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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, MACCDivision 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 MonthsOverall BP Control at 24 Months%
Pa
tien
ts
BP Goal
<140/<90 mmHg
--INVEST-- -- ALLHAT --
63 6371
6157 54
72
0
10
20
30
40
50
60
70
80
4845
-- LIFE --
CAS
NCASCASNCASCHLOR
AML
LIS
LOS
ATEN
JNC VI
70
90
110
130
150
0 1.5 3 4.5 6 12 18 24 30 36
(mm
Hg)
CAS
NCAS
Time (Months)
Diastolic
Systolic
CAS (n) 11,267
NCAS (n) 11,309
8594 7738 7119 8558 8639 7758 7842 5721 3659
8676 7726 7148 8573 8694 7710 7850 5834 3679
Blood Pressure ControlBlood Pressure Control
-18.7
-10.0
-19.0
-10.2
-20
-15
-10
-5
0
p = 0.26
p = 0.41C
han
ge
in B
P (
mm
Hg
)
Systolic Diastolic
24 Months
0.80 1.21.0
CAS Better NCAS Better
CAS NCAS n = 11267 n = 11309
Outcome No. (%) No. (%) p value
First Event 1119 (9.93) 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
Primary and Secondary Outcomes Primary and Secondary Outcomes
Unadjusted Relative Risk with 95% CI
Relative Risk
Pepine, JAMA 2003;290:2805-16
0.5 1 1.5 2 2.5
Factor # Events /#
Pts
Event Rate
HR p value
CHF (Class I, II, III) 302/1256 24% <0.0001
Diabetes 913/6400 14% <0.0001
US Resident 1999/17131 12% <0.0001
Renal Insufficiency 114/424 27% <0.0001
Stroke/TIA 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
Age (By Year) <0.0001
Hazard Ratio
Factors Independently Associated With Increased Factors Independently Associated With Increased Risk of the Primary Outcome (Risk of the Primary Outcome (Death, MI or Stroke)Death, MI or Stroke)
Hazard Ratio Estimates From Multivariate Stepwise Model
Pepine JACC 2006; 47: 547 - 551Pepine 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 - 551Pepine JACC 2006; 47: 547 - 551
Subgroup
No. Events/
No. Patients
Event Rate
(%)
Diabetes
Absent
<140 mm Hg 775/11491 6.7
140 mm Hg 580/4684 12.4
Present
<140 mm Hg 501/4225 11.9
140 mm Hg 412/2175 18.9
Prior MI
Absent
<140 mm Hg 682/10730 6.4
140 mm Hg 574/4627 12.4
Present
<140 mm Hg 594/4986 11.9
140 mm Hg 418/2232 18.7
0.5 1.0 1.5 2.0
Reduced Risk Increased Risk
HR
Risk of Death, MI or Stroke by Selected Doses of Added Therapy: Effect of ACEI and HCTZ
024
Trandolapril (mg)
CAS
NCAS
HCTZ (mg)
CAS
NCAS
024
012.525
012.525
CASNCAS
Trand/HCTZ (mg)
4/254/25
0.6 0.8 1 1.2Reduced Risk Increased Risk
Pepine JACC 2006; 47: 547 - 551Pepine JACC 2006; 47: 547 - 551
Strategy Added Therapy/ Dose
CAS NCAS n = 8101 n = 8082
Outcome No. (%) No. (%)
New-Onset Diabetes 569 (7.03) 665 (8.23)
Death or New-Onset Diabetes 1050 (12.97) 1177 (14.57)
Primary Event or New Onset Diabetes 1185 (14.63) 1313 (16.25)
1.00.80 1.2
CAS Better NCAS Bettern= patients without diabetes at baseline
Outcomes in Hypertensive CAD Patients Outcomes in Hypertensive CAD Patients Without Diabetes at BaselineWithout Diabetes at BaselineUnadjusted Relative Risk with 95% CI
Pepine JACC 2006; 47: 547 - 551Pepine JACC 2006; 47: 547 - 551
Predictors of Risk for New DiabetesMultivariate AnalysisMultivariate Analysis
Factors not contributing to increased risk: Asian race; renal impairment; CHF; PVD; gender, black race; age; smoking; prior MI
Baseline Covariate HR 95% CI P value
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 1.01 1.01-1.01 <.001
Increased RiskReduced RiskHR
0.5 1.0 1.5 2.0 2.5
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
SBP and Risk of New Onset Diabetes (Unadjusted)
SBP (mm Hg) measured at visit prior to diagnosis
0.5
1.0
1.5
2.0
100 110 120 130 140 150 160 170 180
Haz
ard
Rat
io
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
Risk of New Onset Diabetes by Selected Doses of Risk of New Onset Diabetes by Selected Doses of Added Therapy: Effect of ACEI and HCTZAdded Therapy: Effect of ACEI and HCTZ
Risk of New Onset Diabetes by Selected Doses of Risk of New Onset Diabetes by Selected Doses of Added Therapy: Effect of ACEI and HCTZAdded Therapy: Effect of ACEI and HCTZ
