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Rationale and design of the International Verapamil SR/Trandolapril Study (INVEST): an Internet-based randomized trial in coronary artery disease patients with hypertension

Carl J. Pepine, MD, FACC^*, Eileen Handberg-Thurmond, PhD^*, Ronald G. Marks, PhD, Michael Conlon, PhD, Rhonda Cooper-Dehoff, PharmD, Peter Volkers, PhD, Peter Zellig, MD^** for The INVEST Investigators¹

^* Division of Cardiovascular Medicine, University of Florida, College of Medicine, Gainesville, Florida, USA
Department of Biostatistics, University of Florida, College of Medicine, Gainesville, Florida, USA
Research Pharmacy Division of Shands Hospital, University of Florida, College of Medicine, Gainesville, Florida, USA
^** Knoll AG BASF Pharma, Ludwigshafen, Germany

View larger version (36K): [in a new window]   Figure 1 Diagram of INVEST plan. Patients are randomized (R) at visit 1 (0) to either a calcium antagonist antihypertensive care strategy (bottom) or the noncalcium antagonist antihypertensive care strategy (top). Initial study drug assignments would include verapamil SR or atenolol, respectively. The doses provided are recommended but can be modified by the prescription on the basis of the physician’s knowledge of the patient’s condition (see Fig. 2). The patient’s return for follow-up titration visits (T) at 6, 12 and 18 weeks, when additional drugs or doses can be utilized as outlined. ( ) shows maximal dose of trandolapril offered.

View larger version (43K): [in a new window]   Figure 2 Example of INVEST study drug titration screen. The calcium antagonist care strategy titration screen is shown with the protocol-recommended dose of verapamil SR at randomization. The physician has the option of modifying the dose according to those shown. Once verified, the physician clicks the submit icon at the bottom left, and the patient’s instructions as they will appear on the label are printed in the box. An electronic signal is sent to the database core to record the drug dose and strategy assignment and also to the mail order pharmacy to initiate distribution of study drug to the patient. A similar titration screen appears for the noncalcium antagonist strategy drugs (not shown).

View larger version (63K): [in a new window]   Figure 3 Boxes on left show various steps at the study site. Notations on right indicate role of the INVEST on-line system in the step (from top to bottom). The system provides physicians with the electronic version of the protocol and appropriate references (e.g., JNC VI, links to medical data sources, etc.) to familiarize physicians with the project. The database core controls all data, checks for correctness and determines whether the patient is eligible by comparing data entries made during the first visit with eligibility criteria. Randomization assigns initial study medication strategy. Titration screen presents physicians with protocol-specific options regarding study medications. Physicians determine final prescription. The drug notification system relays final prescription to the drug distribution center to dispense medications and mail to the patient. The system schedules and prints out follow-up visit within protocol-specified window and medication expected in the mail. When the patient returns for follow-up visits, the database core assures that all data values entered are acceptable. Should the patient require change in treatment according to protocol, medications are titrated by the database core and options are presented to the physician by the titration core. In a manner similar to that of first visit, the physician modifies medications within protocol boundaries and the prescription is generated, verified by the physician and forwarded to the drug distribution core.