Results from the Avoiding Cardiovascular Events in Combination Therapy in
Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a large morbidity
and mortality study, showed that the ACE inhibitor benazepril plus the
calcium-channel blocker amlodipine were more effective than treatment with the
ACE inhibitor and diuretic in reducing major fatal and nonfatal cardiovascular
events [1].

Now, after its presentation and publication in 2008, a series of letters to the
editor in the March 12, 2009 issue of the New England Journal of Medicine pose
questions about the use of concomitant therapies, as well as previously asked
questions about the inconsistency of the findings with the Antihypertensive and
Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT).

Drs Barry Davis (University of Texas School of Public Health, Houston) and Paul
Whelton (Loyola University Medical Center, Maywood, IL), writing on behalf of
the ALLHAT group, point out that outcomes achieved in ACCOMPLISH are far better
than those achieved in ALLHAT, despite a higher baseline risk [2]. They
specifically question the 25- to 50-mg dose of hydrochlorothiazide used with
benazepril. Chlorthalidone, the ALLHAT diuretic, is estimated to be twice as
potent as hydrochlorothiazide and to have a longer duration of effect in the
12.5- to 25-mg dose range.

"The results of ACCOMPLISH trial may suggest that doses of thiazide-type
diuretics that are equivalent to 25 mg or less of hydrochlorothiazide per day
are less effective for the prevention of cardiovascular events than full doses
of amlodipine or doses of diuretics used in previous trials," they write.

In reply, Drs Kenneth Jamerson (University of Michigan, Ann Arbor) and Michael
Weber (SUNY Downstate Medical College, Brooklyn, NY) write that ALLHAT and
ACCOMPLISH are different trials, one being a comparison of monotherapies and the
other a comparison of treatment combinations [3]. The difference in event rates
in the trials might reflect the lower achieved blood pressures as well as the
superiority of the combination.

Regarding the choice of hydrochlorothiazide, the ACCOMPLISH investigators have
defended it previously, as well as in their letter, by noting it is one of the
most commonly prescribed antihypertensive drugs, and its use achieved adequate
blood-pressure lowering in ACCOMPLISH.

Speaking with heartwire, Dr Martin Strauss (St Michael's Hospital, Toronto, ON),
said that chlorthalidone can cause metabolic side effects, especially
hypokalemia and elevated blood sugars. "In ALLHAT, that's also what it was
associated with, and so even though it might be a more potent antihypertensive
agent, because of the long-term metabolic consequence, it is very uncommonly
used."

Strauss, along with Drs Jordan Weinstein (St Michael's Hospital, Toronto, ON)
and Gary Newton (Mount Sinai Hospital, Toronto, ON), also write to question the
use of concomitant therapies, specifically whether the withdrawal of
calcium-channel blockers led to more symptomatic angina requiring more
revascularization in patients with diuretics [4]. Patients requiring the drugs
were excluded from ACCOMPLISH.

"Many of these patients had coronary artery disease, and we know that
calcium-channel blockers reduce angina and reduce the need for
revascularization," said Strauss. "That was the primary end point, so the fact
that calcium-channel blockers were withdrawn, even when people were perfectly
stable, may have exaggerated the response."

Strauss commended the use of background treatment with the ACE inhibitor because
analyses have suggested the drugs reduce the risk of cardiovascular events above
and beyond what would be expected from blood-pressure¡Vlowering alone. He was
cautious, however, in extrapolating the results beyond the ACCOMPLISH patient
population.

"ACCOMPLISH was a unique trial in that it was hypertension in high-risk
patients," he told heartwire. "The average patient age was 68 years, and 60%
were diabetics and 50% had prior coronary events, while all others had vascular
disease or chronic renal disease. Whatever results are in ACCOMPLISH, it's
applicable only to this high-risk patient population."

A third letter to the editor from Dr David Parra and Robert Rosenstein (Veterans
Affairs Medical Center, West Palm Beach, FL) questions whether potassium levels
or the presence of hypokalemia could explain the differences between treatment
groups [5]. Jamerson and Weber replied they found no interaction between
hypokalemia and cardiovascular events and reiterated their conclusions that
ACCOMPLISH showed the benefits of combining amlodipine with an ACE inhibitor in
high-risk hypertensive patients.


Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or
hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;
359: 2417-28. Abstract
Davis BR, Whelton PK. Benazepril plus amlodipine or hydrochlorothiazide for
hypertension [correspondence]. N Engl J Med 2009; 360:1148.
Jamerson KA, Weber MA. Benazepril plus amlodipine or hydrochlorothiazide for
hypertension [author reply]. N Engl J Med 2009; 360:1149-1150.
Strauss MH, Weinstein J, Newton GE. Benazepril plus amlodipine or
hydrochlorothiazide for hypertension [correspondence]. N Engl J Med 2009;
360:1148.
Parra D, Rosenstein R. Benazepril plus amlodipine or hydrochlorothiazide for
hypertension [correspondence]. N Engl J Med 2009; 360:1147-1148.