INVEST Revisited: Review of Findings from the International Verapamil SR–Trandolapril Study

Rhonda M Cooper-DeHoff; Eileen M Handberg; Giuseppe Mancia; Qian Zhou; Annette Champion; Udo F Legler; Carl J Pepine


Expert Rev Cardiovasc Ther. 2009;7(11):1329-1340. 

In This Article


INVEST was an international, multicenter study with a prospective, randomized, open, blinded end point evaluation design,[12] conducted in accordance with the principles of the Declaration of Helsinki. The hypothesis was that risk for adverse outcomes was equivalent comparing a verapamil SR-based with an atenolol-based strategy when the strategies were deployed to achieve the same BP control. Patients were eligible for inclusion if they were aged over 50 years and had documented CAD with essential hypertension as defined by the Sixth Report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC VI)[9] requiring drug therapy. Patients taking β-blockers within 2 weeks of randomization, or taking β-blockers for an MI that occurred in the previous 12 months were excluded to avoid withdrawal phenomena in patients randomized to the calcium antagonist strategy.[10]

The protocol specified in-person clinic evaluations every 6 weeks for the first 6 months followed by every 6 months thereafter until the end of the study. Evaluations included physical examination, assessment of BP, pulse and angina symptoms in the prior 4 weeks, compliance with study medications and assessment of subjective well-being. The latter instrument allowed participants to rate their overall well-being in the prior 4 weeks as 'excellent', 'good', 'fair' or 'poor'. BP was treated to a target of lower than 140/90 mmHg or BP lower than 130/85 mmHg when diabetes or renal impairment was present.

Patients were randomized to receive either verapamil SR or atenolol, and the addition of trandolapril and/or HCTZ was recommended when necessary to achieve BP goals (Figure 1). Importantly, drugs, doses and combinations were carefully selected for INVEST based on their relevant and complimentary actions for optimal BP treatment and control in the high-risk CAD population.

Figure 1.

INVEST treatment strategies. The drugs, order of addition and recommended doses for each step of each strategy are summarized. Nonstudy antihypertensive drugs could be added to control blood pressure except for β-blockers in those assigned to the verapamil SR strategy and calcium antagonists for those assigned to the atenolol strategy. Titration ranges: atenolol, 25–200 mg/day; hydrochlorothiazide, 12.5–100 mg/day; trandolapril, 1–8 mg/day; and verapamil SR, 120–480 mg/day.
HCTZ: Hydrochlorothiazide; INVEST: The International Verapamil SR–Trandolapril Study; SR: Sustained release.
Reproduced with permission from [24]

A novel, study-specific internet-based data-entry system was developed and utilized to collect data from sites in all 14 countries in real time.[10] The system had important validation logic built-in to identify nonphysiologic and/or highly variable BP responses. The system also included an electronic dosing/prescribing module that was developed with logic to automatically recommend uptitration of medication (i.e., dose increase or drug addition) when BPs were reported that did not meet goal, and with the exception of the initial dosage regimens, all regimens were dosed twice daily to ensure consistent 24-h BP coverage. However, the electronic prescribing system was flexible to allow the practitioner to tailor the therapy (dose and drugs) for individual patients.[13]

In addition to BP treatment, patients received concomitant guideline-based treatment for comorbidities like diabetes, renal impairment, lipid disorders, peripheral arterial disease and angina.

Patients were followed for BP control and outcomes for at least 2 years after randomization. The overall objective of INVEST was to compare the risk for the primary outcome (PO), defined as all-cause death, nonfatal MI or nonfatal stroke, following treatment with the two strategies. Secondary outcomes included not only all-cause death, nonfatal MI and nonfatal stroke individually, but also new-onset diabetes and trends for cancer, Parkinson's disease, Alzheimer's disease, autoimmune disease and gastrointestinal bleeding, since these had all been anecdotally attributed to long-term use of calcium antagonists.

Depression is common in CAD patients,[14,15] and is an important risk factor for subsequent CHD events.[15] Because use of β-blockers is associated with generalized fatigue and depression, we conducted the Study of Antihypertensive Drugs and Depressive Symptoms (SADD-Sx) substudy[16] to examine the tolerability of the two strategies and to assess for depression at baseline and after 1 year of treatment. For the substudy, 2317 consecutively randomized INVEST patients in the USA were mailed questionnaires, including a sociodemographic survey at baseline and the Center for Epidemiologic Studies-Depression (CES-D) scale at baseline and after 1 year of study participation.

Another ongoing substudy includes ambulatory BP monitoring (ABPM), in which a portion of the INVEST population underwent ABPM at baseline and after 1 year of follow-up. Analysis from this substudy is underway and publications will be forthcoming. We also conducted the INVEST Genetics Substudy (INVEST GENES) in which almost 6000 INVEST participants provided a sample of DNA. While genetic analyses continue and many publications exist,[17–23] summary of these data is beyond the scope of this review.


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