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The International Verapamil-Trandolapril Study (INVEST): A Randomized Controlled Trial

Carl J. Pepine, MD; Eileen M. Handberg, PhD; Rhonda M. Cooper-DeHoff, PharmD; Ronald G. Marks, PhD; Peter Kowey, MD; Franz H. Messerli, MD; Giuseppe Mancia, MD; José L. Cangiano, MD; David Garcia-Barreto, MD; Matyas Keltai, MD; Serap Erdine, MD; Heather A. Bristol, MS; H. Robert Kolb, RN; George L. Bakris, MD; Jerome D. Cohen, MD; William W. Parmley, MD; for the INVEST Investigators

JAMA. 2003;290:2805-2816.

Context  Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients, safety and efficacy of antihypertensive agents for coronary artery disease (CAD) have been discerned only from subgroup analyses in large trials.

Objective  To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (CAS) or a non–calcium antagonist strategy (NCAS).

Design, Setting, and Participants  Randomized, open label, blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older, which was conducted September 1997 to February 2003 at 862 sites in 14 countries.

Interventions  Patients were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). Strategies specified dose and additional drug regimens. Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of less than 140 mm Hg (systolic) and less than 90 mm Hg (diastolic); and less than 130 mm Hg (systolic) and less than 85 mm Hg (diastolic) if diabetes or renal impairment was present. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment.

Main Outcome Measures  Primary: first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke; other: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pressure control at 24 months.

Results  At 24 months, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release; 4934 (62.9%) were taking trandolapril; and 3430 (43.7%) were taking hydrochlorothiazide. In the NCAS group, 6083 patients (77.5%) were taking atenolol; 4733 (60.3%) were taking hydrochlorothiazide; and 4113 (52.4%) were taking trandolapril. After a follow-up of 61 835 patient-years (mean, 2.7 years per patient), 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90-1.06). Two-year blood pressure control was similar between groups. The JNC VI blood pressure goals were achieved by 65.0% (systolic) and 88.5% (diastolic) of CAS and 64.0% (systolic) and 88.1% (diastolic) of NCAS patients. A total of 71.7% of CAS and 70.7% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg.

Conclusion  The verapamil-trandolapril–based strategy was as clinically effective as the atenolol-hydrochlorothiazide–based strategy in hypertensive CAD patients.

Author Affiliations: Division of Cardiovascular Medicine, Departments of Medicine (Drs Pepine, Handberg, Cooper-DeHoff and Mr Kolb) and Statistics (Dr Marks and Ms Bristol), University of Florida College of Medicine, Gainesville; Department of Medicine, Lankenau Hospital, Wynnewood, Pa (Dr Kowey); Department of Medicine, Ochsner Clinic, New Orleans, La (Dr Messerli); Department of Medicine, Universita Degli Studi, Monza, Italy (Dr Mancia); Clinica Las Americas, Hat Rey, Puerto Rico (Dr Cangiano); Instituto de Cardiologia y Cirugia Cardiovascular, Havana, Cuba (Dr Garcia-Barreto); Department of Cardiology, Semmelweis University, Budapest, Hungary (Dr Keltai); Cardiology Institute, University of Istanbul, Istanbul, Turkey (Dr Erdine); Department of Preventive Medicine, Rush University, Chicago, Ill (Dr Bakris); Department of Medicine, Saint Louis University, St Louis, Mo (Dr Cohen); and Department of Medicine, University of California, San Francisco (Dr Parmley).

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