Recent Clinical Trial Results A Critique

1
Recent Clinical Trial Results - A Critique

• William Cushman, MD
• Professor, Preventive Medicine and Medicine
• University of Tennessee College of Medicine
• Chief, Preventive Medicine
• Memphis VA Medical Center

2
How low should BP be treated with
antihypertensive medications?

• Epidemiologic data suggest a continual gradient
  of risk with increasing BP beginning at 115/75 mm
  Hg.
• However, most BP trials demonstrating major CVD
  benefits of antihypertensive treatment have
  treated to specific goals
• SBP lt150-160 mm Hg SHEP mean SBP 142-143 mm Hg
  supports SBP goal 140 mm Hg
• DBP lt90 mm Hg (lt80 mm Hg in DM)
• Trials testing lower goals for CVD or renal
  outcomes have mostly failed to show further
  benefit, but are often underpowered

3
Systolic Blood Pressure and Cardiovascular
Mortality in Type 2 Diabetes MRFIT Screenees
250
Nondiabetic Patients Diabetic Patients
225
200
175
150
CV Mortality Rate/10,000 Person-Years
125
100
75
50
25
0
lt120
120139
140159
160179
180199
³200
SBP (mm Hg)
SBPsystolic blood pressure CVcardiovascular.
Stamler J, et al. Diabetes Care. 199316434-444.
4
Cushman, et al. Am J Cardiol 20079944i-55i
5
ADVANCE a factorial randomised trial of blood
pressure lowering andintensive glucose control
in11,140 patients with type 2 diabetes
Presented at European society of Cardiology,
Vienna, 9/2/07
Effects of a fixed combination of the ACE
inhibitor, perindopril, and the diuretic,
indapamide on major vascular events
Lancet 2007 Sept 8370829-40
6
Randomised study treatments

• Blood pressure lowering
• Double-blind perindopril-indapamide versus
  matching placebo
• 2.0 / 0.625mg or placebo for first 3 months
• 4.0 / 1.25mg or placebo thereafter
• Blood glucose lowering (ongoing)
• Open-label gliclazide MR-based intensive therapy
  targeting an HbA1c of 6.5 versus usual
  guideline-based care

50 of active group and 60 of placebo group
also had open-label ACE inhibitor added by end of
trial
Lancet 2007370829-40
7
Stroke and Major CVD Reduction in PROGRESS
ACEI perindopril 4 mg Diuretic indapamide 2.5
mg
PROGRESS Collaborative Group. Lancet 2001358
1033-41
8
Primary study outcomes

• Macrovascular
• Non-fatal stroke, non-fatal myocardial infarction
  or death from any cardiovascular cause (including
  sudden death)
• Microvascular
• New of worsening nephropathy or diabetic eye
  disease
• Prespecified analyses
• Macrovascular and microvascular jointly
• Macrovascular and microvascular separately

Combined outcome added in 2005
Lancet 2007370829-40
9
Blood pressure reduction
BP 145/81 mm Hg _at_ baseline
165
Placebo
Perindopril-Indapamide
155
Systolic
145
135
? 5.6 mmHg (95 CI 5.2-6.0) plt0.001
125
Mean Blood Pressure (mmHg)
115
105
95
85
Diastolic
75
? 2.2 mmHg (95 CI 2.0-2.4) plt0.001
65
R
6
12
18
24
30
36
42
48
54
60
Follow-up (Months)
Lancet 2007370829-40
10
Primary outcomesMajor macro or microvascular
event
Number of events
Per-Ind
Placebo
Relative risk
Favours
Favours
(n5,569)
(n5,571)
reduction (95 CI)
Per-Ind
Placebo

Combined macromicro
861
938
9 (0 to 17)
Macrovascular
480
520
8 (-4 to 19)
Microvascular
439
477
9 (-4 to 20)
0.5
1.0
2.0
Hazard ratio
2P0.04
Lancet 2007370829-40
11
All-cause mortality
10
5
Cumulative incidence ()
Relative risk reduction 14 95 CI 2-25 p0.025
0
0
6
12
18
24
30
36
42
48
54
60
Follow-up (months)
Lancet 2007370829-40
12
ADVANCE BP reduction in contextUK Prospective
Diabetes Study
SBP
UK Prospective Diabetes Study
13
Sponsored by the National Heart, Lung, and Blood
Institute
14
ACCORD Three Medical Strategy Questions

• Glycemia
• Intensive control (HbA1clt6.0) vs Standard
  control (HbA1c 7.0-7.9)
• BP
• Intensive control (SBP lt120 mmHg) vs Standard
  control (SBP lt140 mmHg)
• Lipids
• Fibrates to increase HDL-C and lower TG
  statins to lower LDL-C vs
• Statins to lower LDL-C alone

