Recent Clinical Trial Results: A Critique

1
Recent Clinical Trial Results A Critique

• Ronald G. Victor, M.D.Chief, Hypertension
  DivisionNorman Audrey Kaplan ChairSO
  HWESTERN Medical Center

2
How well have recent trials addressed 3 questions?

• Does drug class matter?
• BP targets how low should we go?
• Can HTN be prevented?

3
Controversies in CV Medicine
Management of Hypertension Is It the Pressure
or the Drug?
Its Only the BP William J. Elliott M. Charlotte
Jonsson Henry R. Black
Drug Counts Peter S. Sever Neil R. Poulter
Sever et al. Circulation. 20061132754-2772 (A).
4
Angiotensin II
AT1R
Superoxide Inflammation Cell Growth,
Fibrosis Aldosterone, NE
? BP
Atherosclerosis
?Glucose
Remodeling of Heart Vessels
Plaque Progression
MI Stroke
Victor, J Clin Hypertens, 2007 in press
Death
5
Hypothesis

• For equivalent reductions in BP,
  RAAS blockers provide more target organ
  protection and prevent more CV
  events than do other antihypertensives

• Recent ACEI trials
• Recent ARB trials
• b-blockers as comparators

6
Recent ACEI Trials

• BP Titration Trials
• ALLHAT
• ASCOT

• ACEI Add-on Trials
• HOPE
• EUROPA
• PEACE

7
ALLHATSmaller Fall in BP With ACEI but Identical
Outcome
Lisinopril
Amlodipine
Chlorthalidone
Blood Pressure
1 CHD Outcome
Systolic
n33,357
? BP2/1 Plt.01
mm Hg

Diastolic
Pns
Years After Randomization
ALLHAT Collaboration Research Group. JAMA.
20022882981-2997 (A).
8
ASCOT BP-LATerminated Early Due to Mortality
Difference
1 CHD End Point
Blood Pressure
10
180
8
Systolic
Atenolol thiazide
140
Amlodipine perindopril
6
? BP3/2 Plt.0001
mm Hg

100
4
n19,257
Diastolic
2
60
HR0.90 P.1052
0
0
0
1
2
3
4
5
6
0
1
2
3
4
5
Years After Randomization
Dahlöf et al. Lancet. 2005366895-906 (A).
9
ASCOT BP-LALarge Difference in Stroke Favoring
CCB/ACEI
Stroke
180
Blood Pressure
5.0
4.0
HR0.77 P.0007
140
3.0
? BP3/2 P.0001
mm Hg

100
2.0
1.0
60
0
0.0
0
1
2
3
4
5
Years After Randomization
Dahlöf et al. Lancet. 2005366895-906 (A).
10
ACEI vs Placebo for Added CV Protection
Yusuf et al. N Engl J Med. 2000342145-153 (A)
Fox et al. Lancet. 2003362782-788
(A)Braunwald et al. N Engl J Med.
20043512058-2068 (A).
11
CHD Added Protection With ACEIs But Not CCBs
ACEIs
CCBs
INSIGHT
NICOLE
UKPDS39
STOP2/CCB
NORDIL
ALLHAT-ACEI
ELSA
SPN
NCS
ACTION
PEACE
CAPPP
INVEST
Odds Ratio for CHD
ALLHA-/CCB
PROGRESS
PREVENT
STOP2/ACE-1
VHAS
ANBP2
EUROPA
CONVINCE
STONE
HOPE
SYST-EUR
CAMELOT
Syst-China
PROGRESSCom
CAMELOT
IDNT2
28 trials N179,122
Systolic BP Difference Between Randomized Groups
(mm Hg)
Verdechia et al. Hypertension. 200546386-392
(A).
12
Stroke Added Protection With CCBs But Not ACEIs
ACEIs
CCBs
MIDAS
PART-2
CAPPP
VHAS
ALLHAT-/ACEI
CONVINCE
UKPDS39
NICS
ANBP2
ALLHAT-CCB
EUROPA
SHELL
PREVENT
Odds Ratio of Stroke
INSIGHT
PROGRESS
STOP2/ACE-1
INVEST
PROGRESSCom
STOP2/CCB
NORDIL
PEACE
ACTION
Syst-China
CAMELOT
HOPE
ELSA
SYST-EUR
IDNT2
NICOLE
CAMELOT
STONE
SCAT
Systolic BP Difference Between Randomized Groups
(mm Hg)
Verdechia et al. Hypertension. 200546386-392
(A).
13
HOPE Small ABPM Substudy (n20)
Clinic data underestimated BP reduction with
ramipril
Day ? BP10/4
Night ? BP17/8
180
Baseline
140
Systolic
BP (mm Hg)
Ramipril
100
Diastolic
60
Clock Time (hours)
Svensson. Hypertension. 200138e28-e32 (A).
14
Superiority of Ambulatory (Nocturnal) BP for
Predicting CV Death
3.5
Nocturnal BP
N5292
3.0
24-hour BP
2.5
Daytime BP
Adjusted 5-Year Risk of CV Death ()
2.0
Conventional Office BP
1.5
1.0
0.5
90
110
130
150
170
190
210
230
Systolic BP (mm Hg)
Dolan. Hypertension. 200546156-161 (A).
15
Recent ARB Trials

