• Death
• Nonfatal MI
• Nonfatal stroke
• Newly diagnosed diabetes
• BP control
• Cancer
• Gastrointestinal (GI) bleeding
• Alzheimer's Disease
• Parkinson's Disease
• Cardiovascular (CV) hospitalizations
• Quality of life
• Compliance

• Death
• Nonfatal MI
• Nonfatal Stroke
• Newly Diagnosed Diabetes
• BP Control
• Cancer
• GI Bleeding
• Alzheimer's Disease
• Parkinson's Disease
• CV Hospitalizations
• Quality of Life
• Compliance

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).

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.

• Hypertension
• Coronary Artery Disease

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

• 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.
• 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 International Verapamil SR-Trandolapril Study (INVEST). Psychosom Med. 2005 May-Jun;67(3):398-406.
• 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 Cardiol. 2004 Oct;27(10):571-6.
• 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.
• 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 antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003 Dec 3;290(21):2805-16.
• 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(12):884-93.
• 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):715-21. Epub 2008 Jul 9.

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.