Reduced Risk Increased Risk
024
Trandolapril (mg)Verapamil SR
Atenolol
HCTZ (mg)Verapamil SR
Atenolol
024
012.525
012.525
Verapamil SR
Trand/HCTZ (mg)
4/254/25
0.5 1 1.5 2
Strategy Added Therapy/ Dose
Atenolol
HR
Cooper-Dehoff Am J Cardiol 2006; 98; 890-894
-100
-30
-20
-10
0STOP-2
INSIG
HT
ALLHAT
% R
educ
tion
of N
ew D
iabe
tes
ACE-I or ARBACE-I or ARB CA+ACE-I or ARB
CA+ACE-I or ARB
CACA
INVEST
ALPINE
SCOPE
CHARM
ANBP2
LIFE
HOPE
ALLHAT
CAPPP
STOP-2
VALUE
PEACE
ASCOT
CV Pharmacotherapy and Newly Diagnosed DiabetesCV Pharmacotherapy and Newly Diagnosed Diabetes
Adapted from Pepine, Cooper-Dehoff JACC 2004;44:509
Randomized active treatment vs. SOC (e.g. β-B+/or diuretic)Randomized active treatment vs. SOC (e.g. β-B+/or diuretic)
Primary Outcome vs Mean Follow-Up SBPPrimary Outcome vs Mean Follow-Up SBPOverall Population (N = 22,576)
Mean Follow-Up SBP (mm Hg)
16633737721668591709234Total patients (N) 68913225343759649319645
Patients with primary outcome (n)
26657
20259
>120 to ≤130
>110 to ≤120
≤110 >130 to ≤140
>140 to ≤150
>150 to ≤160
>180>170 to ≤180
>160 to ≤170
Incidence (95% CI) HR
INVEST Results: Overall PopulationINVEST Results: Overall Population
SBP <1408.1% 14.5%
SBP 140 HR (95% CI)0.58 (0.53-0.63)
Incidence and Risk of Primary Outcome
Mean DBP (mm Hg) 76.573.267.5 87.784.281.178.7 90.7 97.4
Meserli Ann Int Med 2006 in press
INVEST Results: Prior MI SubgroupINVEST Results: Prior MI Subgroup
Mean Follow-up SBP (mm Hg)
236541122621712133647112Total patients (N) 825610818824523710426
Patients with primary outcome (n) 24
7024
Patients With Prior MI (N = 7218)
Primary Outcome vs Mean Follow-Up SBPPrimary Outcome vs Mean Follow-Up SBP
>120 to 130
>110 to 120
≤110 >130 to 140
>140 to 150
>150 to 160
>180
Incidence (95% CI) Hazard Ratio*
Es
tima
ted
Ha
zard
Ra
tio
4
3
2
1
0
Inc
ide
nc
e (
%)
50
40
30
20
10
0
60
>160 to 170
>170 to 180
Mean DBP (mm Hg) 76.072.467.0 87.783.680.478.1 89.3 95.9
Meserli Ann Int Med 2006 in press
124 94218 87375681113725673815 1755453240462403
PP: Risk for Primary OutcomePP: Risk for Primary OutcomeINVEST Subanalysis: PP and Risk INVEST Subanalysis: PP and Risk
PP (mm Hg)
Inci
den
ce
(%)
of
Pri
mar
y O
utc
om
eNadir = 54 mm Hg
0
1
2
3
4
5
>30
to 3
5
>35
to 4
0
>40
to 4
5
>45
to 5
0
>50
to 5
5
>55
to 6
0
>60
to 6
5
>65
to 7
0
>70
to 7
5
>75
to 8
0
>80
to 8
5
>85
to 9
0
>90
to 9
5
>95
to 1
00>1
0030
6089439Total patients
Primary Outcome(Death, MI, or stroke)
Hazard Ratio
Stepwise Cox proportional hazards model to estimate hazard ratio (HR);HR = 1 set at PP=50 mm Hg
Est
ima
ted
Haz
ard
Ra
tio
40
30
20
10
0
Meserli Ann Int Med 2006 in press
INVEST: Predictors of High Depressive Symptoms (CESD 16)
PredictorPredictor Std coeffStd coeff t-statistict-statistic p-valuep-value
Baseline CESD Score 0.712 27.4 < .001
Stroke at baseline 0.065 2.56 0.01
Assignment to NCAS 0.055 2.22 0.03
Not significant: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 HRQOLBaseline to 2yr
•SBP category (1: SBP ≤ 120, 2: 120 < SBP ≤ 130, 3: 130 < SBP ≤ 140, 4: 140 < SBP ≤ 150, 5: 150 < SBP ≤ 160, 6: >160 mmHg )
•OR
Visit 1 (n = 22,576)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 2 (n = 17,287)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 3 (n = 15,480)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 4 (n=14,278)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 5 (n = 17,131)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 6 (n = 17,333)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 7 (n = 15,468)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Visit 8 (n = 15,734)
654321
4.5
4.0
3.5
3.0
2.5
2.0
1.5
1.0
.5
Baseline 6 wk 12 wk 18 wk
6 mon 12 mon 18 mon 24 mon
Gong AHA Sci Ses 2006
• 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
Summary and Conclusions