• VALUE
• LIFE

Ang I
Alternative Pathways
ACE
Ang II
ARB
AT2R
AT1R
BP
CVD
16
Controversies in CV Medicine
Do angiotensin receptor blockers INCREASE the
risk of MI (MI Paradox)?
Pro Martin H. Strauss Alistair S. Hall
ConRoss T. Tsuyuki Michael A. McDonald
Strauss and Hall. Circulation. 2006114838-854
(B) Tsuyuki and McDonald. Circulation.
2006114855-860 (B).
17
VALUEValsartan Associated With Higher Rate of MI
ButSlower and Smaller Fall in BP
Blood Pressure
Myocardial Infarction
Valsartan based (80-160 mg)
N15,245
Amlodipine based (5-10 mg)
Systolic
mm Hg

Diastolic
HR1.19 P.02
Months After Randomization
Julius et al. Lancet. 20043632022-2031 (A).
18
VALUE Monotherapy SubgroupComparable Risk
Reduction With Comparable BP Reduction
Blood Pressure
Myocardial Infarction
Valsartan 80-160 mg
N7080
Amlodipine 5-10 mg
Systolic
mm Hg

HR1.041 P.788
Diastolic
Months After Randomization
Julius et al. Hypertension. 200648385-391 (A).
19
LIFEBenefit of Losartan Over Atenolol But
Blood Pressure
1 Composite End Point
Losartan 50-100 mg
Atenolol 50-100 mg
Systolic
n9193
? BP1/0 P.014
mm Hg

Diastolic
HR.87 P.021
Months After Randomization
Dahlöf et al. Lancet. 2002359995-1003 (A).
20
Losartan Was Superior to Atenolol Against Stroke
but Not MI
Stroke
Myocardial Infarction
8
8
Losartan 50-100 mg
6
6
Atenolol 50-100 mg


4
4
2
2
Adjusted risk reduction -7.3, P.491
Adjusted risk reduction 24.9, P.0010
0
0
0
12
36
48
24
60
6
18
42
54
30
66
0
12
36
48
24
60
6
18
42
54
30
66
Months After Randomization
Dahlöf et al. Lancet. 2002359995-1003 (A).
21
Higher Central Aortic BP(Hemodynamic Load) With
?-Blockers?
Brachial BP
Central Aortic BP (Derived)
Amlodipine
Atenolol
140
140
Atenolol
120
120
100
100
Amlodipine
80
80
0.2
0.4
0.6
0.8
0
1
0.2
0.4
0.6
0.8
0
1
CAFÉ Investigators. Circulation.
20061131213-1225 (A).
22
Brits Not Bully on b-Blockers
News National Institute for Health and Clinical
Excellence removes b blockers as first-line
treatment for uncomplicated hypertension
Susan Mayor
--Prevent fewer strokes than other
agents --Predispose to new-onset diabetes
(especially when combined with a thiazide)
Mayor S. BMJ. 20063338.
23
New Onset Diabetes in ASCOT
Atenolol ? thiazide