Cushman, et al. Am J Cardiol 20079944i-55i
15
ACCORD Double 2 x 2 Factorial Design
Lipid
BP
Fibrate vs Placebo
Intensive
Std
Intensive Glycemic Control
1383
1374
1193
1178
5128
Standard Glycemic Control
1391
1370
1184
1178
5123
2371
2362
2765
10,251
2753
4733
5518
Lipid treatment groups blinded until end of
trial
Primary analysis compares marginals for main
effects
16
ACCORD Timeline
17
ACCORD BP reduction in context of UK Prospective
Diabetes Study and ADVANCE
ACCORD
SBP
UK Prospective Diabetes Study
18
Meta-analysis of Low-dose Diuretics versus Placebo
Outcome RR P
Diuretics Diuretics better worse
CHD 0.79 0.002
Heart failure 0.51 lt0.001
Stroke 0.71 lt0.001
CVD events 0.76 lt0.001
CVD mortality 0.81 0.001
Total mortality 0.90 0.002
0.40
0.65
0.90
1.15
JAMA. 20032892534-2544
19
Hypertension Treatment by Drug Class
Diuretics
ß-Blocker
ACE Inhibitors
ALLHAT
ARBs
CCBs
IMS Health NDTI, 1978-2002
20
Hypertension Trial
42,418 high-risk hypertensive patients
90 previously treated 10 untreated
STEP 1 AGENTS (Double-blind)
Chlorthalidone 12.5-25 mg
Lisinopril 10-40 mg
Doxazosin 1-8 mg
Amlodipine 2.5-10 mg
N9,061
N9,054
N15,255
N9,048
Blinded drugs titrated and atenolol, clonidine,
reserpine, and/or hydralazine added as needed to
achieve BP goal lt140/90 mm Hg
21
Major Outcomes
Relative Risks and 95 Confidence Intervals
Amlodipine/Chlorthalidone
CHD
0.98 (0.90-1.07)
All-Cause Mortality
0.96 (0.89-1.02)
Stroke
0.93 (0.82-1.06)
Combined CVD
1.04 (0.99-1.09)
Heart Failure
1.38 (1.25-1.52)
ESRD
1.12 (0.89-1.40)
0.50
1
2
Favors Favors Amlodipine
Chlorthalidone
All subgroups were similar
22
Major Outcomes
Relative Risks and 95 Confidence Intervals
Lisinopril/Chlorthalidone
CHD
0.99 (0.91-1.08)
All-Cause Mortality
1.00 (0.94-1.08)
Stroke
1.15 (1.02-1.30)
Combined CVD
1.10 (1.05-1.16)
Heart Failure
1.19 (1.07-1.31)
ESRD
1.11 (0.88-1.38)
0.50
1
2
Favors Favors Lisinopril
Chlorthalidone
All subgroups were similar, except race
23
Only Subgroup DifferencesLisinopril vs
Chlorthalidone in Blacks/Non-Blacks for CVD
Stroke
Non-Blacks
Blacks
1.10 (0.94 - 1.28)
CHD
0.94 (0.85 - 1.05)
1.06 (0.95 - 1.18)
Mortality
0.97 (0.89 - 1.06)
1.19 (1.09 - 1.30)
Combined CVD
1.06 (1.00 - 1.13)
1.40 (1.17 - 1.68)
Stroke
1.00 (0.85 - 1.17)
1.32 (1.11 - 1.58)
Heart Failure
1.15 (1.01 - 1.30)
1.29 (0.94 - 1.75)
ESRD
0.93 (0.67 - 1.30)
0.50 1 2
0.50
1
2
Favors Favors Lisinopril
Chlorthalidone
Favors Favors Lisinopril
Chlorthalidone
24
Cumulative Event Rates for Heart Failure by
Treatment Group
Amlodipine Lisinopril

Number at risk









Amlodipine

9,048

8,535

8,185

7,801

6,785

3,775

1,780

210

Lisinopril

9,054

8,496

8,096

7,689

6,698

3,789

1,837

313


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VALUE Heart Failure
Hospitalisation for HF or Death From HF
9 8 7 6 5 4 3 2 1 0
Valsartan-based regimen
Amlodipine-based regimen
Proportion of Patients With First Event ()
HR 0.89 95 CI 0.771.03 P 0.12
0 6 12 18 24 30 36 42 48 54 60 66
Time (months)
Number at risk
Valsartan
7649
7485
7444
7312
7169
6852
7012
6671
6072
3860
1513
6498
Amlodipine
7596
7486
7444
7312
7176
6874
7033
6702
6100
3823
1511
6534
Julius S et al. Lancet. June 2004363.
26
Heart Failure by Treatment Group
Chlorthalidone Amlodipine Lisinopril

