SAN FRANCISCO — A new analysis supports a controversial study that challenged the favored role of diuretics in combination therapy for hypertension, but some experts remain skeptical.
Dr. Kenneth Jamerson, lead investigator of the Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial, said the results of a substudy he presented at the annual meeting of the American Society of Hypertension confirm that the main trial constitutes a paradigm shift in treating hypertension. His coinvestigator, Dr. George Bakris, director of the hypertension center and professor of medicine at the University of Chicago, echoed that assessment at a press conference.
The ACCOMPLISH trial's conclusion that a fixed-dose combination of an ACE inhibitor and a calcium channel blocker was superior to a combination of an ACE inhibitor and a diuretic for initial antihypertensive therapy “has huge implications for the millions of patients that are taking blood pressure medication,” said Dr. Jamerson, professor of medicine at the University of Michigan, Ann Arbor.
Other experts on a separate panel at the meeting were not convinced. Dr. William C. Cushman, chief of preventive medicine at the Memphis Veterans Affairs Medical Center and professor of preventive medicine at the University of Tennessee, Memphis, said the literature supports three drug classes as the mainstays of combination therapy for hypertension: diuretics, blockers of the renin-angiotensin-aldosterone system (RAAS), and calcium channel blockers.
“Based on all the data that we have, I would still put diuretics in a very favorable position in any combinations of these,” Dr. Cushman said.
Here's the back story: Diuretics have been a mainstay of antihypertensive therapy for half a century. Recent guidelines have promoted the use of combination therapy to treat hypertension rather than starting with a single agent in higher-risk patients. The double-blind, industry-sponsored ACCOMPLISH trial was the first to compare two antihypertensive combinations as initial therapy.
The study randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive fixed-dose pills containing either the ACE inhibitor-diuretic combination of benazepril-hydrochlorothiazide (HCTZ) or benazepril plus amlodipine, a calcium channel blocker. After 36 months, the risk of cardiac events was significantly lower in the benazepril-amlodipine group (9.6%) compared with the benazepril-HCTZ group (11.8%), a 20% relative risk reduction (N. Engl. J. Med. 2008;359:2417–28).
Critics pounced on several aspects of the study, including the fact that the 0.9-mm Hg difference between groups in systolic blood pressure results was based on clinic measurements, which are less accurate than ambulatory blood pressure monitoring (N. Engl. J. Med. 2009;360:1147–50).
A new substudy of 573 ACCOMPLISH subjects who underwent 24-hour ambulatory blood pressure monitoring, however, showed good blood pressure control that was similar between groups and, if anything, may have been slightly better in the benazepril-HCTZ group, with a nonsignificant 1.6-mm Hg difference in mean 24-hour systolic pressures between groups, Dr. Jamerson reported at the meeting. (See box.)
The substudy confirms that the reduced cardiovascular risk seen with benazepril-amlodipine was due to other beneficial characteristics of this combination therapy and not driven by differences in blood pressures between groups, Dr. Jamerson said.
He has received funding from, or been a consultant and speaker for, Novartis Pharmaceuticals and other drug companies, and as president of the International Society of Hypertension in Blacks, he sought industry support for the organization. Novartis markets trade versions of the benazepril-amlodipine and benazepril-HCTZ combinations, and both combinations have generic versions on the market.
European guidelines on hypertension treatment favor combination therapy and suggest that combinations of ACE inhibitor with a diuretic or a calcium channel blocker are equally good. “We show evidence that they're not,” Dr. Jamerson said.
“They very likely may have to rethink their guidelines.” U.S. guidelines generally prefer combinations that include a diuretic, he added. “I think this directly challenges that. I consider it a paradigm shift. It's up to the entire community to decide.”
Dr. Bakris said that the subanalysis should pave the way for a change in recommendations. As editor of the hypertension portion of the electronic clinical resource tool UpToDate, he will be dropping a caveat about the ACCOMPLISH results and UpToDate will recommend the benazepril-amlodipine combination for initial therapy. Dr. Bakris has been a consultant, speaker, or adviser for Novartis and other pharmaceutical companies.
“The results of ACCOMPLISH may challenge current diuretic-based guidelines. I don't think this is absolutely clear,” Dr. Angela L. Brown said in the panel discussion. “I don't think we really know that yet just from this one trial,” said Dr. Brown of Washington University, St. Louis. She has been a consultant, adviser, or lecturer for Novartis, Boehringer Ingelheim, and Forest Laboratories.