INVEST: INternational VErapamil SR Trandolapril STudy

Hypertension Clinical Trial

Official title:

INternational VErapamil SR Trandolapril STudy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00133692
• Other study ID #: INVEST
• Status: Completed
• Phase: Phase 4
• First received: August 22, 2005
• Last updated: September 16, 2011
• Start date: September 1997
• Est. completion date: February 2003

Study information

• Verified date: August 2010
• Source: University of Florida
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Institutional Review Board
• Study type: Interventional

Clinical Trial Summary

Because blood pressure affects the heart, blood vessels, kidneys, and the entire body, it is important to keep it as normal as possible. There are several different ways to control blood pressure and to prevent or limit the development of heart disease due to high blood pressure. The purpose of this study is to compare two treatments to see how well they work and the difference in their side effects. One treatment includes the use of a calcium antagonist drug (Isoptin sustained release [SR] or Verapamil SR). The other treatment excludes the calcium antagonist and may include a non-calcium antagonist drug called a beta blocker (Tenormin or Atenolol). Both treatments may also include medication called angiotensin converting enzyme (ACE) inhibitors and water pills. None of the drugs in this study are experimental, they are all approved by the Food and Drug Administration (FDA).

Description:

INVEST is an investigator initiated international, prospective, randomized study comparing two pharmacotherapy strategies to control hypertension in ambulatory patients with coronary artery disease (CAD). One strategy, the calcium antagonist care strategy, centers on a calcium antagonist (verapamil SR) followed by addition of an ACE inhibitor (trandolapril) and then diuretic (hydrochlorothiazide) as needed to achieve target blood pressures (BP). The other strategy, the non-calcium antagonist care strategy, uses a beta-blocker (atenolol) followed by addition of low-dose diuretic and then an ACE inhibitor (trandolapril) as needed to reach target BP. In either strategy additional drugs can be added provided the calcium antagonist is retained in the calcium antagonist care strategy and calcium antagonists are omitted in the non-calcium antagonist care strategy.

The study is organized into 15 international regions with about 1,500 study investigators randomizing approximately 22,000 patients who will be treated for at least two years. The primary response variable is the occurrence of adverse outcome, defined as any of the following events: all cause mortality, nonfatal MI or nonfatal stroke. A number of secondary response variables, including newly diagnosed diabetes will also be evaluated.

The primary objective of this trial is to examine the hypothesis that the risk for adverse outcomes (all cause mortality, nonfatal MI or nonfatal stroke) in hypertensive patients with CAD is at least equivalent during treatment of hypertension with a calcium antagonist strategy when compared with a non-calcium antagonist strategy.

Unique features of INVEST are, in addition to its size and international scope, its design to mimic standard clinical practice and its all electronic online data entry, drug distribution system, study management system, and electronic physician compensation. This system will permit the entire trial to be conducted via the Internet. This design is believed to be a forerunner of clinical trials research for the future.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 22000
• Est. completion date: February 2003
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 50 Years and older

Eligibility

Inclusion Criteria:

• Male or female

• Age 50 to no upper limit

• Hypertension documented according to the 6th report of the Joint National Committee on Detection and Evaluation of the treatment of high BP (JNC VI) and the need for drug therapy (previously documented hypertension in patients currently taking antihypertensive agents is acceptable)

• Documented CAD (e.g., classic angina pectoris (stable angina pectoris; Heberden angina pectoris), myocardial infarction three or more months ago, abnormal coronary angiography, or concordant abnormalities on two different types of stress tests)

• Willingness to sign informed consent

Exclusion Criteria:

• Unstable angina, angioplasty, coronary artery bypass graft surgery (CABG) or stroke within one month. Patients taking beta blockers after myocardial infarction are excluded if study enrollment is planned within 12 months of myocardial infarction. No time limitation if not taking beta-blocker.

• Use of a ß-blocker within past two weeks

• Patients without a pacemaker and any of the following:

• Sinus bradycardia (< 50 beats/min.)

• Sick sinus syndrome

• Atrioventricular (AV)-block of more than 1st degree

• Documented contraindication to verapamil; documented contraindication to both atenolol and hydrochlorothiazide

• Atrial fibrillation/flutter with Wolff-Parkinson-White (WPW)-Syndrome

• Severe heart failure (New York Heart Association [NYHA] IV).

• Concomitant illnesses (e.g., severe renal failure [Serum creatinine =4.0 mg/dl], severe hepatic failure or known cirrhosis, etc.) which may affect outcome variables or where life expectancy is two years or less or which are likely to require frequent hospitalizations and/or treatment adjustments.

• Patients with psychiatric, cognitive, or social (e.g., alcoholism, etc.) conditions that would interfere with giving consent or cooperating or remaining available for follow-up for two years.