27
Event Rates for Heart Failure by Treatment Group
for Year 1

.02
Amlodipine
Lisinopril
Cumulative HF Rate

.01
Chlorthalidone
0
0
.5
1
Years to HF
Davis, et al. Circulation. 20061132201-10

28
Events Lisinopril vs AmlodipineRelative Risk
and 95 Confidence Intervals
CHD
1.01 (0.91-1.11)
Death
1.05 (0.97-1.13)
Combined CHD
1.04 (0.97-1.12)
Stroke
1.23 (1.08-1.41)
p0.047
Combined CVD
1.06 (1.00-1.12)
ESRD
0.99 (0.77-1.26)
Cancer
1.01 (0.91-1.12)
GI Bleed
1.20 (1.06-1.37)
HF
0.87 (0.78-0.96)
p0.045
Angina
1.09 (1.00-1.19)
Revascularization
1.00 (0.91-1.11)
PAD
1.19 (1.01-1.40)
0.50
1
2
Favors Lisinopril
Favors Amlodipine
Leenen, et al. Hypertension. 200648374-384
29
Second Australian National Blood Pressure Study
(ANBP-2)

• Enalapril/ACEI vs. HCTZ, n 6,083
• Randomized, open-label (blinded endpoint review)
• All CV events or death from any cause
• HR 0.89 (0.79-1.00), p0.05
• First events
• CVD HR 0.88 (0.77-1.01), p 0.07
• CHD HR 0.86 (0.70-1.06), p 0.16
• Stroke HR 1.02 (0.78-1.33), p 0.91
• HF HR 0.85 (0.62-1.18), p 0.33

NEJM 2003348583-92
30

• ALLHAT ANBP-2
• Design Randomized double-blind PROBE
• Thiazide dose similar to SHEP unknown
• Number in 2 arms 24,309 6,083
• On assigned drug _at_ 5 yrs
• ACEI Diuretic ACEI
  Diuretic
• 72 80 58 62
• BP _at_ 5 yrs 135/75 mm Hg
  142/79 mm Hg
• 5-10 times as many CV events in ALLHAT than
  ANBP-2

PROBE prospective randomized open-label,
blinded end-points
31
ASCOT Design
Treatment algorithm to BP targets lt 140/90 mm Hg
or lt 130/80 mm Hg in patients with diabetes
Open-label n 19,257 RZ
amlodipine 5-10 mg
atenolol 50-100 mg
add
add
bendroflumethiazide-K 1.25-2.5 mg
perindopril 4-8 mg
add
Mean BP difference 2.7/1.9 mm Hg Plt0.0001
Primary endpoint Nonfatal MI fatal CHD
doxazosin GITS 4-8 mg
add
additional drugs, eg, moxonidine/spironolactone
Lancet. 2005366895-906
32
ASCOT-BPLA Summary of all End Points
Unadjusted Hazard ratio (95 CI) 0.90
(0.79-1.02) 0.87 (0.76-1.00) 0.87
(0.79-0.96) 0.84 (0.78-0.90) 0.89
(0.81-0.99) 0.76 (0.65-0.90) 0.77
(0.66-0.89) 0.84 (0.66-1.05) 1.27
(0.80-2.00) 0.68 (0.51-0.92) 0.98
(0.81-1.19) 0.65 (0.52-0.81) 1.07
(0.62-1.85) 0.69 (0.63-0.77) 0.85
(0.75-0.97) 0.86 (0.77-0.96) 0.84 (0.76-0.92)
Primary Non-fatal MI (incl silent) fatal
CHD SecondaryNon-fatal MI (exc. Silent) fatal
CHD Total coronary end pointTotal CV event and
proceduresAll-cause mortalityCardiovascular
mortalityFatal and non-fatal strokeFatal and
non-fatal heart failure Tertiary Silent
MI Unstable anginaChronic stable
anginaPeripheral arterial diseaseLife-threatenin
g arrhythmiasNew-onset diabetes
mellitusNew-onset renal impairment Post hoc
Primary end point coronary revasc procs CV
death MI stroke
0.50
0.70
1.00
1.45
2.00
Atenolol ? thiazide better
Amlodipine ? perindopril better
The area of the blue square is proportional to
the amount of statistical information
Dahlöf B et al ASCOT Investigators. Lancet.
2005366895-906.
33
ASCOT vs ALLHAT
34
INVEST Design
n22,576
Non-Calcium Antagonist Strategy
Calcium Antagonist Strategy
Verapamil sustained release, 240 mg/d, plus
trandolapril, 2 mg/d for patients with diabetes,
renal impairment, or heart failure
Atenolol, 50 mg/d, Plus Trandolapril, 2 mg/d for
Patients with Diabetes, Renal Impairment, or
Heart Failure
Step 1
Step 2Add Drug
Verapamil sustained Release, 240 mg/d, Plus
Trandolapril, 2 mg/d
Atenolol, 50 mg/d, Plus Hydrochlorothiazide, 25
mg/d
Step 3IncreaseDose
Verapamil Sustained Release, 180 mg Twice Daily,
Plus Trandolapril, 2 mg Twice Daily
Atenolol, 50 mg Twice Daily, Plus
Hydrochlorothiazide, 25 mg Twice Daily
Verapamil Sustained Release, 180 mg Twice Daily,
Plus Trandolapril, 2 mg Twice Daily, Plus
Hydrochlorothiazide, 25 mg/d
Atenolol, 50 mg Twice Daily, Plus
Hydrochlorothiazide, 25 mg Twice Daily, Plus
Trandolapril, 2 mg/d
Step 4Add Drug
MaximumTreatment
Maximum Tolerated Dose, and/or Add Nonstudy
Antihypertensive Medication
Maximum Tolerated Dose, and/or Add Nonstudy
Antihypertensive Medication
Pepine CJ, et al. JAMA. 20032902805-2816.
www.hypertensiononline.org
35
INVEST Relative Risk of Primary and Secondary
Outcomes
FavorsCAS
FavorsNCAS
0.6
0.8
1.0
1.2
1.4
CAS Calcium Antagonist StrategyNCAS
Non-Calcium Antagonist Strategy
RR (95 CI)
Pepine CJ, et al. JAMA. 20032902805-2816.
36
Are the difference in ASCOT and INVEST results
from

