There are multiple ways of controlling
high blood pressure nowadays, but what almost all have
in common is the requirement to take frequent pills.
This raises compliance problems, because the pills can
cause side effects at worst, and even at best don't
make the patient feel better. With no disease symptoms
to alleviate, the immediate incentive to comply with
medication is weak. In the US, for example, only about
a third of hypertensive patients have their blood pressure
under control.
One solution floated from time
to time is to vaccinate patients against hypertension.
Now scientists are a step closer to making it a reality.
A Swiss-German collaboration reports in the March 8
edition of The Lancet on a phase IIa trial of
such a vaccine. The vaccine CYT006-AngQb consists of
angiotensin II chemically linked to a recombinant virus-like
particle, an RNA-phage.
BEEN
THERE
A vaccine that targeted the renin-angiotensin-aldosterone
system (RAAS) has already been tried, which generated
antibodies to angiotensin I. It didn't reduce blood
pressure and was abandoned.
Now it's the turn of angiotensin
II to get the immune system's attention, which makes
sense given that angiotensin II has already been targeted
very successfully with receptor-blocking drugs.
Twenty-four placebo controls joined
48 subjects, who were split equally between a 100mg
dose group and a 300mg dose group, in a 14-week trial
of the vaccine that focused mainly on safety and tolerability
but also measured efficacy.
MIXED
RESULTS
The results are tantalizing, but couldn't yet be called
convincing. On the question of tolerability, the vaccine's
performance was unexceptional. There were more adverse
events than with placebo, but all of these were either
injection-site inflammation, or transient flu-like symptoms
that lasted three or four days.
Blood pressure reduction was modest,
modest enough that the 100mg dose can probably be immediately
discounted. The 300mg dose did produce a significant
reduction in systolic BP (p=0.015), and a nearly-significant
reduction in diastolic BP (p=0.065). The average decline
over 14 weeks was 9.0 mmHg and 4.0 mmHg for systolic
and diastolic pressure respectively.
That's a real effect, but not one
that can match optimum drug therapy. Better news was
the vaccine's strong effect in reducing the early morning
blood pressure surge associated with so many heart attacks
and hemorrhagic strokes. Between 5am and 8am, the reduction
from baseline was quite significant (p=0.012 systolic,
p=0.036 diastolic).
The actual number of anti-angiotensin
antibodies rose for two weeks after the first injection,
then levelled off, then rocketed after a week four booster,
then dipped sharply after six weeks, then shot up again
after a week 12 booster, then slowly tailed off. At
48 weeks, antibody levels were about the same as at
two weeks under this regimen. But blood pressure wasn't
measured at this point, it was measured at 14 weeks;
when antibody levels were about five times higher in
the 300mg group, at the peak of the second major spike
in numbers. That might tend to make the vaccine look
more effective than it really is on a typical day.
RISKY
BUSINESS
Another caveat: while the tolerability was acceptable,
many experts worry that deliberately generating antibodies
against an endogenous peptide like angiotensin could
trigger autoimmune disease. In fact that happened in
an Alzheimer's trial that was stopped in 2001. It's
unlikely that this trial had either the power or the
duration to rule out this danger.
Moreover, a fast-reacting renin-angiotensin-aldosterone
system can save lives in cases of severe dehydration,
trauma, or clinical shock, so inhibiting this system
should not be undertaken lightly. The RAAS can be rapidly
strengthened in patients taking angiotensin receptor
inhibitors, simply by stopping their drugs. But a vaccine,
once injected, will keep working for weeks. These patients
might stand up to shock just as well as those with a
fully-functioning RAAS, or they might not. There is
no ethical way to find out.
It's easy to forget that lowering
blood pressure is not a true clinical endpoint, but
a surrogate. The purpose of the vaccine must be to prevent
cardiovascular disease. Sequestering angiotensin and
reducing blood pressure can cause plasma renin levels
to rise, and indeed they did at 300mg, modestly but
significantly. Renin, the authors note, is itself a
direct cardiovascular risk factor, so this effect too
needs to be watched.
Finally, it's an assumption, not
a proven fact, that a drug which requires, four, six
or eight injections a year is really going to improve
compliance over a pill-a-day regimen. These are all
questions for phases IIb and III. For the moment, we
already have a minor milestone: the first successful
attempt to significantly reduce blood pressure through
induced antibody response.
For more on HBP, see "Don't
dismiss ED hypertension"
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