Download Overview of Alpha-blockers in Hypertension : Reappraisal of

supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
5
Editorial
Overview of Alpha-blockers in Hypertension :
Reappraisal of Perspectives
Manokar Panchanatham*, Siddharth N Shah**
Introduction
H
ypertension is the biggest public
health problem of the world. It is
far bigger in prevalence than coronary
heart disease, diabetes mellitus, cancer
and HIV. The field of “Hypertension” is
increasingly being recognised as a major
cause of stroke, renal and cardiovascular
disease. It has not seen the emergence of
any new molecules for the management of
this silent killer. It has received less public
health initiative compared to the Big 4 due
to the perceived ease of diagnosis and
management by the medical community.
Also it does not involve any of the “shock
and awe” impact of the Big 4 on the
common man. It underscores the fact that
hypertension remains the most under
diagnosed, most under treated and most
modifiable risk factor in the public health
domain.
The key focus of policy makers,
clinicians and researches in hypertension
has been to find newer, safer and effective
drugs to manage hypertension. Relatively
the effort to ensure definite diagnosis,
prompt treatment and ensure treatment
adherence has been at best lackadaisical.
To put in a religious perspective, we have
been obsessed by the choice of path to
God that we miss Him eventually.
*
Interventional Cardiologist,
Sri Ramachandra University,
Chennai; **Bhatia Hospital,
Saifee Hospital, S. L. Raheja
Hospital, Mumbai;
**
Editor-in-Chief – JAPI
Alpha blockers have been in our
armamentarium since 1976 when
prazosin was introduced in the
market. Subsequently doxazosin and
t e r a z o s i n h a ve a p p e a r e d a n d l o n g
acting formulations of all of them have
been available to ensure once a day
administration. The much hyped “First
dose phenomenon” is done away with
by developing newer technology like
GITS and administering the drug at bed
time. Many studies have demonstrated
their equivalence in safety and efficacy
at equipotent doses. Hence it is rational
to assume that in alpha blockers the
benefits and demerits are a class effect
and not a molecule effect. Increasing
understanding of the positive metabolic
effects and ideal hemodynamic effects
of “alpha-blockers” developed over 45
years ago has prompted us to review this
drug which went into hibernation over
the decades.
As is well known, management of
hypertension require more than two
drugs for effective long term good blood
pressure control. The metabolically
effective “alpha adrenergic receptor
blocker” is a preferred drug of choice
as add on drug. The drug is associated
with a relatively low incidence of serious
side effects and can be combined with
almost all the antihypertensive agents
used as first line agents recommended
for management of hypertension.
Are Alpha Blockers an Effective
Antihypertensive Therapy?
As a first line agent
In the TOMHS study 1,2 the average
doxazosin related BP reduction was up
to 20 mm Hg in systolic and 10 mm Hg in
diastolic blood pressure. Like all agents
the BP fall is directly proportional to the
starting BP. Higher the BP more dramatic
the fall.
ALLHAT study3 made us squirm about
its use as a first line agent and hence it is
abandoned worldwide for this indication.
As a second line agent
GATES study 4 done in 195 patients for
role of doxazosin as a second line agent
on top of preexisting antihypertensive
therapy(usually monotherapy) showed
3 7 . 3 % / 1 0 . 7 % e f f i c a c y i n SB P / DB P
lowering.
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supplement to Journal of the association of physicians of india • Published on 1st of every month 1st september, 2014 • VOL. 62
ASOCIA study 5 was a short (16 wk) but big trial
(3631 patients) which showed target BP achievement
in 39% at 4 weeks and 61% in 16 weeks with doxazosin
as add on therapy vs placebo. It also showed a15% fall
in pulse pressure and rate pressure product by 19%
and thus reduce resting myocardial oxygen demand.
As a third line agent
ASCOT-BPLA study 6 compared an amlodipine
based regimen(± perindopril) vs atenolol based
regimen (± thiazide) in 19,257 patients. Doxazosin
was added as a third line agent to non responders
and intolerant patients. Eventually almost half (9799
patients) received doxazosin and it helped 31% achieve
targets. It vindicates safety and efficacy as a third line
agent.
A small Japanese study 7 of 41 patients looked at
usefulness of doxazosin on top of CCB + ACE/ARB
as a third line agent for hypertension control and
established its role as add on choice. It also had
an interesting observation that they were equally
effective in obesity associate hypertension endorsing
Toyonaga’s earlier findings. 8
Are Alpha Blockers Safe?
Safety and tolerability are used interchangeably
when describing drug effects. However alpha blockers
demonstrate the paradox between the two in an
interesting fashion. When tolerability is considered,
Itskovitz et al9 showed in 16,000 patients with a variety
of concomitant disease including CHF, peripheral
vascular disease, COPD, diabetes and obesity, that
drop out due to adverse events was only 2%. Side
effect profile was very favourable; e.g. comparable
to placebo 10 and better than other anti hypertensives
especially chlorthalidone with respect to impotence
(↓ 6% vs ↓ 10%). 11
Safety
The concept that treatment for one condition may
precipitate another underlying masked predisposed
condition has gained momentum and public attention
with the glitazone family. In fact Alpha blockers
were pioneers in this field. ALLHAT randomised
42424 patients for HT treatment with 9067 receiving
doxazosin and was prematurely terminated at 2
years raising safety concerns about alpha blockers
(25% increase in secondary endpoint, combined
cardiovascular disease). 12
ALLHAT FINDINGS
•
The primary endpoint of fatal CHD or non-fatal
CHD, nor total mortality differed between the
two groups.
