morbidity and mortality in contemporary cad patients with hypertension treated with either a...

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


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


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


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


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


-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


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


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

morbidity and mortality in contemporary cad patients with hypertension treated with either a...

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