While ACE inhibitors and
ARBs show comparable results when used solo, they
can spell trouble in combination |
A large Canadian study has found
little difference between a leading angiotensin-converting-enzyme
(ACE) inhibitor and a relatively unproven angiotensin-receptor
blocker (ARB) in their effect on cardiovascular disease
outcomes. The results suggest that at least one ARB,
the studied drug telmisartan, is as good as ramipril,
a well-regarded ACE inhibitor, and is a useful substitute
for patients who tolerate ACE inhibitors poorly. There
was a surprise, however: while both drugs did their
job admirably when used solo, combining the two didn't
yield any additional benefit in cardiovascular outcomes.
In fact, at standard doses, the drug combo came with
an increased burden of side effects.
The ONTARGET study, reported in
the April 10 issue of the New England Journal of
Medicine and presented to the American College of
Cardiology, certainly cut no corners in getting to the
bottom of the question. Three groups of just over 8,500
patients each were assigned either the ACE inhibitor
ramipril at 10mg/day, the ARB telmisartan at 80mg/day,
or both in combination at the same doses. They were
followed for an average 56 months.
Individuals enrolled in the trial
had either proven vascular disease or high-risk diabetes,
with heart failure cases excluded. Primary outcomes
were death from cardiovascular causes, heart attack,
stroke or hospitalization for heart failure. The confluence
of results was astounding: in the ramipril group, 16.5%
of patients succumbed to a primary outcome. In the telmisartan
group, that quota was 16.7%, and in the study arm taking
the drug combo, 16.3% of individuals reached the primary
endpoint. That amounts to absolutely zero difference
in outcome.
The ARB telmisartan appeared to
be better tolerated, however — rates of angioedema
and cough were significantly lower. Cough, the number
one complaint of ACE inhibitor patients, ran at 4.2%
in the ramipril group but just at 1.1% in those on telmisartan.
Hypotensive symptoms, conversely, were more prevalent
in the telmisartan group — except for the most
serious hypotensive effect, syncope, which was equally
frequent in both groups at 0.2%.
BOOSTED
COMPLIANCE
Lead investigator Dr Salim Yusuf of McMaster University
told NRM: "If anything, our study underestimated
the difference in tolerability because we excluded numbers
of people at the outset who had poor tolerability to
ACE inhibitors. We had far better compliance rates than
are seen with ACE inhibitors in the community. Typically,
30 to 40% show poor compliance, but in our study, most
of these were persuaded to remain on the treatment."
Nevertheless, he said, he would
expect to start new patients — even with heart
failure — on an ACE inhibitor. This drug class
is backed by a preponderant weight of evidence that
ARBs can't yet match. "I would switch if there were
issues with tolerability," he says.
In the US, the lower cost of ACE
inhibitors is often cited in their favour — that
is, when other factors are equal. But in Canada, the
price differential is relatively trivial. ACE inhibitor
therapy typically costs about 50 to 60 cents per day,
while ARB therapy is about a dollar a day.
DON'T
MIX
These low costs might encourage physicians to try both
at once, but the ONTARGET study offers little encouragement
on that score, at least for patients with high-risk
diabetes or "normal" vascular disease. The risk of hypotensive
symptoms was nearly double that of ARBs alone and almost
triple that of ACE inhibitors. There was a small but
significant added risk of syncope, and — worse
still — of renal dysfunction. The combination brought
no improvement in outcomes to counterbalance these negative
effects, even though it did lower blood pressure further
— a result Dr Yusuf describes as "puzzling."
While the combination of ACE inhibitors
and ARBs appeared to bring no added benefit in typical
cardiovascular disease, it has been shown to help in
heart failure in two major studies, including a previous
study of Dr Yusuf's: the well-known CHARM-added study.
But neither of these studies used standard or even consistent
doses of ACE inhibitors. Instead, they added standard
doses of ARBs to a whole range of patients on various
other treatments.
Dr Yusuf would have no qualms about
using both drugs together in heart failure, but cautions
that it would be wise to stick to the tested, full-dose
combinations used in this trial (ramipril at 10mg/day,
telmisartan at 80mg/day) or the similar VALIANT study
(80mg of valsartan twice daily added to 50mg of captopril
three times daily).
|
