This Article  • Full text  • PDF  • Send to a friend  • Save in My Folder  • Save to citation manager  • Permissions  Citing Articles  • Citation map  • Citing articles on HighWire  • Citing articles on ISI (258)  • Contact me when this article is cited  Related Content  • Related article  • Similar articles in JAMA  Topic Collections  • Drug Therapy, Other  • Hypertension  • Randomized Controlled Trial  • Alert me on articles by topic

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).

RELATED ARTICLE

The Return on INVEST
Michael H. Alderman
JAMA. 2003;290(21):2859-2861.
EXTRACT | FULL TEXT  

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES

Which patients would benefit the most from the perindopril-amlodipine combination?
Danchin
Eur Heart J Suppl 2008;10:G29-G35.
ABSTRACT | FULL TEXT  

Characterization of Resistant Hypertension: Association Between Resistant Hypertension, Aldosterone, and Persistent Intravascular Volume Expansion
Gaddam et al.
Arch Intern Med 2008;168:1159-1164.
ABSTRACT | FULL TEXT  

Risk/Benefit Assessment of {beta}-Blockers and Diuretics Precludes Their Use for First-Line Therapy in Hypertension
Messerli et al.
Circulation 2008;117:2706-2715.
FULL TEXT  

Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST)
Kolloch et al.
Eur Heart J 2008;29:1327-1334.
ABSTRACT | FULL TEXT  

Trials That Matter: The Effect of a Fixed-Dose Combination of an Angiotensin-Converting Enzyme Inhibitor and a Diuretic on the Complications of Type 2 Diabetes
Bakris and Berkwits
ANN INTERN MED 2008;148:400-401.
FULL TEXT  

Editorial: The new European Society of Hypertension/European Society of Cardiology (ESH/ESC) Guidelines
Mancia and Grassi
Therapeutic Advances in Cardiovascular Disease 2008;2:5-12.
 

Metabolic and Clinical Outcomes in Nondiabetic Individuals With the Metabolic Syndrome Assigned to Chlorthalidone, Amlodipine, or Lisinopril as Initial Treatment for Hypertension: A report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Black et al.
Diabetes Care 2008;31:353-360.
ABSTRACT | FULL TEXT  

Predicting Stroke Risk in Hypertensive Patients With Coronary Artery Disease: A Report From the INVEST
Coca et al.
Stroke 2008;39:343-348.
ABSTRACT | FULL TEXT  

Should We Target the Sympathetic Nervous System in the Treatment of Obesity-Associated Hypertension?
Biaggioni
Hypertension 2008;51:168-171.
FULL TEXT  

Diastolic Pressure in Type 2 Diabetes: Can target systolic pressure be reached without "diastolic hypotension"?
Osher and Stern
Diabetes Care 2008;31:S249-S254.
ABSTRACT | FULL TEXT  

Beta-blocker therapy in hypertension: a need to pause and reflect.
Giles et al.
J Am Coll Cardiol 2008;51:516-517.
FULL TEXT  

Standards of Medical Care in Diabetes--2008
American Diabetes Association
Diabetes Care 2008;31:S12-S54.
FULL TEXT  

Race and Ethnicity in Trials of Antihypertensive Therapy to Prevent Cardiovascular Outcomes: A Systematic Review
Park and Taylor
Ann Fam Med 2007;5:444-452.
ABSTRACT | FULL TEXT  

Electrocardiographic abnormalities in patients with cluster headache on verapamil therapy
Cohen et al.
Neurology 2007;69:668-675.
ABSTRACT | FULL TEXT  

REPRINT Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention
Rosendorff et al.
Hypertension 2007;50:e28-e55.
FULL TEXT  

Blood Pressure Control and Improved Cardiovascular Outcomes in the International Verapamil SR-Trandolapril Study
Mancia et al.
Hypertension 2007;50:299-305.
ABSTRACT | FULL TEXT  

Hypertension Treatment: How Important Is Consistency of Effect?
Sica
Hypertension 2007;50:287-288.
FULL TEXT  

{beta}-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials
Sipahi et al.
ANN INTERN MED 2007;147:10-18.
ABSTRACT | FULL TEXT  

2007 Guidelines for the Management of Arterial Hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC)
Authors/Task Force Members: et al.
Eur Heart J 2007;0:ehm236v1-75.
FULL TEXT  

Treatment of Hypertension in the Prevention and Management of Ischemic Heart Disease: A Scientific Statement From the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention
Rosendorff et al.
Circulation 2007;115:2761-2788.
FULL TEXT  

Long-Term Safety of a Novel Antianginal Agent in Patients With Severe Chronic Stable Angina: The Ranolazine Open Label Experience (ROLE)
Koren et al.
J Am Coll Cardiol 2007;49:1027-1034.
ABSTRACT | FULL TEXT  

Review: Angiotensin-converting enzyme inhibitors and coronary heart disease prevention
Donnelly and Manning
Journal of Renin-Angiotensin-Aldosterone System 2007;8:13-22.
ABSTRACT  

