International Verapamil-Trandolapril
Study (INVEST)
Overview
• Prospective, Randomized, Open, Blinded End-Point
Evaluation (PROBE) trial comparing verapamil- vs.
atenolol-based treatment strategies
• Designed to determine if one treatment strategy was
equivalent to the other in reducing all-cause mortality,
nonfatal myocardial infarction, or stroke
• Men and women (n=22,576) ≥ 50 years of age with
hypertension and coronary artery disease
• The patient population was selected to reflect the
composition of a primary care practice including
women, diabetics, ethnic minorities, and the elderly
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
International Verapamil-Trandolapril
Study (INVEST)
Treatment strategies
• Calcium antagonist strategy (CAS) using
verapamil-SR
• Non-calcium antagonist strategy (NCAS) using
atenolol
• Addition of trandolapril to the regimen of patients
with concomitant diabetes, renal failure, or heart
failure was recommended
• Additional antihypertensive therapy was allowed
to achieve and maintain goal blood pressure
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
INVEST: Primary and Secondary
Endpoints
Primary composite endpoint
First occurrence of
• Death (all-cause), or
• Nonfatal myocardial infarction, or
• Nonfatal stroke
Secondary endpoints
• Each of the above as individual endpoints
• Cardiovascular death
• Time to most serious event (death, then MI, then stroke)
• Angina
• Cardiovascular hospitalizations
• Blood pressure control
• Cancer, Alzheimer’s disease, Parkinson’s disease, and
gastrointestinal bleeding
• New diagnosis of diabetes mellitus
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
INVEST: Design
Calcium Antagonist Strategy Non-Calcium Antagonist Strategy
Verapamil-SR 240 mg/d, plus Atenolol 50 mg/d, plus trandolapril
trandolapril 2 mg/d for patients with 2 mg/d for patients with diabetes,
diabetes, renal impairment, or heart Step 1 renal impairment, or heart failure
failure*
Verapamil-SR 240 mg/d, plus Step 2 Atenolol 50 mg/d, plus
trandolapril 2 mg/d Add Drug hydrochlorothiazide 25 mg/d
Verapamil-SR 180 mg twice daily, Step 3 Atenolol 50 mg twice daily, plus
plus trandolapril 2 mg twice daily Increase hydrochlorothiazide 25 mg twice
Dose daily
Verapamil-SR 180 mg twice daily, Atenolol 50 mg twice daily, plus
plus trandolapril 2 mg twice daily, Step 4 hydrochlorothiazide 25 mg twice
plus hydrochlorothiazide 25 mg/d Add Drug daily, plus trandolapril 2 mg/d
Maximum tolerated dose and/or Maximum Maximum tolerated dose and/or
add nonstudy antihypertensive add nonstudy antihypertensive
medication
Treatment medication
See the Speaker’s Notes below for more detailed information about the dose titration scheme employed in this
study.
