Morbidity and Mortality in Contemporary CAD Patients With
Hypertension Treated With Either a Verapamil/Trandolapril or
Beta-Blocker/Diuretic Strategy (INVEST):
Main Outcomes, Predictors of Risk, Diabetes,
New Diabetes, BP and Depression/QoL Sub-analyses
Carl J. Pepine, MD, MACC
Division of Cardiovascular Medicine
University of Florida College of Medicine
Gainesville, Florida
INVEST OVERVIEW
• Background
– Limited data on optimal care of hypertensive CAD patients
• Design
– PROBE assessing outcomes (e.g. death, MI, stroke) in hypertensive
CAD patients treated w/ either a calcium antagonist (verapamil SR) or
noncalcium antagonist (atenolol) -based strategy with addition of
trandolapril and/or HTCZ to both strategies for BP control
• Hypothesis
– Treatment strategies are equivalent
• BP Goals
– <140/<90 or <130/<85 for diabetes and renal dysfunction
• Recruitment Characteristics
– Conducted in 862 Sites in 14 Countries in 3 geographic regions
– Recruitment from 9/97-12/00; 22,576 patients
– Follow-up complete in 2/03; 61,643 patient years (mean 2.7y/pt)
Overall BP Control at 24 Months
--INVEST-80
% Patients
70
72
63
63
60
-- ALLHAT --
-- LIFE --
71
61
57
54
48
50
45
40
30
20
10
0
JNC VI
<140/<90 mmHg
BP Goal
CAS
NCAS
CAS
NCAS
CHLOR
AML
LIS
LOS
ATEN
Blood Pressure Control
150
Systolic
24 Months
CAS
NCAS
110
90
Diastolic
70
0
1.5
3
4.5
6
12
18
24
30
36
11,267
8594
7738
7119
8558
8639
7758
7842
5721
3659
NCAS (n) 11,309
8676
7726
7148
8573
8694
7710
7850
5834
3679
CAS (n)
Time (Months)
0
Change in BP (mmHg)
(mmHg)
130
Systolic
Diastolic
-5
-10
-10.0 -10.2
p = 0.26
-15
-20
-18.7 -19.0
p = 0.41
Primary and Secondary Outcomes
Unadjusted Relative Risk with 95% CI
Outcome
First Event
CAS
n = 11267
No. (%)
1119 (9.93)
NCAS
n = 11309
No. (%)
p value
1150 (10.17)
0.57
Death
873 (7.75)
893 (7.90)
0.72
Nonfatal MI
151 (1.34)
153 (1.35)
0.95
Nonfatal Stroke
131 (1.16)
148 (1.31)
0.33
CV Death
431 (3.83)
431 (3.81)
0.68
CV Hospitalization
726 (6.44)
709 (6.27)
0.35
0.80
1.0
CAS Better
1.2
NCAS Better
Relative Risk
Pepine, JAMA 2003;290:2805-16
Factors Independently Associated With Increased
Risk of the Primary Outcome (Death, MI or Stroke)
Hazard Ratio Estimates From Multivariate Stepwise Model
Factor
# Events
/# Pts
Event
Rate
HR
p value
CHF (Class I, II, III)
302/1256
24%
<0.0001
Diabetes
913/6400
14%
<0.0001
1999/17131
12%
<0.0001
114/424
27%
<0.0001
322/1629
20%
<0.0001
Smoker
1242/10454
12%
<0.0001
MI
1012/7218
14%
<0.0001
PVD
440/2699
16%
<0.0001
CABG/PCI
877/6166
14%
<0.0001
Black
352/3029
12%
0.0780
US Resident
Renal Insufficiency
Stroke/TIA
Age (By Year)
<0.0001
0.5
1
1.5
2
2.5
Hazard Ratio
Pepine JACC 2006; 47: 547 - 551
Risk of Primary Outcome (Death, MI or Stroke) :
High-Risk Subgroups and SBP Achieved on Treatment