Diastolic Blood Pressure in Coronary Artery Disease
Weber et al.
ANN INTERN MED 2007;146:149-149.
FULL TEXT  

Standards of Medical Care in Diabetes--2007
American Diabetes Association
Diabetes Care 2007;30:S4-S41.
FULL TEXT  

Prevalence, Awareness, Treatment, and Control of Hypertension Among United States Adults 1999-2004
Ong et al.
Hypertension 2007;49:69-75.
ABSTRACT | FULL TEXT  

The Cardiovascular Disease Continuum Validated: Clinical Evidence of Improved Patient Outcomes: Part I: Pathophysiology and Clinical Trial Evidence (Risk Factors Through Stable Coronary Artery Disease)
Dzau et al.
Circulation 2006;114:2850-2870.
FULL TEXT  

New-onset diabetes mellitus less deadly than elevated blood pressure?: following the evidence in the administration of thiazide diuretics.
Phillips
Arch Intern Med 2006;166:2174-2176.
FULL TEXT  

Progress and problems for randomized clinical trials: from streptomycin to the era of megatrials
Hilbrich and Sleight
Eur Heart J 2006;27:2158-2164.
ABSTRACT | FULL TEXT  

Lowering of Blood Pressure--The Lower, the Better?: Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous? Ann Intern Med 144: 884-893, 2006
Messerli et al.
J. Am. Soc. Nephrol. 2006;17:2345-2352.
FULL TEXT  

Optimal Blood Pressure Levels in Patients With Coronary Artery Disease
Tobis and Fonarow
J Am Coll Cardiol 2006;48:839-840.
FULL TEXT  

Antihypertensive treatment with beta-blockers and the spectrum of glycaemic control
Sarafidis and Bakris
QJM 2006;99:431-436.
ABSTRACT | FULL TEXT  

Dogma Disputed: Can Aggressively Lowering Blood Pressure in Hypertensive Patients with Coronary Artery Disease Be Dangerous?
Messerli et al.
ANN INTERN MED 2006;144:884-893.
ABSTRACT | FULL TEXT  

Blood Pressure Reduction Is Not the Only Determinant of Outcome
Sever et al.
Circulation 2006;113:2754-2774.
FULL TEXT  

Re-examining the efficacy of {beta}-blockers for the treatment of hypertension: a meta-analysis
Khan and McAlister
CMAJ 2006;174:1737-1742.
ABSTRACT | FULL TEXT  

Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology
Authors/Task Force Members et al.
Eur Heart J 2006;27:1341-1381.
FULL TEXT  

Role of Diuretics in the Prevention of Heart Failure: The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
Davis et al.
Circulation 2006;113:2201-2210.
ABSTRACT | FULL TEXT  

Antihypertensive Therapy and the Risk of New-Onset Diabetes
Sarafidis and Bakris
Diabetes Care 2006;29:1167-1169.
FULL TEXT  

Recent Trials in Hypertension: Compelling Science or Commercial Speech?
Psaty et al.
JAMA 2006;295:1704-1706.
FULL TEXT  

Differing effects of antihypertensive drugs on the incidence of diabetes mellitus among patients with hypertensive kidney disease.
Thornley-Brown et al.
Arch Intern Med 2006;166:797-805.
ABSTRACT | FULL TEXT  

Depressive Symptoms in Coronary Artery Disease Patients After Hypertension Treatment
Ried et al.
The Annals of Pharmacotherapy 2006;40:597-604.
ABSTRACT | FULL TEXT  

Thiazide Diuretics in the Treatment of Hypertension: An Update
Salvetti and Ghiadoni
J. Am. Soc. Nephrol. 2006;17:S25-S29.
ABSTRACT | FULL TEXT  

Chronic Kidney Disease as a Situation of High Added Risk in Hypertensive Patients
Segura et al.
J. Am. Soc. Nephrol. 2006;17:S136-S140.
ABSTRACT | FULL TEXT  

Role of Angiotensin II in Cardiovascular Disease -- Therapeutic Implications of More Than a Century of Research
Ferrario
Journal of Renin-Angiotensin-Aldosterone System 2006;7:3-14.
ABSTRACT  

Statin and beta-blocker therapy and the initial presentation of coronary heart disease.
Go et al.
ANN INTERN MED 2006;144:229-238.
ABSTRACT | FULL TEXT  

Predictors of Adverse Outcome Among Patients With Hypertension and Coronary Artery Disease
Pepine et al.
J Am Coll Cardiol 2006;47:547-551.
ABSTRACT | FULL TEXT  

Favourable long term prognosis in stable angina pectoris: an extended follow up of the angina prognosis study in Stockholm (APSIS)
Hjemdahl et al.
Heart 2006;92:177-182.
ABSTRACT | FULL TEXT  

Ranolazine is associated with cardiovascular and metabolic improvement: a win-win for patients with diabetes
Cooper-DeHoff and Pepine
Eur Heart J 2006;27:5-6.
FULL TEXT  

Kidney-Heart Interactions: Epidemiology, Pathogenesis, and Treatment
Berl and Henrich
CJASN 2006;1:8-18.
FULL TEXT  