• The INVEST population all having known CAD (vs
  none in ASCOT)?
• Atenolol QD (ASCOT) vs BID (INVEST)?
• Different calcium channel blockers?
• Different thiazide diuretic dose levels added to
  atenolol?
• lower than previous outcome studies (ASCOT)
• Similar to previous outcome studies (INVEST)

37
MRC in the Elderly Effects of Treatment on
Coronary Events
N 4396
Diuretic vs ß-blocker, P 0.006
Cumulative events
Interval from entry (years)
MRC Working Party. BMJ. 1992304405-412
38
Elliott 2006 Meta-AnalysisAtenolol (b-blocker)
vs Other Treatments
Elliott WJ. JACC. 200647 (Suppl)361A.
39
LIFE Cumulative Event Rates
n9,193
Primary Composite Endpoint
Fatal/Nonfatal Stroke
ARR 13.0, P.021 URR 14.6, P.009
ARR 24.9, P.001 URR 25.8, P.0006
16
14
Atenolol
Atenolol
12
10
Patients With First Event ()
8
Losartan
Losartan
6
4
2
0
0
6
12
18
24
30
36
42
48
54
60
66
Fatal/nonfatal MI
CV Mortality
ARR -7.3, PNS URR -5.0, PNS
ARR 11.4, PNS URR 13.3, PNS
Atenolol
Losartan
Patients With First Event ()
Atenolol
Losartan
Study Month
Study Month
ARRadjusted risk reduction URRunadjusted risk
reduction
Dahlöf et al. Lancet. 2002359995-1003
40
VALUE Hazard Ratios for Pre-specified Analyses
Hazard Ratio Valsartan/Amlodipine
Primary cardiac composite endpoint cardiac
mortality cardiac morbidity All myocardial
infarction All congestive heart failure All
stroke All-cause death New-onset diabetes
0.5
1
2
Favours valsartan
Favours amlodipine
Julius S et al. Lancet. 20043632022-2031.
41
Conclusions

• Thiazide-type diuretics should be preferred
  initial therapy for hypertension, unless there is
  a compelling indication for another class
• JNC 7 Thiazide-type diuretics should be initial
  drug therapy for most, either alone or combined
  with other drug classes.
• VA-DoD CPGs Thiazide-type diuretics are
  preferred in patients with uncomplicated
  hypertension most compelling indications should
  include a diuretic.

42
ALLHATCumulative Percent Controlled (BP lt140/90
mm Hg) at Five Years
Derived from Cushman et al. J Clin Hypertens.
20024393-404
43
Initial Combinations of Medications
Diuretics
Can add reserpine, aldosterone antagonist or
amiloride, a-blocker, alternative CCB,
vasodilator, b-blocker, ab-blocker, and/or
central agonist
ACE inhibitors or ARBs
Calciumantagonists
Compelling indications may modify this.
44
Questions?