The Recent Treatment Trials,, VALUE -- ASCOT

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

Reduction in Events
CHF Strokes LVH CVD CHD events Fatal/Non-fatal D
eaths 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. 1996271214-1218 Arch Intern Med
1993S76-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 Endpointsin Value Study
9
Valsartan Antihypertension Long-Term
Use Evaluation Trial (VALUE)
Early control of BP appears to make
a difference in outcome
10
ASCOT Trial Baseline 1
9,339 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 2005366895
11
Primary Objectives
ASCOT Trial
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 2005366895
12
ASCOT Trial
BP Targets lt140/90 m Hg or lt130/80 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 2005366895
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 ccb/ace is superior to
  older therapybbl/diuretic 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 2005366895
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.
• Messerli, 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 ----
  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 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 some
  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 Lisinopril
Group Group Group
Combined CVD Total 30.9 32.0
33.3 GFR gt 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 lt60 mL/min per 1.73 m2 38.7
41.1 41.3
Significant difference LC
Annals Intern Med 2006144176
29
Coronary Heart Disease Events in ALLHAT by
Glomerular Filtration Rate at Baseline
Variable 6-Year Rates per 100
Chlorthalidone Amlodipine Lisinopril
Group Group Group
Nonfatal MI and fatal CHD Total 11.5 11.3
11.4 GFR gt 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 lt60 mL/min per 1.73 m2 15.2 16.0
15.1
Annals Intern Med 2006144176
30
THE LATEST CONTROVERSY
PREHYPERTENSION--- WHAT SHOULD WE DO ABOUT IT?
THE TROPHY TRIAL
31
JNC 7 Blood Pressure Classification
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

• Do not support the term pre hypertension
• 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
Optimal lt120/80 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. 20013581682.
35
(No Transcript)
36
Prehypertension
Hypertension

• Lifestyle Intervention
• Pharmacologic Intervention

37
Sustained Effect of Early vs Late Treatment with
ACEI in SHR
Harrap SB. Hypertension. 199016603.
38
TOHP Study
Arch Intern Med. 1997157657.
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.
Nonpharmacologic therapy
SD Nesbitt
42
Trends in Systolic BP
- 10.4 mmHg
- 2.0 mmHg
43
Kaplan-Meier Curves of Clinical Hypertension in
the Two GroupsNumbers under the graph refer to
hypertension-free individuals
1.0
0.9
Candesartan Placebo
0.8
0.7
0.6
Cumulative incidence
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 18
4 118 85
44
TROPHY Conclusions

• Over a period of four years, nearly two thirds
  of the placebo group developed stage 1
  hypertension.
• 2. 1 Treatment with an ARB suppressed onset of
  stage 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 hemorrhages 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
In persons gt68 years of age CCBs have a 86
increased incidence of gastrointestinal bleeding
compared to users of B-blockers.
Pahor M, et al. Lancet 1996347(9008)1061-65
48
Nurses Health Study The results of this study
of 14,617 hypertensive women show that calcium
channel blockers increased incidence of
myocardial infarction by 64, compared to those
taking thiazide diuretics.
Michels KB, et al. Circ 19982897(16)1540-48
49
CCBs increase risk of suicide more than 5-fold
compared to nonusers.
CCBs and ACE-inhibitors have a 30 increased
incidence of depression requiring medication,
compared to non-users.
Lindberg G, et al. BMJ 1998316741-45
Halls J. Epidemiology 19967(5)478-84
50
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

51
Based upon these new data, what should the
treatment algorithm look like? Are the JNC 7
recommendations still valid?
52
Algorithm for Drug Treatment of Hypertension
Initial Drug Choices
Without Specific or Compelling Indications
Stage 2 Hypertension (SBP gt160 or DBP gt100
mmHg) 2-drug combination for most (usually
thiazide-type diuretic and ACEI/ARB/CCB or BB
??
Stage 1 Hypertension (SBP 140159 or DBP 9099
mmHg) Thiazide-type diuretics for most. May
consider ACEI, ARB, CCB, or BB ??---or
combination.
Combination therapy may also be appropriate
initial therapy in patients with diabetes or
renal disease
53
(No Transcript)
54
(No Transcript)
55
TROPHY Study Cardiovascular Risk Factor Profile

• 96 have at least 1
• additional Risk Factor
• 81 have 2 additional Risk Factors
• 33 have 4 additional Risk Factors

Number of Risk Factors
Nesbitt S. Am J Htn. 200518980.
56
Baseline Characteristics of the Intention to
Treat Group (cont.)
Candesartan Placebo N391 N381 Cholesterol
202.934.9 205.7 39.1Chol ? 200
(mg/dL) 53.6 57.5 Triglycerides 145.886.1 159.8
110.8 Trig ? 150 (mg/dL) 34.9 41.2 HDL
(mg/dL) 48.913.7 49.214.5lt40 male / lt50
female 36.3 36.8 Glucose (mg/dL) 95.511.2 95.9
18.2 Creatinine (mg/dL) 0.84.2 0.85.2
Note Values represent mean SD where noted.
57
The Median Time to Development of Hypertension


Years
3.3
2.2
Candesartan Placebo
58
Prevention of Hypertension
90
Early Treatment
Prevalence
50
20
18
50
80
Age
59
TOHP Study
Enrollment DBP Endpoint First Screen 81-97 A) Trea
tment of Hypertension Initiated Second
Screen 82-92 B) 3X (at any return visit) Third
Screen 83-89 - average 140 and or 90 or higher
Arch Intern Med. 1997157657.
60
Trials of Hypertension Prevention TOHP II
n1400 individuals with diastolic BP 80-89 mm Hg
Incidence of Hypertension (BP gt 140/90)
Time, months
Arch Intern Med. 1997157657.
61
VALUE Analysis of Results Based on BP Control
at 6 Months
Pooled Treatment Groups
Odds Ratio

Fatal/Non-fatal cardiac events
0.75 (0.670.83)

Fatal/Non-fatal stroke
0.55 (0.460.64)

All-cause death
0.79 (0.710.88)
Myocardial infarction
0.86 (0.731.01)

Heart failure hospitalizations
0.64 (0.550.74)
0.4
0.6
0.8
1.0
1.2
1.4
Controlled patients (n 10755)
Non-controlled patients (n 4490)
Hazard Ratio 95 CI
SBP lt 140 mmHg at 6 months.
P lt 0.01.
Weber MA et al. Lancet. 2004363204749.
62
CONFUSING MESSAGES FROM THE HYPERTENSION
TREATMENT TRIALS

• What and whom shall we believe?