Amlodipine ? perindopril
HR 0.68 (0.600.77) Plt.0001
Years
Dahlöf et al. Lancet. 2005366895-906 (A).
24
New Onset Diabetes and CV Outcomesin VALUE
Aksnes TA et al., S. Hypertension. 200750467-473
.
25
b-Blockers no longer 1st or 2nd line Rx for HTN?
2 big caveats
UNCOMPLICATED HTN (10 vs. 20 prevention)
Standard b-blockers (need data on a-,b-
blockers)
Generic cardevilol now 4/pill at Wal-Mart
26
Does drug class matter how far have we come?
27
Not Far Enough

• Selection bias for high-risk older patients
• Unplanned crossover between groups
• Nonequivalent reductions in BP (hemodynamic
  load)
• Incomplete RAAS blockade

28
(Pro)renin receptor
DRI
Prorenin
Renin
PRA
Angiotensinogen
ACE-I
ACE
B-blocker
Ang I
Non-ACE pathway
Ang II
Ang IV
Ang III
ARB
Victor , J Clin Hypertens, 2007 in press.
29
COOPERATE ARB Plus ACEIfor Greater RAAS
Inhibition
1? Renal End Point
Blood Pressure
Losartan 100 mg
Systolic
Trandolapril 3 mg
Combination

mm Hg
n263
P.02
Diastolic
Months After Randomization
Nakao et al. Lancet. 2003361117-124 (A).
30
ARB Plus ACEI for Greater Cardiovascular
Protection?
ONTARGET/TRANSCEND
Ramipril 10 mg
Telmisartan 80 mg
/-
ABPM Substudy
The ONTARGET/TRANSCEND Investigators. Am Heart J.
200414852-61 (A).
31
For now.
Optimal CV risk reduction includes

• Combination antihypertensive Rx
• To attain BP targets
• Protect against MI and stroke
• Lipid-lowering Rx
• Antiplatelet Rx

Polypill?
32
How well have recent HTN trials addressed 3
questions?

• Does drug class matter?
• BP targets how low should we go?
• Can HTN be prevented?

33
What are the optimal systolic diastolic BP
targets for patients with CAD?
2 recent post-hoc analyses with different
conclusions

• Messerli et al. (INVEST)
• Sipahi et al. (CAMELOT)

34
Dont let diastolic BP fall lt70-80 mmHg
J-Curve?
Messerli F et al., Ann Int Med 2006144884-889
35
Get systolic BP lt 120 mmHg and dont worry about
diastolic BP

• CAMELOT-
• IVUS substudy
• n274
• Entry BP 130/77

--Wide CIs --Small effects
Sipahi I, et al., JACC 2006 48833-838.
36
2007 AHA Guidelines Treatment of Hypertension in
the Prevention and Management of Ischemic Heart
Disease
In achieving a target BP lt 130/80 mmHg for
secondary prevention, the BP should be lowered
slowly and caution is advised in inducing falls
of diastolic BP below 60mmg.
Rosendorff C et al., Circulation
2007,1152761-2788.
37
How well have recent HTN trials addressed 3
questions?

• Does drug class matter?
• BP targets how low should we go?
• Can HTN be preventedwith early
• RAAS blockade?

38
TROPHY

• BUT we need
• active comparator
• (ARB gt CCB?)
• longer follow-up
• younger patients

Placebo
100
Candesartan 16 mg qd
80
Active Treatment in Candesartan Arm
60
Cumulative Incidence of HTN ()
Year 4Plt.007RRR15.6
40
Year 2Plt.001RRR66.3
20
0
0
1
2
3
4
Study Year
TROPHYTrial of Preventing Hypertension.Julius
S, Nesbitt, S et al. N Engl J Med.
20063541685-1697 (A).
39
CONCLUSION--Future Needs

• ABPM central aortic BP
• Larger sample size achieving lower BP targets
• Younger study patients (at high risk)
• Dissociate trial objectives design from
  financial or economic agenda of the funding
  agencies.