INVEST trial shows equivalence of CCB and beta blocker strategies in patients with CAD and hypertens

April 02, 2003

Chicago, IL - A massive hypertension trial designed to compare a calcium-channel-blocker-based strategy with an initial beta-blocker approach in patients who also have coronary artery disease has shown the two strategies to be equivalent. Preliminary results of the 22000-patient INVEST study, reported at a late-breaking session here at the American College of Cardiology 2003 Scientific Sessions, mean "we now have an alternative treatment strategy to beta blockers in this patient population," as presenter Dr Carl Pepine (University of Florida College of Medicine, Gainesville) said.

He explained that the problem of hypertension together with coronary artery disease is growing, but "data on optimal management are lacking." Fifty to sixty million Americans have hypertension and a further 15 million have CAD, and there have been very few randomized controlled trials in those who have both conditions, he noted.

"Until now, physicians who cared for patients with both hypertension and CAD commonly treated these patients with beta blockers, but there are questions about their efficacy, particularly in those over 60," he noted.

PROBE trial design

The International Verapamil SR-Trandolapril Study (INVEST) randomized patients initially to verapamil sustained-release (n=11267) or an atenolol-based approach (n=11309), with an additional four-step strategy. The study was an open design with blinded end-point evaluation (PROBE), and analysis was performed on an intention-to-treat basis.

Blood-pressure goals were 140/90 mm Hg or 130/85 mm Hg for those with diabetes or renal dysfunction. Those who did not reach this goal on monotherapy were allowed to increase their dose or add a second drugthe ACE inhibitor trandolapril in the verapamil-based arm and the diuretic hydrochlorothiazide in the atenolol arm. The next step was to increase doses of these drugs, if blood-pressure control was not achieved. Finally, a third drug could be addedhydrochlorothiazide in the verapamil arm and trandolapril in the atenolol arm. The protocol also permitted the use of nonprotocol antihypertensive drugs. The study was funded by Abbott Laboratories, which markets a combination verapamil sustained-release/trandolapril product, Tarka®.

Patients were tracked for two to five years. The primary outcomefirst occurrence of death, nonfatal stroke, or nonfatal myocardial infarctionwas no different between the two treatment arms (RR 0.98; p =0.62), Pepine reported. Blood-pressure lowering was almost identical with both regimens over four years, with more than 90% of patients in both groups achieving the required diastolic blood-pressure control.

"The study adds to the growing evidence that a multidrug strategy is best in hypertension," Pepine said.

New-onset diabetes lower in calcium-channel-blocker arm

One intriguing finding of the study was a significantly lower rate of new-onset diabetes in the CCB arm. This could have "important public health implications, but will require confirmation," Pepine said.

Of the patients in the CCB arm, 499 (6.16%) developed diabetes during the course of the study compared with 589 (7.29%) in the atenolol arm. For death or new-onset diabetes, the figures were 971 (11.99%) and 1083 (13.4%), respectively, a 13% relative risk reduction.

"The factors that led to the lower incidence of new-onset diabetes in the CCB arm are at this time unknown," Pepine told a press briefing. It could be that the ACE inhibitor employed as the second drug in that arm was protective, as was seen in ALLHAT, he said, or the hydrochlorothiazide may have provoked some cases of diabetes. He added that there is also evidence to suggest that calcium channel blockers may protect against new-onset diabetes.

He told heartwire that ALLHAT "had the same frequency of new-onset diabetes but the investigators chose to ignore it." When questioned by chair Dr Bertram Pitt about the new-onset diabetes, Pepine said analysis so far suggests it was the use of hydrochlorothiazide as the second step in the beta-blocker arm that had contributed to the new-onset diabetes, rather than a protective effect of the ACE inhibitor.

Ethnic subgroups, women, derive same benefits

INVEST was the first randomized study where the majority (52%) of patients were women, Pepine noted. In addition, 36% of participants were Hispanic and 16% African Americanthere were no differences in outcome among any of these ethnic groups, he said.

But the researchers did identify some very high-risk subgroupsthose older than 70 and those with congestive heart failure both had event rates three times that of those under 70 or non-heart failure patients, respectively. There was no difference in outcome between the two strategies employed in these elderly or heart failure populations. However, those who had had a prior MI (a third of the study population) fared as well as those no previous MI, Pepine said.

Summing up, he commented: "I am a firm supporter of beta blockers, but what I think these results are telling us is that there are other treatments for hypertension and we have alternatives." In addition, "a strategy requiring multiple drugs will be most likely to achieve the JNC VI blood-pressure goals," he said. Finally, the prevention of death and new-onset diabetes in the calcium-channel-arm is "hypothesis generating and requires further confirmation."

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