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Baseline Demographics
Calcium Non-Calcium
Antagonist Strategy Antagonist Strategy
(n=11,267) (n=11,309)
Mean age (yrs) 66.0 66.1
Women (%) 51.9 52.3
Race/ethnicity (%)
White 48.5 48.3
Hispanic 35.7 35.6
Black 13.4 13.5
Asian 0.6 0.8
Other 1.9 1.9
Mean BMI (kg/m2) 29.1 29.2
BMI = Body Mass Index
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Baseline Conditions
(expressed as percentages)
Calcium Antagonist Non-Calcium Antagonist
Strategy Strategy
(n=11,267) (n=11,309)
Myocardial infarction 32.1 31.8
Abnormal angiogram 38.9 39.5
Concordant stress abnormalities 21.3 21.1
Angina pectoris 66.2 67.0
CABG or PCI 27.3 27.3
Stroke 5.3 5.0
Left ventricular hypertrophy 21.5 22.3
Unstable angina > 1 mo ago 11.4 11.5
Arrhythmia 7.1 7.1
Heart failure (class I-III) 5.5 5.6
History of smoking 46.6 46.0
Diabetes* 28.1 28.6
Hypercholesterolemia* 55.9 55.6
*History of or currently taking antidiabetic or lipid-lowering medications
CABG= Coronary Artery Bypass Graft(s); PCI= Percutaneous Coronary Interventions
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Baseline Medications
(expressed as percentages)
Calcium Antagonist Non-Calcium Antagonist
Strategy Strategy
(n=11,267) (n=11,309)
Aspirin or other
57.0 56.4
antiplatelet drugs
Other NSAIDS 17.6 17.9
Antidiabetic medications 22.1 22.9
Lipid-lowering agent 36.8 36.6
Nitrates 35.4 36.6
Potassium supplements 6.9 6.9
Hormone replacement* 17.7 18.5
*Data for women only (n=5,850 for CAS; 5,920 for NCAS)
NSAIDS = Nonsteroidal anti-inflammatory drugs
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Baseline Blood Pressures
Calcium Non-Calcium
Antagonist Antagonist
Strategy Strategy
Antihypertensive Medication Use (n=9,758) (n=9,791)
Mean systolic blood pressure (mmHg) 149.5 149.5
Mean diastolic blood pressure (mmHg) 86.3 86.3
Blood pressure controlled (%)
Systolic 24.4 24.1
Diastolic 53.7 54.2
Both 22.1 21.6
No Antihypertensive Medication Use (n=1,509) (n=1,518)
Mean systolic blood pressure (mmHg) 159.2 160.1
Mean diastolic blood pressure (mmHg) 92.9 92.6
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Protocol-Specified Drug
Use at 12 and 24 Months
Verapamil-SR Atenolol Trandolapril Hydrochlorothiazide
12 Months 24 Months
100
90 *P70
Female
Male
White
Black
Hispanic
Other ethnicities
Diabetes
No diabetes
Hypercholesterolemia
No hypercholesterolemia
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
CAS = Calcium Antagonist Strategy
NCAS = Non-Calcium Antagonist Strategy RR (95% CI)
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: Primary Composite Endpoint
in Subgroups by Treatment Strategy
Cardiovascular Conditions
Favors CAS Favors NCAS
Prior myocardial infarction
No prior myocardial infarction
Congestive heart failure
No congestive heart failure
Revascularization
No revascularization
Left ventricular hypertrophy
No left ventricular hypertrophy
0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8
CAS = Calcium Antagonist Strategy
RR (95% CI)
NCAS = Non-Calcium Antagonist Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
With permission from the American Medical Association.
INVEST: New Onset of
Diabetes During Study
10 RR = 0.85 (0.77 – 0.95)
8.23
8 7.03
Patients (%)
6
4
2
0
Calcium Antagonist Non-Calcium Antagonist
Strategy Strategy
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
INVEST: Summary
• The verapamil-based regimen (calcium antagonist
strategy) and the atenolol-based regimen (non-
calcium antagonist strategy) were similar on the
primary composite endpoint of all-cause mortality,
nonfatal MI, or nonfatal stroke
• The verapamil- and atenolol-based regimens
showed similar efficacy in blood pressure control,
cardiovascular death, and cardiovascular
hospitalizations
• The verapamil-based regimen was associated with
a small but significantly lower incidence of new
onset diabetes
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org
INVEST: Conclusions for the Clinician
• The verapamil-based regimen (calcium antagonist strategy)
was as effective as the atenolol-based regimen (non-calcium
antagonist strategy) in reducing morbidity and mortality in
patients with both hypertension and coronary artery disease
• Multi-drug treatment regimens can achieve goal blood
pressures in a majority of patients with hypertension and
coronary artery disease
• Benefits with each treatment regimen were observed in all
study subgroups (women, ethnic minorities, elderly, and
diabetics)
• Although beta-blockers remain the preferred therapy for
patients following myocardial infarction, a verapamil-based
regimen provides an acceptable alternative for patients with
coronary artery disease in whom a beta-blocker-based
regimen is either contraindicated or not tolerated.
Pepine CJ, et al. JAMA. 2003;290:2805-2816. www.hypertensiononline.org