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Hypertension
• Myocardial Ischemia

Intervention

Drug:
• Verapamil SR/Trandolapril/Hydrochlorothiazide (HCTZ)

• Atenolol/HCTZ/Trandolapril

Locations

Country	Name	City	State
United States	University of Florida	Gainesville	Florida

Sponsors (2)

Lead Sponsor	Collaborator
University of Florida	Abbott

Country where clinical trial is conducted

United States, 

References & Publications (47)

Bakris GL, Cooper-Dehoff RM, Zhou Q, Kupfer S, Champion A, Pepine CJ; INVEST Investigators. Dual therapy in hypertensive patients with coronary artery disease: the role of calcium channel blockers and beta-blockers. Am J Cardiovasc Drugs. 2007;7 Suppl 1:2 — View Citation

Bakris GL, Gaxiola E, Messerli FH, Mancia G, Erdine S, Cooper-DeHoff R, Pepine CJ; INVEST Investigators. Clinical outcomes in the diabetes cohort of the INternational VErapamil SR-Trandolapril study. Hypertension. 2004 Nov;44(5):637-42. Epub 2004 Sep 20. — View Citation

Bangalore S, Messerli FH, Cohen JD, Bacher PH, Sleight P, Mancia G, Kowey P, Zhou Q, Champion A, Pepine CJ; INVEST Investigators. Verapamil-sustained release-based treatment strategy is equivalent to atenolol-based treatment strategy at reducing cardiovas — View Citation

Bangalore S, Messerli FH, Franklin SS, Mancia G, Champion A, Pepine CJ. Pulse pressure and risk of cardiovascular outcomes in patients with hypertension and coronary artery disease: an INternational VErapamil SR-trandolapril STudy (INVEST) analysis. Eur H — View Citation

Bavry AA, Anderson RD, Gong Y, Denardo SJ, Cooper-Dehoff RM, Handberg EM, Pepine CJ. Outcomes Among hypertensive patients with concomitant peripheral and coronary artery disease: findings from the INternational VErapamil-SR/Trandolapril STudy. Hypertensio — View Citation

Beitelshees AL, Gong Y, Wang D, Schork NJ, Cooper-Dehoff RM, Langaee TY, Shriver MD, Sadee W, Knot HJ, Pepine CJ, Johnson JA; INVEST Investigators. KCNMB1 genotype influences response to verapamil SR and adverse outcomes in the INternational VErapamil SR/ — View Citation

Beitelshees AL, Navare H, Wang D, Gong Y, Wessel J, Moss JI, Langaee TY, Cooper-DeHoff RM, Sadee W, Pepine CJ, Schork NJ, Johnson JA. CACNA1C gene polymorphisms, cardiovascular disease outcomes, and treatment response. Circ Cardiovasc Genet. 2009 Aug;2(4) — View Citation

Brooks CS, Sowers JR. Importance of achieving lower blood pressure in hypertensive patients with diabetes. Hypertension. 2004 Nov;44(5):614-5. Epub 2004 Sep 13. — View Citation

Brunner M, Cooper-DeHoff RM, Gong Y, Karnes JH, Langaee TY, Pepine CJ, Johnson JA; INVEST Investigators. Factors influencing blood pressure response to trandolapril add-on therapy in patients taking verapamil SR (from the International Verapamil SR/Trando — View Citation

Coca A, Messerli FH, Benetos A, Zhou Q, Champion A, Cooper-DeHoff RM, Pepine CJ. Predicting stroke risk in hypertensive patients with coronary artery disease: a report from the INVEST. Stroke. 2008 Feb;39(2):343-8. Epub 2007 Dec 27. — View Citation

Conti CR, Cooper-DeHoff RM. How will INVEST and other hypertension trials change clinical practice? Clin Cardiol. 2001 Nov;24(11 Suppl):V24-9. — View Citation

Cooper-Dehoff R, Cohen JD, Bakris GL, Messerli FH, Erdine S, Hewkin AC, Kupfer S, Pepine CJ; INVEST Investigators. Predictors of development of diabetes mellitus in patients with coronary artery disease taking antihypertensive medications (findings from t — View Citation

Cooper-DeHoff R, Handberg E, Heissenberg C, Johnson K. Electronic prescribing via the internet for a coronary artery disease and hypertension megatrial. Clin Cardiol. 2001 Nov;24(11 Suppl):V14-6. — View Citation

Cooper-DeHoff RM, Aranda JM Jr, Gaxiola E, Cangiano JL, Garcia-Barreto D, Conti CR, Hewkin A, Pepine CJ; INVEST Investigators. Blood pressure control and cardiovascular outcomes in high-risk Hispanic patients--findings from the International Verapamil SR/ — View Citation

Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010 Jul 7;304(1):61-8. doi: 10.1001/j — View Citation

