140/90 m Hg or <130/80 mm Hg in Patients with Diabetes
Unblinded - Probe Design

Amlodipine 5-10 mg Atenolol 50-100 mg

add add

Perindopril 4-8 mg Bendroflumethiazide-K

1.25 - 2.5 mg
add
Doxazosin 4-8 mg

Other medications

More than 50% in each group were on 2 or more medications; 26% crossed
over to other study drugs; 40% used Rx not prescribed by investigators
*Lancet 2005;366:895
13
ASCOT Trial*

•No significant difference in primary outcome

(fatal & non fatal MI) but CCB/ACE-I significantly
reduced secondary endpoints, i.e., total CHD and CV
events including strokes

•BP control better with CCB/ACE-I, especially 1st

few months (differences 5.9/2.1 mm Hg at 3 months)

•Mean trial differences: 2.7/1.9 mm Hg between therapies

Did the differences in BP or specific treatments
determine the outcome?
14

ASCOT INVESTIGSTORS
CONCLUSIONS

• “Contemporary therapy is
superior to older therapy in the
management of hypertension”---

• “RESULTS ARE
GENERALIZABLE-”-
15

PROBLEMS with those conclusions.

1-The B-blocker used in the ASCOT

trial was inappropriately dosed.

Atenolol is not a once-a-day drug

16

2- It is well-known that in the elderly

B-blockers are not as effective in

lowering BP as a CCB or a diuretic

17

ASCOT Trial*

Report failed to reference or mention

ALLHAT, SHEP or STOP-2 studies

where results were somewhat different

Lancet 2005;366:895
18

• THERE IS LITTLE DOUBT THAT A combination of

an ACEI and a CCB is effective and is a
reasonable choice for therapy for many
hypertensives. At present, however, there is no
strong evidence that this is a preferred combination
when compared to a diuretic/ ACEI or ARB
19

British Hypertension Society 2006

“Based on recent clinical trial data,

[ASCOT TRIAL plus other data]

B-blockers should no longer be used

as initial antihypertensive therapy”

20

B-blockers may be 1st step treatment

In younger people but probably
should be considered as 3rd or
4th step therapy in other patients.

Strong implication that B-blockers

should be withdrawn from treatment
unless compelling indication for
their use---(angina, heart failure,
etc.)
British Hypertension Society, 2006
21

How should we interpret

the hypertension

clinical trial results?

22

Should conclusions of a clinical trial

be based on results of primary or

secondary outcomes?

How much statistical manipulation

is acceptable to prove a point?

23

Criticisms of the ALLHAT Conclusions

Conclusions were based solely on analyses of secondary

endpoints.

“ We should remember [as we were told by the ALLHAT

investigators] that secondary endpoints are ‘soft data’ that
should not form a basis for main conclusions or lead to a
labeling of a drug class as preferred” Messerli ----

WHAT ABOUT ASCOT?

24

Conflicting Data
1. ALLHAT (favors a diuretic) Blinded
2. ASNBP-2 (favors an ACE-I) not blinded.
3. STOP-2
(equal outcomes B-BL/D vs CCB or ACE-I)
4. ASCOT
(different outcomes CCB/ACE-I vs B-BL/D)
5.VALUE
(CCB reduces MI events more than an ARB)

Are there explanations for these differences?

25

CRITICS
ALLHAT
• Wrong add-on drugs
• Demographics favored diuretics
• Should have adhered to primary outcome results
• BP differences accounted for difference in outcome
VALUE – ASCOT
Statistical manipulations to explain results
ASCOT
• Wrong comparator medication
• Secondary analyses for conclusions?
• Are the results “generalizable”?
26

• THE MESSAGE IS CLEAR. WHILE THERE MAY BE

REASONS TO USE SPECIFIC DRUGS, MOST OF THE
BENEFIT REPORTED IN THE CLINICAL TRIALS

RESULTED FROM BP LOWERING with multiple

drug therapy. TRIAL RESULTS ARE,THEREFORE, NOT

REALLY CONFUSING.
27

Why do some experts insist on

finding new reasons for not using

diuretics?

The latest is that they increase ESRD

Some NEW Data from ALLHAT

28
Cardiovascular Disease Events in ALLHAT by
Glomerular Filtration Rate at Baseline

Variable 6-Year Rates per 100

Chlorthalidone Amlodipine
Combined CVD Lisinopril
Group Group Group
Total 30.9 32.0 33.3

GFR > 90 mL/min

per 1.73 m2 25.6 25.3 29.1
GFR 60 - 89 mL/min
per 1.73 m2 29.6 31.2 31.3*
GFR <60 mL/min
per 1.73 m2 38.7 41.1 41.3*

*Significant difference L:C Annals Intern Med 2006;144:176

29
Coronary Heart Disease Events in ALLHAT by
Glomerular Filtration Rate at Baseline

Variable 6-Year Rates per 100

Chlorthalidone Amlodipine Lisinopril
Nonfatal MI Group Group Group
and fatal CHD
Total 11.5 11.3 11.4

GFR > 90 mL/min

per 1.73 m2 8.7 7.6 9.0
GFR 60 - 89 mL/min
per 1.73 m2 10.9 10.9 10.6
GFR <60 mL/min
per 1.73 m2 15.2 16.0 15.1
Annals Intern Med 2006;144:176
30

THE LATEST CONTROVERSY

PREHYPERTENSION---

WHAT SHOULD WE DO ABOUT IT?

