INVEST compares two antihypertension regimens

Verapamil shows edge over beta-blocker-based treatment strategy

The wealth of studies on hypertension and its management notwithstanding, major gaps in knowledge still exist and a universal treatment approach remains elusive. Many of these studies have also contributed to the fine-tuning of treatment guidelines. But as Prof. Rainer Kolloch, head of the department of medicine at the Gilead Medical Center in the University of Munster, put it, what is lacking is something that will unify and simplify them in light of the need to do more than just lower or normalize blood pressure (BP) but to protect the vasculature.

    "We have primarily to deal with the vasculature to prevent stroke, to prevent heart disease, to prevent kidney disease," he told Filipino cardiololgists and related specialists during a medical symposium organized by Abbott Laboratories last year. "And we have to establish a unified tool to meet this challenge," he stressed.

    Kolloch spoke on Optimizing Antihypertensive Treatment in High- Risk Patients: Trials to Date and Contribution of INVEST. INVEST is the International Verapamil SR/Trandolapril Study that compared two treatment strategies for patients with hypertension and coronary artery disease (CAD). "We compared two treatment strategies because comparing one drug to another is not the important thing we have to do in the reality of daily practice," Kolloch said.

    INVEST randomized 22,576 patients from 862 sites in 14 countries into two treatment arms. The first employed a calcium-antagonist strategy (CAS) consisting of either verapamil alone or combined with ACE inhibitor trandolapril. The second used a non-"calcium-antagonist" strategy (NCAS) consisting of the beta-blocker atenolol alone or combined with a diuretic (hydrochlorothiazide). The objective was to compare mortality and morbidity outcomes while lowering lower than 140/90 mm Hg as recommended by the Sixth Joint National Committee on Hypretension (JNC 6). Follow-up period was two years.

    Kolloch said that one of the most important lessons learned from clinical trials on hypertension is that single-drug regimens hardly yield favorable results. Mono-therapy, he said, is able to help only 15 percent of patients reach their target blood pressure. In 85 percent, additional tools or more drugs are necessary.

    In INVEST, both CAS and NCAS led to a significant degree of BP control. In both treatment arms, more than 70 percent of the patients reached a BP level of 140/90 mm Hg or lower by the second year of treatment. BP reduction was also comparative in both groups. Both treatment strategies led to a systolic-BP reduction of 19 mm Hg, and diastolic-BP reduction of 10 mm Hg.

    Both groups also had practically similar rates of reduction in end points (death, heart attack, or stroke). Kolloch pointed out that while seemingly unremarkable, these are important data, as they indicate that the verapamil-trandolapril combination is at least equal to the gold standard in controlling high blood pressure and its attendant complications.

    Subjects on the CAS exhibited a 15-percent decrease in the relative risk for developing new-onset diabetes mellitus. Since the coexistence or onset of diabetes greatly increases the risk of death in hypertension, this benefit was seen as extremely compelling.

    Previous studies have identified left ventricular hypertrophy, a prior stroke, coronary artery bypass grafting or angioplasty, hypercholesterolemia, and increase in body mass index among the risks for new-onset diabetes among hypertensives. But the studies failed to see the role of add-on antihypertensive therapy.

    "It takes at least two to three years [before] the curves diverge," Kolloch said "All the recent studies have missed this result because they haven't been long enough to show this effect."

    Given the advantage the CAS has over NCAS in reducing new-onset-diabetes risk, Kolloch looked more closely into how add-on drugs work. With verapamil, the addition of an ACE inhibitor reduced diabetes risk in a dose-dependent manner. If the same ACE inhibitor were added to a beta-blocker-based therapy, the protection against new-onset diabetes was not as potent. However, the addition of a diuretic to either a verapamil-based or beta-blocker-based treatment strategy significantly increased the risk for new-onset diabetes. Adding verapamil to an ACE inhibitor/diuretic combo did not raise diabetes risk, but adding a beta-blocker did.

    "I think this is an important finding," said Kolloch. "The combination of verapamil-trandolapril reduces the risk of new-onset diabetes compared with the combination of beta-blocker-diuretic. And the data of INVEST confirm findings from previous studies."

    He added: "The data indicate that the use of trandolapril reduces the risk of new-onset diabetes in the verapamil strategy, while hydrochlorothiazide increases the risk in both strategies." Such factors as congestive heart failure, left ventricular hypertrophy, hypercholesterolemia, and being Hispanic also contribute to new-onset-diabetes risk.

    The CAS approach also proved to have an excellent safety and tolerability profile, especially in such matters as dyspnea, light-headedness, bradycardia, and wheezing.