Cooper-DeHoff RM, Handberg EM, Cohen J, Kowey P, Messerli FH, Mancia G, Cangiano JL, Gaxiola E, Garcia-Barreto D, Hewkin AC, Pepine CJ; INVEST Investigators. Characteristics of contemporary patients with hypertension and coronary artery disease. Clin Card — View Citation

Cooper-DeHoff RM, Handberg EM, Mancia G, Zhou Q, Champion A, Legler UF, Pepine CJ. INVEST revisited: review of findings from the International Verapamil SR-Trandolapril Study. Expert Rev Cardiovasc Ther. 2009 Nov;7(11):1329-40. doi: 10.1586/erc.09.102. — View Citation

Cooper-DeHoff RM, Zhou Q, Gaxiola E, Cangiano JL, Garcia-Barreto D, Handberg E, Pepine CJ; INVEST Investigators. Influence of Hispanic ethnicity on blood pressure control and cardiovascular outcomes in women with CAD and hypertension: findings from INVEST — View Citation

Denardo SJ, Gong Y, Nichols WW, Messerli FH, Bavry AA, Cooper-Dehoff RM, Handberg EM, Champion A, Pepine CJ. Blood pressure and outcomes in very old hypertensive coronary artery disease patients: an INVEST substudy. Am J Med. 2010 Aug;123(8):719-26. doi: — View Citation

Denardo SJ, Messerli FH, Gaxiola E, Aranda JM Jr, Cooper-Dehoff RM, Handberg EM, Gong Y, Champion A, Zhou Q, Pepine CJ. Characteristics and outcomes of revascularized patients with hypertension: an international verapamil SR-trandolapril substudy. Hyperte — View Citation

Denardo SJ, Messerli FH, Gaxiola E, Aranda JM Jr, Cooper-Dehoff RM, Handberg EM, Gong Y, Champion A, Zhou Q, Pepine CJ. Coronary revascularization strategy and outcomes according to blood pressure (from the International Verapamil SR-Trandolapril Study [I — View Citation

Elliott WJ, Hewkin AC, Kupfer S, Cooper-DeHoff R, Pepine CJ. A drug dose model for predicting clinical outcomes in hypertensive coronary disease patients. J Clin Hypertens (Greenwich). 2005 Nov;7(11):654-63. — View Citation

Erdine S, Handberg EM, Kolb B. Characteristics of patients with coronary artery disease and hypertension: a report from INVEST. Clin Cardiol. 2001 Nov;24(11 Suppl):V6-8. — View Citation

Gerhard T, Gong Y, Beitelshees AL, Mao X, Lobmeyer MT, Cooper-DeHoff RM, Langaee TY, Schork NJ, Shriver MD, Pepine CJ, Johnson JA; INVEST Investigators. Alpha-adducin polymorphism associated with increased risk of adverse cardiovascular outcomes: results — View Citation

Gong Y, Handberg EM, Gerhard T, Cooper-Dehoff RM, Ried LD, Johnson JA, Pepine CJ; INVEST Investigators. Systolic blood pressure and subjective well-being in patients with coronary artery disease. Clin Cardiol. 2009 Nov;32(11):627-32. doi: 10.1002/clc.2050 — View Citation

Johnson AD, Gong Y, Wang D, Langaee TY, Shin J, Cooper-Dehoff RM, Schork NJ, Binkley P, Pepine CJ, Johnson JA, Sadee W. Promoter polymorphisms in ACE (angiotensin I-converting enzyme) associated with clinical outcomes in hypertension. Clin Pharmacol Ther. — View Citation

Keltai M, Johnson JA, Kowey PR, Ried LD, Tueth M. INVEST substudies: design and patient characteristics. Clin Cardiol. 2001 Nov;24(11 Suppl):V9-11. — View Citation

Kolloch R, Legler UF, Champion A, Cooper-Dehoff RM, Handberg E, Zhou Q, Pepine CJ. Impact of resting heart rate on outcomes in hypertensive patients with coronary artery disease: findings from the INternational VErapamil-SR/trandolapril STudy (INVEST). Eu — View Citation

Kolloch RE. INVEST: results of combined strategies to control blood pressure. Clin Cardiol. 2001 Nov;24(11 Suppl):V12-3. — View Citation

Langaee TY, Gong Y, Yarandi HN, Katz DA, Cooper-DeHoff RM, Pepine CJ, Johnson JA. Association of CYP3A5 polymorphisms with hypertension and antihypertensive response to verapamil. Clin Pharmacol Ther. 2007 Mar;81(3):386-91. — View Citation

Mancia G, Messerli F, Bakris G, Zhou Q, Champion A, Pepine CJ. Blood pressure control and improved cardiovascular outcomes in the International Verapamil SR-Trandolapril Study. Hypertension. 2007 Aug;50(2):299-305. Epub 2007 Jul 2. — View Citation