•
Chlorthalidone provided superior BP lowering
efficacy at the doses used by 3 mm Hg systolic.
•
The increase in HF incidence occurred in all
subgroups except chlorthalidone. The RR risk
of HF with lisinopril, amlodipine and doxazosin
was 1.19, 1.38, 1.80 respectively.
•
The increase in HF incidence did not increase
the mortality in any of the subgroups.
•
The divergence in HF occurred very early in the
trial and the separation was noticed very early
on, within the first few months of therapy and
all the difference occurred only in the first year
and the separation disappeared significantly at
one year for lisinopril and reduced dramatically
for amlodipine and to a significant extent for
doxazosin in the second year.
•
The diagnosis of HF was made on the basis of
SHEP criteria by site physician (1 symptom
and 1 sign of HF) 13 (e.g. pedal oedema was one
criteria used). The protocol did not include a
measurement of EF or BNP either before or
at the time of HF diagnosis. The clinical trials
centre was informed of HF only if patient was
hospitalised or died.
OTHER TRIAL EVIDENCES
•
ACE inhibitors have been shown to reduce the
HF incidence by 20-25% across all agents and all
trials 14 .
•
Doxazosin has been shown to be effective
therapy in the treatment of CHF. 15
Unanswered questions
Would it have made a difference in results if the
following changes had been made in ALLHAT
Protocol?
1.I n c l u s i o n o f EF / BN P a s s e s s m e n t p r i o r t o
enrolment
2.More comprehensive HF assessment by a
cardiologist
3. Allowing up-titration of doxazosin beyond 8 mg
4.Use of long acting preparation of doxazosin or
other long acting alpha blocker preparations
5.Having HF as a primary endpoint
6.The confounding effect of prior treatment drug
on the outcomes (i.e. diuretic being replaced by
study drug)
7.Discrimination between systolic and diastolic
heart failure (since diuretics have a clear edge
in the latter )
8.The equivalent results beyond year 1 of follow
up with interim MIs contributing to a larger
number of individuals with impaired LVEF
could have tilted the results eventually 16
9.Lack of mortality difference occurring because
of the increased mortality in diuretic group due
to malignancy (renal 17 and colonic 18)
supplement to Journal of the association of physicians of india • Published on 1st of every month 1st se ptember, 2014 • VOL. 62
There is a pertinent need to critically analyse the
findings to form an independent opinion on this safety
debate.
Alpha blockers - is there Anything New?
L o n g a c t i n g p r e p a r a t i o n s a p p e a r t o h a ve a
better pharmacokinetic profile with obvious
pharmacodynamic benefits.
1.Lower incidence of postural hypotension and its
associated symptoms. 19
2.More consistent BP lowering with night dose with
preserved nocturnal dip. 20,21
3. Average of 3 bpm reduction in heart rate. 5
4.No increased incidence of heart failure in 40,000
patient years exposure 22
5. Pleiotropic effects
a.Decrease total and LDL cholesterol and
increase HDL. 23
b.Reduce or neutral effect on plasma glucose
and improve insulin sensitivity. 24
c.Improves endothelial function and reduces
arterial stiffness. 25
d.Recovery of spontaneous baroreflex sensitivity
and short-term heart rate variability. 26
Guidelines
European Society of Cardiology, European Society
of Hypertension, 27 NICE guidelines 28 all are noncommittal about alpha blockers in hypertension.
They mention it as add-on option (in case of failure of
preferred combinations) or step 4 combination. None
endorse or boycott alpha blockers. JNC 8 29 is equivocal
about the indications of alpha blockers.
Take Home Message
7
Benign Prostatic Hyperplasia
It is often touted as a compelling indication for
alpha blockers. 33 The positive effect on impotence is
also cited as an indication in young and uncomplicated
hypertensive.
Pregnancy and lactation
Given the wealth of evidence with labetalol
(combined alpha and beta blocker ) in pregnancy, it
seems rational to consider it as an option for pregnancy
(class C drug).
Phaeochromocytoma/chronic lead poisoning34
Both are uncommon in incidence but commonly
sought out in differential diagnosis workup. Alpha
blockers in combination with beta blockers work
effectively in this subset of patients.
Should we Start?
Yes always as add on and in combination with
diuretics.
Should we Stop?
Hypertensive patients well controlled on alpha
blockers should continue to take them for life unless
they develop heart failure or other such complications.
Since all alpha blockers are off patent at present,
further trials supported by pharmaceutical industry
are unlikely in the future. Hence physician based
initiative or regulatory authority funded trials can
only throw light on the unanswered questions posed
herewith and enlighten the exact role of alpha blockers
in present day hypertension management.
Disclaimer
The information contained in the manuscript
reflects independent, evidence-based opinions and
views of the contributing expert authors; it does not
suggest or endorse the opinions or views of Pfizer
ltd, directly or indirectly. Some of the information
contained herein, may be off-label in nature. Pfizer
ltd. does not promote / suggest / recommend any such
off-label use of its product(s).
Alpha blockers have been superseded by ACE/ARB,
CCBs and Diuretics as a first choice anti hypertensive
drug. However to achieve target BP goals, combination
therapy is an inevitable scenario in more than 2/3
patients. Add on therapy is usually indicated in most
patients in natural history of hypertension. Alpha
blockers provide a definite choice in this setting.
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