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ASCOT TRIAL
Abbas Zaidi
20/09/05
Hypertension is one of the most
prevalent risk factors for
cardiovascular disease, affecting as
many as 800 million people
worldwide.
 It is estimated that at least 80
percent of people with high blood
pressure may also have other
uncontrolled cardiovascular risk
factors with elevated cholesterol
being the most common.


In a typical Western country with a
population of 50 million people, about
eight million receive treatment for high
blood pressure; beta-blockers and
diuretics.
The NICE guideline advises that first-line treatment
should be
 A low-dose thiazide diuretic



Except in patients under 55 with moderately raised blood
pressure, for whom a beta-blocker may be more effective
and should be considered as an alternative first-line
therapy.

If monotherapy is unsuccessful, a beta-blocker should be
added.

The combination of a thiazide and a beta-blocker may still
be effective in patients under 55 but is associated with a
slightly increased risk of diabetes.
Introduction

Several randomized clinical trials in hypertension have
documented that most of the antihypertensive drug classes
reduce major cardiovascular end points such as heart
attack, stroke, and congestive heart failure to a similar
extent. Therefore, most authoritative guidelines have time and
again recommended to preferentially use b-blockers and
diuretics because they are less expensive than the newer
drugs, such as calcium antagonists and blockers of the reninangiotensin system (ARBs).

The rationale for the design of the Anglo-Scandinavian Cardiac
Outcomes Trial (ASCOT) was the lack of outcome data for
the two most commonly used newer drug classes--that is,
calcium antagonists and ACE inhibitors, and to compare this
combination with a b-blocker/diuretic combination.
Aim

The primary objective of ASCOT was to
compare the long-term effect on nonfatal myocardial infarction (MI) and
fatal coronary heart disease of a
standard antihypertensive regimen (bblockers and diuretic) with a more
contemporary combination of a calcium
antagonist blocker and an ACE
inhibitor.

It was conducted in more than 650
general practices and 32 regional
medical centers across the United
Kingdom, Ireland, and the 5
Scandinavian countries (Denmark,
Finland, Iceland, Norway, and
Sweden).

The ASCOT results predicted that, if the
amlodipine and perindopril combination
were prescribed in only half of the
patients currently receiving a betablocker/diuretic combination for the
treatment of high blood pressure, over a 5
1/2 year period

There would be nearly 100 000 fewer
cardiovascular events and procedures,
nearly 40 000 fewer strokes and 35 000
fewer deaths from cardiovascular disease.
There would also be over 90 000 fewer
patients who develop type 2 diabetes.

Method: ASCOT was an independent, multicenter, randomized
study designed to evaluate the separate and combined effects
of antihypertensive and lipid-lowering therapy on cardiac
outcome in patients (n = 19,342) with hypertension and no
history of coronary heart disease.

The study used a prospective, randomized, open,
blinded end point (PROBE) design to compare the
effects of a calcium antagonist-based regimen
(amlodipine) plus an ACE inhibitor (perindopril, if
necessary) versus a b-blocker-based
regimen (atenolol) (plus a diuretic,
bendroflumethiazide-K, if necessary).
ASCOT LLA

A subset of patients were further
randomized to receive atorvastatin
10 mg/d (n = 5168) or placebo (n =
5137) in a double-blind fashion.
The trial protocol called for bringing
nondiabetic patients to blood pressure
targets of < 140 mm Hg systolic
blood pressure and < 90 mm Hg
diastolic blood pressure
 Diabetic patients to targets of < 130
mm Hg SBP and < 80 mm Hg DBP.


The 2 antihypertensive regimens were
administered in 6 incremental steps,
depending on whether patients achieved
their blood pressure goals. First-line
drugs were increasing doses of
amlodipine or atenolol, followed by
combination with perindopril or BFZ,
respectively, to bring patients to goal. If
this was not sufficient, the alpha-blocker,
doxazosin could be added as a third drug,
at the discretion of the physician, to either
of the 2 drug combinations
"Newer" Regimen
"Standard" Regimen
Step 1
Amlodipine
5 mg
Atenolol
50 mg
Step 2
Amlodipine
10 mg
Atenolol
100 mg
Step 3
Amlodipine
10 mg
Atenolol
100 mg
Perindopril
4 mg
BFZ + K
1.25 mg
Amlodipine
10 mg
Atenolol
100 mg
Perindopril
8 mg
BFZ + K
2.5 mg
Amlodipine
10 mg
Atenolol
100 mg
Perindopril
8 mg
BFZ + K
2.5 mg
Doxazosin GITS
4 mg
Doxazosin GITS
4 mg
Amlodipine
10 mg
Atenolol
100 mg
Perindopril
8 mg
BFZ + K
2.5 mg
Doxazosin GITS
8 mg
Doxazosin GITS
8 mg
Step 4
Step 5
Step 6



In October 2004, the independent Data Safety
Monitoring Board (DSMB) recommended stopping
ASCOT due to benefits in favor of
amlodipine/perindopril-based antihypertensive
therapy compared with atenolol/bendroflumethiazideK-based antihypertensive therapy.
.
The data safety monitoring board determined
that there was a higher event rate in the
atenolol arm.
Blood pressure was well controlled in both arms of the study (Table 2). At the end of the
study, mean blood pressure was lower in the amlodipine/perindopril group by 2.9/1.8
mm Hg.
Table 2. ASCOT-BPLA: Mean Blood Pressure Over Time
Amlodipine/
Perindopril
Atenolol/
BFZ
Baseline
Study end
Baseline
Study end
SBP (mm Hg)
164.1
135.5
163.9
136.3
DBP (mm Hg)
94.8
71.1
94.5
78.4
BFZ = bendroflumethiazide; DBP = diastolic blood pressure; SBP = systolic blood pressure





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The combination reduced
Major cardiovascular events by 16%
(P<0.001),
Stroke by 23% (P=0.003)
Cardiovascular mortality by 24%
Total mortality by 11% (P=0.025)
compared with the regimen of the betablocker atenolol with or without
bendroflumethiazide.
There were significantly fewer new
cases of diabetes, 567 versus 799
(P<0.0001)

What Were the Reasons for These Results?
Several possible explanations for the results:
 Better blood pressure lowering with
amlodipine/perindopril
 An adverse interaction between atenolol/thiazide
and the statin
 A beneficial interaction between atenolol/thiazide
and the statin
 Extra blood pressure-lowering benefits of
amlodipine/perindopril; and
 Non-blood pressure-lowering disadvantages for
atenolol/thiazide.


The ASCOT researchers said that
the blood pressure by itself can
only explain 15% to 35% of the
positive outcomes in the
amlodepine arm.
Conclusion
The results of ASCOT are substantial
and important.
 We must consider whether the muchused regimen of beta-blockers
followed by thiazides is the
automatic choice for our patients.
