Principal Investigator: Carl J. Pepine, MD Division of Cardiovascular Medicine University of Florida...

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


• 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?


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


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.


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

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• 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

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• 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


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


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%


• 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


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

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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


Canada

USA

MexicoCuba

Australia New Zealand

France

Spain

Turkey

ItalyGermanyHungary

Participation

862 Sites14 Countries

JAMA. 2003. 290;2805-2816


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


• 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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• 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

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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


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

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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

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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

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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

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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


n = 11 267

No. (%)

Atenolol– based group

n = 11 309

No. (%)

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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


Better

Atenolol–based group

Better


n = 8098

No. (%)

Atenolol– based group

n = 8078

No. (%)

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• 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

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Abbott Laboratories 2003 December 2003 03J-615-9937-4 Printed in U.S.A.


Principal Investigator: Carl J. Pepine, MD Division of Cardiovascular Medicine University of Florida...

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