Standards of Medical Care in Diabetes-2006
American Diabetes Association
Diabetes Care 2006;29:S4-S42.
FULL TEXT  

JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice
Prepared by: British Cardiac Society, British Hype
Heart 2005;91:v1-v52.
FULL TEXT  

Calcium Antagonists: Effects on Cardio-Renal Risk in Hypertensive Patients
Nathan et al.
Hypertension 2005;46:637-642.
ABSTRACT | FULL TEXT  

Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers for Prevention of Type 2 Diabetes: A Meta-Analysis of Randomized Clinical Trials
Abuissa et al.
J Am Coll Cardiol 2005;46:821-826.
ABSTRACT | FULL TEXT  

An Updated Meta-Analysis With a Few Surprises
Kaplan
Hypertension 2005;46:257-258.
FULL TEXT  

Angiotensin-Converting Enzyme Inhibitors and Calcium Channel Blockers for Coronary Heart Disease and Stroke Prevention
Verdecchia et al.
Hypertension 2005;46:386-392.
ABSTRACT | FULL TEXT  

Impact of Achieved Blood Pressure on Cardiovascular Outcomes in the Irbesartan Diabetic Nephropathy Trial
Berl et al.
J. Am. Soc. Nephrol. 2005;16:2170-2179.
ABSTRACT | FULL TEXT  

Clinical Outcomes in Antihypertensive Treatment of Type 2 Diabetes, Impaired Fasting Glucose Concentration, and Normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT)
Whelton et al.
Arch Intern Med 2005;165:1401-1409.
ABSTRACT | FULL TEXT  

Review: atenolol may be ineffective for reducing cardiovascular morbidity or all cause mortality in hypertension
Cruickshank
Evid. Based Med. 2005;10:74-74.
FULL TEXT  

A Study of Antihypertensive Drugs and Depressive Symptoms (SADD-Sx) in Patients Treated With a Calcium Antagonist Versus an Atenolol Hypertension Treatment Strategy in the International Verapamil SR-Trandolapril Study (INVEST)
Ried et al.
Psychosom. Med. 2005;67:398-406.
ABSTRACT | FULL TEXT  

Recent hypertension trials: Implications and controversies
Williams
J Am Coll Cardiol 2005;45:813-827.
ABSTRACT | FULL TEXT  

Update in Nephrology and Hypertension
Vidt
ANN INTERN MED 2005;142:433-438.
FULL TEXT  

A Systematic Review of Drug Therapy to Delay or Prevent Type 2 Diabetes
Padwal et al.
Diabetes Care 2005;28:736-744.
ABSTRACT | FULL TEXT  

Joint National Committee VII and European Society of Hypertension/European Society of Cardiology Guidelines for Evaluating and Treating Hypertension: A Two-Way Road?
Mancia and Grassi
J. Am. Soc. Nephrol. 2005;16:S74-S77.
ABSTRACT | FULL TEXT  

Standards of Medical Care in Diabetes
American Diabetes Association
Diabetes Care 2005;28:S4-S36.
FULL TEXT  

Angiotensin-Converting Enzyme Inhibitors and Diuretics: Optimal Combination Therapy
Krantz and Mehler
ANN INTERN MED 2004;141:893-893.
FULL TEXT  

What Is the Optimal Blood Pressure and Drug Therapy for Patients With Coronary Artery Disease?
Pepine
JAMA 2004;292:2271-2273.
FULL TEXT  

Clinical Outcomes in the Diabetes Cohort of the International Verapamil SR-Trandolapril Study
Bakris et al.
Hypertension 2004;44:637-642.
ABSTRACT | FULL TEXT  

Cardiovascular therapies and risk for development of diabetes
Pepine and Cooper-DeHoff
J Am Coll Cardiol 2004;44:509-512.
ABSTRACT | FULL TEXT  

Hypertensive Therapy: Part II
Franco et al.
Circulation 2004;109:3081-3088.
FULL TEXT  

When Does New Onset Diabetes Resulting From Antihypertensive Therapy Increase Cardiovascular Risk
Bakris and Sowers
Hypertension 2004;43:941-942.
FULL TEXT  

Other articles noted
Evid. Based Med. 2004;9:63-64.
FULL TEXT  

Calcium Antagonists vs. Beta-Blockers for Hypertensive CAD Patients
Journal Watch Cardiology 2004;2004:6-6.
FULL TEXT  

A Large Hypertension Trial, Focused on CAD Patients
JWatch General 2003;2003:1-1.
FULL TEXT  

Cardiovascular News
SoRelle
Circulation 2003;108 :e9077-e9078.
FULL TEXT  

{beta} blockers and calcium antagonists equally effective for hypertension
Gottlieb
BMJ 2003;327:1305-1305.
FULL TEXT  

The Return on INVEST
Alderman
JAMA 2003;290:2859-2861.
FULL TEXT  

Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure
Chobanian et al.
Hypertension 2003;42:1206-1252.
ABSTRACT | FULL TEXT