Pepine JACC 2006; 47: 547 - 551
Subgroup
No. Events/
Event Rate
No. Patients
(%)
Diabetes
Absent
<140 mm Hg
775/11491
6.7
140 mm Hg
580/4684
12.4
<140 mm Hg
501/4225
11.9
140 mm Hg
412/2175
18.9
Present
Prior MI
Absent
<140 mm Hg
682/10730
6.4
140 mm Hg
574/4627
12.4
<140 mm Hg
594/4986
11.9
140 mm Hg
418/2232
18.7
Present
0.5
1.0
1.5
HR
Reduced Risk
Increased Risk
2.0
Risk of Death, MI or Stroke by Selected Doses of
Added Therapy: Effect of ACEI and HCTZ
Strategy
CAS
Added Therapy/ Dose
Trandolapril (mg)
0
2
4
NCAS
0
2
4
CAS
HCTZ (mg)
0
12.5
25
NCAS
0
12.5
25
Trand/HCTZ (mg)
CAS
NCAS
4/25
4/25
0.6
0.8
Reduced Risk
1
1.2
Increased Risk
Pepine JACC 2006; 47: 547 - 551
Outcomes in Hypertensive CAD Patients
Without Diabetes at Baseline
Unadjusted Relative Risk with 95% CI
Outcome
CAS
n = 8101
No. (%)
New-Onset Diabetes
569 (7.03)
Death or
New-Onset Diabetes
1050 (12.97)
Primary Event or
New Onset Diabetes
1185 (14.63)
n= patients without diabetes at baseline
NCAS
n = 8082
No. (%)
665 (8.23)
1177 (14.57)
1313 (16.25)
1.0
1.2
0.80
CAS Better
NCAS Better
Pepine JACC 2006; 47: 547 - 551
Predictors of Risk for New Diabetes
Multivariate Analysis
Baseline Covariate
HR
Race: Other
1.63 1.15-2.33
.007
US residency
1.60 1.36-1.89
<.001
LVH
1.25 1.08-1.44
.003
Prior Stroke/TIA
1.24 1.00-1.53
.047
Race: Hispanic
1.21 1.05-1.39
.009
CABG or Angioplasty 1.18 1.03-1.35
.02
Hypercholesterolemia 1.16 1.03-1.31
.01
BMI kg/m2
95% CI
P value
1.01 1.01-1.01
Factors not contributing to increased risk: Asian race; renal impairment;
CHF; PVD; gender, black race; age; smoking; prior MI
<.001
0.5
Reduced Risk
1.0
HR
1.5
2.0
2.5
Increased Risk
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
SBP and Risk of New Onset Diabetes
(Unadjusted)
Hazard Ratio
2.0
1.5
1.0
0.5
100
110
120
130
140
150
160
170
180
SBP (mm Hg) measured at visit prior to diagnosis
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
Risk of New Onset Diabetes by Selected Doses of
Added Therapy: Effect of ACEI and HCTZ
Strategy
Verapamil SR
Atenolol
Verapamil SR
Atenolol
Added Therapy/ Dose
Trandolapril (mg)
0
2
4
0
2
4
HCTZ (mg)
0
12.5
25
0
12.5
25
Trand/HCTZ (mg)
Verapamil SR
Atenolol
4/25
4/25
0.5
1
1.5
2
HR
Reduced Risk
Increased Risk
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
CV Pharmacotherapy and Newly Diagnosed Diabetes
% Reduction of New Diabetes
0
-10
-20
-30
-100
ACE-I or ARB
CA+ACE-I or
ARB
CA
Randomized active treatment vs. SOC (e.g. β-B+/or diuretic)
Adapted from Pepine, Cooper-Dehoff JACC 2004;44:509
INVEST Results: Overall Population
Primary Outcome vs Mean Follow-Up SBP
Overall Population (N = 22,576)
Incidence and Risk of Primary Outcome
SBP <140 SBP 140
HR (95% CI)
8.1%
14.5%
0.58 (0.53-0.63)
50
3.5
Incidence (95% CI)
HR
Incidence (%)
2.5
30
