INternational VErapamil SR
and Trandolapril STudy
Principal Investigator: Carl J. Pepine, MD
Division of Cardiovascular Medicine
University of Florida College of Medicine
Gainesville, Florida
USA
03J-615-9937-4
What Is INVEST?
• INVEST (the INternational VErapamil SR and
Trandolapril STudy) is the first randomized,
prospective trial to exclusively study patients with
hypertension and coronary artery disease (CAD).
• INVEST is also the first completed study to follow the
guidelines of the Sixth Report of the Joint National
Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure (JNC VI) in using
lower blood pressure goals for special patient
populations.
INternational VErapamil SR and Trandolapril STudy
Leading Causes of Mortality Worldwide
7.4
Ischemic Heart Disease
13.7
5.1
Cerebrovascular Disease
9.5
3.5
Acute Lower Respiratory Infections
6.4
2.3
HIV/AIDS
2.2
Chronic Obstructive Pulmonary Disease
4.2
2.2
Diarrheal Diseases
4.2
4.1
2.2
Perinatal Conditions
4.0
1.5
Tuberculosis
2.8
Millions
1.2
Cancer of the Trachea/bronchi/lungs
2.3
% of Total Deaths
1.2
Road Traffic Accidents
2.2
0.0
INternational VErapamil SR and Trandolapril STudy
2.0
4.0
6.0
8.0
10.0
12.0
14.0
16.0
World Health Report 1998
Hypertension–
A Risk Factor for CV Morbidity and Mortality
Coronary Disease
Stroke
Biennial age-adjusted rate per 1000
50
Peripheral
Arterial Disease
Cardiac Failure
45
40
35
Normal
30
Hypertension
25
20
15
10
5
0
Men
Women
Men
Women
Men
Women
Men
Women
Risk of CV events by hypertensive status in subjects aged 35 to 64 years, Framingham study, 36-year
follow-up.
INternational VErapamil SR and Trandolapril STudy
JAMA. 1996;275:1571-1576
Objective
To compare mortality and morbidity outcomes in patients with
hypertension and CAD treated with either:
Verapamil SR–based treatment strategy
• Verapamil SR alone, or
• In combination with trandolapril, or
• In the triple combination (verapamil SR, trandolapril, and
hydrochlorothiazide [HCTZ])
Atenolol-based treatment strategy
• Atenolol alone, or
• In combination with HCTZ, or
• In the triple combination (atenolol, HCTZ, and trandolapril)
Additional outcomes included blood pressure control, new-onset
diabetes, and angina.
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Rationale for INVEST
• Limited data is available for the management of
patients with hypertension and CAD.
• However, ß–blockers and HCTZ became the standard
of care.
• Verapamil appears to reduce the risk of death and
reinfarction in CAD patients* but rarely has been
studied in large randomized hypertension trials.
• The combination of verapamil SR and trandolapril may
provide better BP control than monotherapies.*
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
INVEST Drug Strategies
• INVEST is not simply a comparison of 2 drugs; it is a
comparison of 2 multidrug treatment strategies.
• It was anticipated that few patients would have their
blood pressure controlled by monotherapy.
• Most patients would need a combination either of
verapamil SR plus trandolapril or of atenolol plus
hydrochlorothiazide (HCTZ).
INternational VErapamil SR and Trandolapril STudy
Rationale for Verapamil SR
Verapamil SR has proven efficacy and safety in several
large-scale clinical trials:
DAVIT II*
Treatment with verapamil after an acute myocardial
showed a significant reduction in major events, death,
or reinfarction (20% risk reduction in total mortality)
VAMPHYRE† Verapamil’s effects on the autonomic nervous system
are favorable
*Am
INternational VErapamil SR and Trandolapril STudy
J Cardiol. 1990;66:779-785
†Am J Hypertens. 2001;14:1083-1089
Rationale for Trandolapril
In large-scale clinical trials, trandolapril has demonstrated
efficacy and safety in hypertensive patients and in post-MI
patients with ejection fraction  35%.
TRACE*
Trandolapril slowed a significant risk reduction with oncedaily dosing. Other ACE-Inhibitors were used with multiple
daily dosing for post MI-patients.
