principal investigator: carl j. pepine, md division of cardiovascular medicine university of florida...
TRANSCRIPT
Principal Investigator: Carl J. Pepine, MDDivision of Cardiovascular Medicine University of Florida College of Medicine Gainesville, FloridaUSA
INternational VErapamil SR and Trandolapril STudy
03J-615-9937-4
INternational VErapamil SR and Trandolapril STudy
• 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.
What Is INVEST?
INternational VErapamil SR and Trandolapril STudy
Leading Causes of Mortality Worldwide
1.2
1.2
1.5
2.2
2.2
2.2
2.3
3.5
5.1
7.4
Road Traffic Accidents
Cancer of the Trachea/bronchi/lungs
Tuberculosis
Perinatal Conditions
Diarrheal Diseases
Chronic Obstructive Pulmonary Disease
HIV/AIDS
Acute Lower Respiratory Infections
Cerebrovascular Disease
Ischemic Heart Disease
% of Total Deaths
Millions
13.7
9.5
6.4
4.2
4.2
4.1
4.0
2.8
2.3
2.2
0.0 2.0 4.0 6.0 8.0 10.0 12.0 14.0 16.0
World Health Report 1998
INternational VErapamil SR and Trandolapril STudy
Hypertension–A Risk Factor for CV Morbidity and Mortality
JAMA. 1996;275:1571-1576
0
5
10
15
20
25
30
35
40
45
50
Normal
Hypertension
Coronary Disease StrokePeripheral
Arterial DiseaseCardiac Failure
Bie
nn
ial a
ge-
adju
sted
rat
e p
er 1
000
Men Women Women Women WomenMen Men Men
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
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.
Objective
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
• 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.*
Rationale for INVEST
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
• 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).
INVEST Drug Strategies
INternational VErapamil SR and Trandolapril STudy
Verapamil SR has proven efficacy and safety in several large-scale clinical trials:
Rationale for Verapamil SR
*Am J Cardiol. 1990;66:779-785†Am J Hypertens. 2001;14:1083-1089
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
INternational VErapamil SR and Trandolapril STudy
In large-scale clinical trials, trandolapril has demonstrated efficacy and safety in hypertensive patients and in post-MI patients with ejection fraction 35%.
Rationale for Trandolapril
* Lancet. 1999;354:9-12 * N Engl J Med. 1995;333:1670-6.
TRACE* Trandolapril slowed a significant risk reduction with once-daily 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
• 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*
Rationale for Atenolol and HCTZ
* Arch Intern Med. 1993;153:154-183
INternational VErapamil SR and Trandolapril STudy
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
Key Features of INVEST
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
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
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Canada
USA
MexicoCuba
Australia New Zealand
France
Spain
Turkey
ItalyGermanyHungary
Participation
862 Sites14 Countries
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Treatment StrategiesTreatment Strategies
Verapamil SR Strategy Atenolol Strategy
Step 1Atenolol 50 mg
Step 2Verapamil SR 240 mg +
Trandolapril 2 mg
Step 2Atenolol 50 mg +
HCTZ 25 mg
Addition of Drug
Step 3Verapamil SR 180 mg twice daily +
Trandolapril 2 mg twice daily
Step 3Atenolol 50 mg twice daily +
HCTZ 25 mg twice daily
Increase Dose
Step 4Verapamil SR 180 mg twice daily +
Trandolapril 2 mg twice daily + HCTZ 25 mg
Step 4Atenolol 50 mg twice daily +
HCTZ 25 mg twice daily + Trandolapril 2 mg
Addition of Drug
Step 1Verapamil SR 240 mg
Increase Dose and/or Add Nonstudy Drug(s)
Diabetes, Renal Dysfunction, Heart Failure–Add Trandolapril
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
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
• 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
Inclusion Criteria
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INternational VErapamil SR and Trandolapril STudy
• 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
Exclusion Criteria
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Baseline Demographics
• 53% Prior MI or Abnormal Angiogram
• 67% Classic Angina
• 28% Diabetic
• 55% Dyslipidemia
• 46% Past Smoking History
• Mean Age = 66 years
• 52% Female
• 48% Caucasian
• 36% Hispanic
• 13% Black
• Mean BMI = 29
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Verpamil SR–Based Group
(n = 11 267)
Atenolol-Based Group
(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 27P = Not significant–comparing all characteristics between strategies
Pertinent Baseline Characteristics
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
78
5260
43
63
82
44 43
0
20
40
60
80
100
% P
atients
Verapamil SR–based group Atenolol–based group
•Mean dose (mg/d) P < 0.001 for all strategy drugs
Antihypertensive Drugs at 24 Months
(288*) (4*) (29*)(76*) (4*) (29*)
Verapamil SR Atenolol Trandolapril HCTZ Nonstrategy
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
70
90
110
130
150
0 1.5 3 4.5 6 12 18 24 30 36 42 48
mm
Hg
Verapamil SR-Based Group
Atenolol-Based Group
Time (Months)
Diastolic
Systolic
Verapamil* (n) 11,267
Atenolol† (n) 11,309
8594 7738 7119 8558 8639 7758 7842 5721 3659 1458 796
8676 7726 7148 8573 8694 7710 7850 5834 3679 1473817
Mean Blood Pressure
-18.7
-10.0
-19.0
-10.2
-20
-15
-10
-5
0
P = 0.41
Ch
ang
e i
n B
P (
mm
Hg
)
Systolic Diastolic
24 Months
P = 0.26
* Verapamil SR–based group† Atenolol–based group
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Alive, Free of MI or Stroke (Primary Outcome)
• Total follow-up 61 835 patient-yrs• Mean follow-up 2.7 yrs/patient• Annual event rate = 3.6%
75
80
85
90
95
100
Cu
mu
lati
ve %
Months
0 6 12 18 24 30 36 42 48 54 60
Log Rank P = 0.57
RR = 0.98, 95% CI 0.90, 1.06
CI for equivalence 0.83, 1.20
Verapamil SR–based groupAtenolol-based group
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
0.80 1.21.0
Outcome 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) 0.94
CV Hospitalization 726 (6.44) 709 (6.27) 0.59
Primary and Secondary Outcomes
Unadjusted Relative Risk with 95% CI
Verapamil SR–based group
Better
Atenolol–based group
Better
Verapamil SR–based group
n = 11 267
No. (%)
Atenolol– based group
n = 11 309
No. (%)
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
Outcome
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
n= patients without diabetes at baseline
Outcomes in Patients Without Diabetes at Baseline
Unadjusted Relative Risk with 95% CI
Verapamil SR–based group
Better
Atenolol–based group
Better
Verapamil SR–based group
n = 8098
No. (%)
Atenolol– based group
n = 8078
No. (%)
JAMA. 2003. 290;2805-2816
INternational VErapamil SR and Trandolapril STudy
• 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.
Summary and Conclusions
JAMA. 2003. 290;2805-2816
Abbott Laboratories 2003 December 2003 03J-615-9937-4 Printed in U.S.A.
INternational VErapamil SR and Trandolapril STudy