2.0
1.5
20
1.0
10
Estimated Hazard Ratio
3.0
40
0.5
0
Patients with primary
outcome (n)
Total patients (N)
Mean DBP (mm Hg)
0.0
Mean Follow-Up SBP (mm Hg)
45
234
196
1709
493
6859
596
7216
437
3737
253
1663
132
689
57
266
59
202
67.5
73.2
76.5
78.7
81.1
84.2
87.7
90.7
97.4
Meserli Ann Int Med 2006 in press
INVEST Results: Prior MI Subgroup
Primary Outcome vs Mean Follow-Up SBP
Patients With Prior MI (N = 7218)
60
Incidence (95% CI)
4
Hazard Ratio*
Incidence (%)
3
40
30
2
20
1
Estimated Hazard Ratio
50
10
0
0
Mean Follow-up SBP (mm Hg)
Patients with primary
outcome (n)
Total patients (N)
26
112
104
647
237
2133
245
2171
188
1226
108
541
56
236
24
82
24
70
Mean DBP (mm Hg)
67.0
72.4
76.0
78.1
80.4
83.6
87.7
89.3
95.9
Meserli Ann Int Med 2006 in press
INVEST Subanalysis: PP and Risk
5
Nadir = 54 mm Hg
Hazard Ratio
Primary Outcome
(Death, MI, or stroke)
40
4
30
3
20
2
10
1
0
Estimated Hazard Ratio
Incidence (%) of Primary Outcome
PP: Risk for Primary Outcome
0
PP (mm Hg)
Total patients
39
94
608 2403 4046 4532 3815 2567 1755 1137 681 375
218 124
87
94
Stepwise Cox proportional hazards model to estimate hazard ratio (HR);
HR = 1 set at PP=50 mm Hg
Meserli Ann Int Med 2006 in press
INVEST: Predictors of High Depressive
Symptoms
(CESD  16)
Predictor
Baseline CESD Score
Stroke at baseline
Assignment to NCAS
Std coeff
t-statistic
p-value
0.712
0.065
0.055
27.4
2.56
2.22
< .001
0.01
0.03
Not significant:
•Age
•Race
•Gender
•Angina
•Abnormal angiogram
•Myocardial infarction
•CABG/PCI
•Cancer
•PVD
•LVH
•CHF
•Smoking
Reid, D ISOQOL, Prague 11/13/03
SBP and OR for Adverse HRQOL
Baseline to 2yr
Baseline
Visit 1 (n = 22,576)
4.5
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
2.0
2.0
1.5
1.5
4.5
4.5
4.0
4.0
3.5
3.5
3.0
3.0
2.5
2.5
2.0
2.0
1.5
1.5
1.0
1.0
1.0
1.0
.5
.5
.5
1
2
3
4
5
6
1
2
Visit 5 (n = 17,131)
4
5
.5
1
6
2
3
6 mon
4
5
1
6
4.5
4.5
4.0
4.0
12 mon
18 mon
4.0
3.0
3.0
3.0
2.5
2.5
2.5
2.5
2.0
2.0
2.0
2.0
1.5
1.5
1.5
1.5
1.0
1.0
1.0
1.0
.5
.5
.5
3.0
1
2
3
4
5
6
1
2
3
4
5
6
4
5
6
5
6
4.5
3.5
3.5
3
Visit 8 (n = 15,734)
3.5
3.5
2
Visit 7 (n = 15,468)
Visit 6 (n = 17,333)
4.5
4.0
3
18 wk
Visit 4 (n=14,278)
Visit 3 (n = 15,480)
Visit 2 (n = 17,287)
4.5
•O
R
12 wk
6 wk
24 mon
.5
1
2
3
4
5
6
1
2
3
4
•SBP category (1: SBP ≤ 120, 2: 120 < SBP ≤ 130, 3: 130 < SBP ≤ 140, 4: 140 < SBP ≤ 150, 5: 150 < SBP ≤ 160, 6: >160 mmHg )
Gong AHA Sci Ses 2006
Summary and Conclusions
• Treatment strategies are equivalent in preventing death,
MI or stroke and controlling blood pressure
• “Strategy concept” requires multiple drugs (trandolapril
plus/minus HCTZ) in most patients to achieve JNC VI BP
goals
• Prevention of death and diabetes as well as depression
by the calcium antagonist strategy could have important
public health implications