•
•
•
•
All-cause mortality risk reduced by 22%
Cardiovascular mortality risk reduced by 25%
Progressive to severe CHF risk reduced by 29%
Sudden death risk reduced by 24%
INternational VErapamil SR and Trandolapril STudy
* Lancet. 1999;354:9-12
* N Engl J Med. 1995;333:1670-6.
Rationale for Atenolol and HCTZ
• Atenolol is indicated for patients with essential
hypertension, angina pectoris, and acute MI
• HCTZ is widely used for treating essential
hypertension and edema
• Along with diuretics, ß-Blocker became the standard
of care for hypertensive patients with CAD*
INternational VErapamil SR and Trandolapril STudy
* Arch Intern Med. 1993;153:154-183
Key Features of INVEST
Size
22 576 hypertensives with CAD recruited from 14 countries
Mean Follow-up
2.7 years
Unique Features
• Largest CV outcomes trial ever completed in hypertensive
patients with CAD
• First trial to use JNC VI Blood Pressure Goals
• First major CV outcome trial to exclusively recruit hypertensive
patients with CAD
• First CV outcome trial using a fixed-dose combination
(verapamil-trandolapril) as part of treatment regimen
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Patient Enrollment
23 482 Patients Assessed for Eligibility
• 508 Ineligible
• 398 Administratively
Retired or
Withdrew Consent
22 576 Patients Randomized
11 267 Verapamil SR–
Based Strategy
11 309 Atenolol–
Based Strategy
11 267 Included in Analysis
11 309 Included in Analysis
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Participation
Germany
Canada
862 Sites
14 Countries
Italy
Hungary
France
USA
Spain
Turkey
Mexico
Cuba
Australia
New Zealand
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Treatment Strategies
Verapamil SR Strategy
Atenolol Strategy
Diabetes, Renal Dysfunction, Heart Failure–Add Trandolapril
Step 1
Verapamil SR 240 mg
Step 1
Atenolol 50 mg
Addition of Drug
Step 2
Verapamil SR 240 mg +
Trandolapril 2 mg
Step 2
Atenolol 50 mg +
HCTZ 25 mg
Increase Dose
Step 3
Verapamil SR 180 mg twice daily +
Trandolapril 2 mg twice daily
Step 3
Atenolol 50 mg twice daily +
HCTZ 25 mg twice daily
Addition of Drug
Step 4
Verapamil SR 180 mg twice daily +
Trandolapril 2 mg twice daily +
HCTZ 25 mg
Step 4
Atenolol 50 mg twice daily +
HCTZ 25 mg twice daily +
Trandolapril 2 mg
Increase Dose and/or Add Nonstudy Drug(s)
Study drugs could be titrated: verapamil SR 120-480 mg/d;
trandolapril 0.5-8 mg/d; atenolol 25-200 mg/d; HCTZ 12.5-100 mg/d
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Inclusion Criteria
• Aged  50 years
• Essential hypertension requiring drug therapy (JNC VI)
• Documented CAD
–Diagnosis of classic angina pectoris
–Remote MI
–Abnormal coronary angiogram
–Abnormalities on 2 different types of stress tests
• Ability and willingness to sign informed consent
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Exclusion Criteria
• Unstable angina, angioplasty, coronary artery bypass graft, stroke
within previous month
• ß-Blocker use within 2 weeks of randomization for an MI that
occurred in the previous 12 months
• Patients without a pacemaker and any of the following: sick sinus
syndrome, bradycardia ( 50 beats/minute), AV block  1st degree
• Atrial fibrillation/flutter with Wolff-Parkinson-White syndrome
• Severe heart failure (New York Heart Association Class IV)
• Hypersensitivity or contraindications to study medication
• Concomitant illnesses that may have affected outcome variables, in
which life expectancy was 2 years or less, or that were likely to
require frequent hospitalizations and/or treatment adjustments
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Baseline Demographics
• Mean Age = 66 years