31

JNC 7
Blood Pressure Classification

BP Classification SBP mmHg DBP mmHg

Normal <120 and <80

Prehypertension 120–139 or 80–89

Stage 1 Hypertension 140–159 or 90–99

Stage 2 Hypertension >160 or >100

32

“Prehypertension”
45 million Americans

Systolic BP: 120-139 mm Hg

OR

Diastolic BP: 80-89 mm Hg

JNC 7 Report: JAMA, 2003

33

European Guidelines - 2003

1) Do not support the term “pre hypertension”

2) Definition of high normal may be

“hypertension” in people with other risk
factors or “normal” or acceptable in people
without other risk factors
34

Baseline BP Predicts Progression

to Hypertension
4 year hypertension incidence rates
60 60
Age 35-64 Age 65-94 49.5
4 Year Hypertension

50 50
37.3
Incidence %

40 40

30 30 25.5

20 17.6 20 16

10 5.3 10

0 0

Optimal Normal High Optimal Normal High Normal

Normal

Optimal = <120/80 mm Hg
Normal = 120-130/80-85 mm Hg
High Normal = 130-139/85-89 mmHg
Adjusted for sex, age, BMI, and baseline BP

Vasan RS. Lancet. 2001;358:1682.

35

Im pact of High
Impact -Norm al BP on CV Risk
Normal
16
14 Men
High-normal BP
Cumulative 1 2
10 Normal BP
incidence of 8
CV events 6 Optimal BP
(%) 4
2
0

12
W omen
Cumulative 1 0 High-normal BP
incidence of 8
CV events 6
(%) 4 Normal BP
2 Optimal BP
0
0 2 4 6 8 10 12
Years

Optimal BP: <120/80 mm Hg; normal BP:-129/80

120 -84 mm Hg; high
-normal BP: 130
-139/85-89 mm Hg.
VasanRS
VasanRS et al.N EnglJ
EnglJ Med.2001;345:1291
-1297.
36

Prehypertension Hypertension

Can we slow down or reverse the trend?

• Lifestyle Intervention
• Pharmacologic Intervention
 37

Sustained Effect of Early vs Late

Treatment with ACEI in SHR

250 Controls
250 Controls
Systolic BP mm Hg

Systolic BP mm Hg
200
Treatment
200
150
Treatment
150
100

4 8 12 16 20 24 16 20 24 28 32 36
Age (weeks)
Age (weeks)

Early Late

Harrap SB. Hypertension. 1990;16:603.

 38

“TOHP” Study
Weight Combined Sodium Usual Care
Incidence of Hypertension,
50

40

30
%

20 8% difference
10 in hypertension incidence

0
0 6 12 18 24 30 36 42 48
Time, mo

Intern Med. 1997;157:657.

39

CAN FURTHER ELEVATIONS IN B.P.

BE PREVENTED BY TREATING
“PRE-HYPERTENSION”? --------- A NEW
4-YEAR TRIAL TO TEST THE
HYPOTHESIS --------THE TROPHY TRIAL
40

TROPHY STUDY PARTICIPANTS

A study of high normal blood pressure individuals

• N= 809
• Average age: 49 years old
• Average Blood Pressure: 134/85 mm Hg
• Average BMI: 29.9 kg/m2

S Nesbitt 2004
 41

TROPHY Study
Primary Hypothesis: Early short term ARB treatment will
reduce the incidence of hypertension.

Candesartan
Entry BP: 16 mg Placebo
130-139/85-89
mm Hg
Nonpharmacologic
n=809 therapy
Ages 30-65
Placebo Placebo
Two years Two years

SD Nesbitt
42

Trends in Systolic BP
140 30

130 20

120 10

ΔBP (mm Hg)

SBP (mm Hg)

110 0

100 -10
- 10.4 mmHg
- 2.0 mmHg
90 -20

80 -30
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48
Months
Placebo Group
Candesartan Group
Difference between groups (C-P)
43

Kaplan-Meier Curves of Clinical

Hypertension in the Two Groups
Numbers under the graph refer to hypertension-free individuals
1.0
0.9 Candesartan
% Cumulative incidence

0.8
Placebo
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 1 2 3 4

Years in study

Candesartan 391 356 309 191 128

Placebo 381 269 184 118 85
44

TROPHY: Conclusions

1. Over a period of four years, nearly two thirds of the placebo

group developed stage 1 hypertension.

2. Treatment with an ARB suppressed onset of stage 1

hypertension during two years of therapy
- Delayed onset of stage 1 hypertension up to two years after
discontinuation of treatment.
- Therapy -Was well tolerated;.
45

Cautions Regarding
Antihypertensive Drug Therapy

Be careful that you do not

climb aboard a bandwagon
that is headed for a cliff.
46

Some Questionable “Based on Assumptions”

Bandwagons:

• Reserpine causes breast cancer

• Diuretics increase heart attack risk
• CCBs cause GI homorrhages and do not reduce CHD
events
• ACE inhibitors should not be used in people with renal
disease
• Diuretics cause ESRD
• B-blockers may no longer be indicated in the treatment of
hypertension
47

A Bandwagon Constructed on Evidence

• LOWER THE BP CVD outcome will be

improved
• Except for some specific instances, it is the
achieved BP level, not specific medications,
that makes the difference
• Most patients require multidrug therapy
48

Based upon these new data, what

should the treatment algorithm
look like?

Are the JNC 7 recommendations

still valid?
49

Algorithm for Drug Treatment of

Hypertension

Initial Drug Choices

Without Specific or Compelling Indications

Stage 1 Hypertension Stage 2 Hypertension*

(SBP 140–159 or DBP 90–99 mmHg) (SBP >160 or DBP >100 mmHg)
Thiazide-type diuretics for most. 2-drug combination for most
May consider ACEI, ARB, CCB, or (usually thiazide-type diuretic and
BB---or combination.

ACEI/ARB/CCB or BB)

*Combination therapy may also be appropriate initial therapy in

patients with diabetes or renal disease
50