Marks R, Bristol H, Conlon M, Pepine CJ. Enhancing clinical trials on the internet: lessons from INVEST. Clin Cardiol. 2001 Nov;24(11 Suppl):V17-23. — View Citation

Messerli F, Frishman WH, Elliott WJ, Bacher PH, Pepine CJ. Antihypertensive properties of a high-dose combination of trandolapril and verapamil-SR. Blood Press Suppl. 2007 Mar;1:6-9. — View Citation

Messerli FH, Mancia G, Conti CR, Hewkin AC, Kupfer S, Champion A, Kolloch R, Benetos A, Pepine CJ. Dogma disputed: can aggressively lowering blood pressure in hypertensive patients with coronary artery disease be dangerous? Ann Intern Med. 2006 Jun 20;144 — View Citation

Pacanowski MA, Gong Y, Cooper-Dehoff RM, Schork NJ, Shriver MD, Langaee TY, Pepine CJ, Johnson JA; INVEST Investigators. beta-adrenergic receptor gene polymorphisms and beta-blocker treatment outcomes in hypertension. Clin Pharmacol Ther. 2008 Dec;84(6):7 — View Citation

Pepine CJ, Conti CR. Managing hypertension in European patients with coronary artery disease: design, results, and clinical implications of INVEST. Ital Heart J. 2004 Jun;5(6):411-6. — View Citation

Pepine CJ, Cooper-Dehoff RM. Cardiovascular therapies and risk for development of diabetes. J Am Coll Cardiol. 2004 Aug 4;44(3):509-12. Review. — View Citation

Pepine CJ, Handberg EM, Cooper-DeHoff RM, Marks RG, Kowey P, Messerli FH, Mancia G, Cangiano JL, Garcia-Barreto D, Keltai M, Erdine S, Bristol HA, Kolb HR, Bakris GL, Cohen JD, Parmley WW; INVEST Investigators. A calcium antagonist vs a non-calcium antago — View Citation

Pepine CJ, Handberg EM. The vascular biology of hypertension and atherosclerosis and intervention with calcium antagonists and angiotensin-converting enzyme inhibitors. Clin Cardiol. 2001 Nov;24(11 Suppl):V1-5. — View Citation

Pepine CJ, Handberg-Thurmond E, Marks RG, Conlon M, Cooper-DeHoff R, Volkers P, Zellig P. Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension. J Am Coll Cardiol. 1998 Nov;32(5):1228-37. — View Citation

Pepine CJ, Kowey PR, Kupfer S, Kolloch RE, Benetos A, Mancia G, Coca A, Cooper-DeHoff RM, Handberg E, Gaxiola E, Sleight P, Conti CR, Hewkin AC, Tavazzi L; INVEST Investigators. Predictors of adverse outcome among patients with hypertension and coronary a — View Citation

Questions and answers related to the INternational VErapamil SR/trandolapril STudy (INVEST). Clin Cardiol. 2001 Nov;24(11 Suppl):V30. — View Citation

Reynolds NA, Wagstaff AJ, Keam SJ. Trandolapril/verapamil sustained release: a review of its use in the treatment of essential hypertension. Drugs. 2005;65(13):1893-914. Review. — View Citation

Ried LD, Tueth MJ, Handberg E, Kupfer S, Pepine CJ; INVEST Study Group. 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 Internation — View Citation

Ried LD, Tueth MJ, Taylor MD, Sauer BC, Lopez LM, Pepine CJ. Depressive symptoms in coronary artery disease patients after hypertension treatment. Ann Pharmacother. 2006 Apr;40(4):597-604. Epub 2006 Mar 28. — View Citation

Uretsky S, Messerli FH, Bangalore S, Champion A, Cooper-Dehoff RM, Zhou Q, Pepine CJ. Obesity paradox in patients with hypertension and coronary artery disease. Am J Med. 2007 Oct;120(10):863-70. — View Citation

Zineh I, Cooper-Dehoff RM, Wessel TR, Arant CB, Sleight P, Geiser EA, Pepine CJ. Global differences in blood pressure control and clinical outcomes in the INternational VErapamil SR-Trandolapril STudy (INVEST). Clin Cardiol. 2005 Jul;28(7):321-8. — View Citation

* Note: There are 47 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	First occurrence of death or nonfatal myocardial infarction (MI) or nonfatal stroke
Secondary	Death
Secondary	Nonfatal MI
Secondary	Nonfatal stroke
Secondary	Newly diagnosed diabetes
Secondary	BP control
Secondary	Cancer
Secondary	Gastrointestinal (GI) bleeding
Secondary	Alzheimer's Disease
Secondary	Parkinson's Disease
Secondary	Cardiovascular (CV) hospitalizations
Secondary	Quality of life
Secondary	Compliance