• 52% Female
• 53% Prior MI or Abnormal
Angiogram
• 48% Caucasian
• 67% Classic Angina
• 36% Hispanic
• 28% Diabetic
• 13% Black
• 55% Dyslipidemia
• Mean BMI = 29
• 46% Past Smoking History
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Pertinent Baseline Characteristics
Verpamil SR–Based
Group
Atenolol-Based
Group
(n = 11 267)
(n = 11 309)
Females (%)
52
52
Caucasians (%)
49
48
Blacks (%)
13
14
Hispanics (%)
36
36
Age > 70 years (%)
33
34
Diabetes (%)
28
29
Mean BMI (kg/m2)
29
29
MI (%)
32
32
Abnormal Angiogram (%)
39
40
Classic Angina Pectoris (%)
66
67
CABG or PCI (%)
27
27
P = Not significant–comparing all characteristics between strategies
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Antihypertensive Drugs at 24 Months
Verapamil SR–based group
Atenolol–based group
100
82
80
78
% Patients
63
60
60
52
44
43
43
40
20
(288*) (76*)
(4*)
(4*)
(29*)
(29*)
0
Verapamil SR
Atenolol
Trandolapril
HCTZ
Nonstrategy
•Mean dose (mg/d) P < 0.001 for all strategy drugs
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
24 Months
Mean Blood Pressure
Change in BP (mm Hg)
0
150
mm Hg
Systolic
130
Verapamil SR-Based Group
Systolic
Diastolic
-5
-10
-10.0 -10.2
P = 0.26
-15
-20
-18.7 -19.0
P = 0.41
110
Atenolol-Based Group
90
Diastolic
70
0
1.5
3
4.5
6
12
18
24
30
36
42
48
Verapamil* (n) 11,267
8594
7738
7119
8558
8639
7758
7842
5721
3659
1458
796
Atenolol† (n)
8676
7726
7148
8573
8694
7710
7850
5834
3679
1473
817
11,309
Time (Months)
INternational VErapamil SR and Trandolapril STudy
* Verapamil SR–based group
† Atenolol–based group
JAMA. 2003. 290;2805-2816
Alive, Free of MI or Stroke (Primary Outcome)
100
RR = 0.98, 95% CI 0.90, 1.06
CI for equivalence 0.83, 1.20
Cumulative %
95
90
85
Log Rank P = 0.57
80
75
Verapamil SR–based group
Atenolol-based group
0
6
12
18
24
30
36
42
48
54
60
Months
• Total follow-up 61 835 patient-yrs
• Mean follow-up 2.7 yrs/patient
• Annual event rate = 3.6%
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
Primary and Secondary Outcomes
Unadjusted Relative Risk with 95% CI
Verapamil SR–
based group
Atenolol–
based group
n = 11 267
n = 11 309
No. (%)
No. (%)
Outcome
First Event
1119 (9.93)
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)
0.94
CV Hospitalization
726 (6.44)
709 (6.27)
0.59
0.80
Verapamil SR–
based group
Better
INternational VErapamil SR and Trandolapril STudy
1.0
1.2
Atenolol–
based group
Better
JAMA. 2003. 290;2805-2816
Outcomes in Patients Without Diabetes at Baseline
Unadjusted Relative Risk with 95% CI
Outcome
Verapamil SR–
based group
Atenolol–
based group
n = 8098
n = 8078
No. (%)
No. (%)
New-Onset Diabetes
569 (7.03)
Death or
New-Onset Diabetes
1050 (12.97)
Primary Event or
New-Onset Diabetes
1185 (14.63)
665 (8.23)
1177 (14.57)
1313 (16.25)
0.80
n= patients without diabetes at baseline
INternational VErapamil SR and Trandolapril STudy
Verapamil SR–
based group
Better
1.0
1.2
Atenolol–
based group
Better
JAMA. 2003. 290;2805-2816
Summary and Conclusions
• Initiating treatment in hypertensive patients with CAD with
either a verapamil SR–based treatment strategy or an
atenolol-based treatment strategy results in equivalent
clinical outcomes and very similar blood pressure control.
• Either strategy requires multiple drugs (trandolapril and/or
HCTZ) in most patients to achieve BP goals.
• Prevention of death and diabetes with the verapamil SR–
based treatment strategy requires confirmation and could
have important public health implications.
INternational VErapamil SR and Trandolapril STudy
JAMA. 2003. 290;2805-2816
INternational VErapamil SR
and Trandolapril STudy
Abbott Laboratories 2003 December 2003 03J-615-9937-4 Printed in U.S.A.