COMPELLING INDICATIONS
Compelling
indications represent
specific comorbid conditions
Heart Failure
Five drug classes
are listed as compelling indications for heart failure.
These
recommendations specifically refer to systolic heart failure,
where the primary
physiologic abnormality is decreased cardiac contractility.
ACE inhibitors are
recommended as the first drugs of choice
based on numerous
outcome studies showing reduced morbidity and
mortality.
Diuretics are also a part of first-line
therapy because they
provide symptomatic
relief of edema by inducing diuresis.
Loop diuretics often are needed, especially in
patients with more advanced
systolic heart
failure.
Evidence from clinical trials has shown that
ACE inhibitors significantly modify disease progression by reducing morbidity
and mortality.
Although systolic
heart failure was the primary disease in these studies, ACE inhibitor therapy
also will control BP in patients with heart failure and hypertension.
ACE inhibitors
should be started with low doses in patients with heart failure, especially
those in acute exacerbation. Heart failure induces a compensatory high-renin
condition, and starting ACE inhibitors under this
circumstance can
cause a pronounced first-dose effect and possible
orthostatic
hypotension.
β-Blocker therapy is appropriate to further modify disease in
systolic heart
failure. In patients on a standard regimen of a diuretic
and ACE inhibitor, β-blockers have been shown to reduce
morbidity
and mortality.54,55 It is of paramount importance
that β-blockers be
dosed appropriately
because of the risk of inducing an acute exacerbation
of heart failure.
They must be started in very low doses, doses
much lower than
those used to treat hypertension, and titrated slowly
to high doses based
on tolerability.
After diuretics,ACE
inhibitors and β-blockers
(collectively considered
standard therapy),
other agents may be added to further reduce
cardiovascular
morbidity and mortality and reduce BP if needed.
Early data
suggested that ARBs may be better than ACE inhibitors in
systolic heart
failure.56 However, when directly compared in a welldesigned
prospective trial,
ACE inhibitors were found to be better.57
ARBs are acceptable
as an alternative therapy for patients who cannot
tolerate ACE
inhibitors and possibly as add-on therapy to those
already on a
standard three-drug regimen.58,59
The addition of aldosterone
antagonists can reduce morbidity and
mortality in systolic heart
failure.60,61 Spironolactone has been
studied
in
severe heart failure and has shown benefit in addition to diuretic
and
ACE inhibitor therapy.60 Eplerenone, the newest aldosterone antagonist,
has
been studied in patients with symptomatic systolic heart
failure
within 3 to 14 days after an acute myocardial infarction in
addition
to a standard three-drug regimen.61 Collectively, both these
agents
should be considered in the specific heart failure population
studied
but only in addition to diuretics, ACE/ARBs, and β-blockers.
Post Myocardial Infarction
Hypertension is a
strong risk factor for myocardial infarction. Once a
patient experiences
a myocardial infarction, controllingBPis essential
for secondary
prevention to reduce the risk of recurrent cardiovascular
events.
β-Blocker
therapy (agents without intrinsic sympathomimetic
activity [ISA]) and
ACE inhibitor therapy are
recommended
in the American
College of Cardiology/American Heart Association
post–myocardial
infarction guidelines.
β-Blockers
decrease cardiac adrenergic stimulation and have been shown in clinical trials
to reduce the risk of a subsequent myocardial infarction or sudden cardiac death.
ACE
inhibitors have been shownto improve cardiac remodeling
and cardiac
function and to reduce cardiovascular events after
myocardial
infarction.
These two drug classes, with β-blockers first, are considered the
first drugs of choice for patients who have experienced a myocardial
infarction.
Eplerenone has been
shown recently to reduce morbidity and
mortality in
patients soon after experiencing an acute myocardial infarction
(within 3 to 14
days). However, this supporting evidence
was in patients
with symptoms of acute left ventricular dysfunction
(systolic heart
failure). Considering that this drug has a propensity
to cause
significant hyperkalemia, and given the patient population
studied, eplerenone
should be used only in selected patients following
a myocardial
infarction.
_
High Coronary Disease Risk
Chronic stable angina, unstable
angina, and myocardial infarction
are all forms of coronary
disease (also known as coronary artery
disease or ischemic heart
disease). These are the most common forms
of hypertension-associated
target-organ disease.
β-Blocker
therapy has the most evidence demonstrating benefits in these patients. β- Blockers are first-line therapy in
chronic stable angina and have the ability to reduce BP, improve myocardial
oxygen consumption, and
decrease demand.
Long-acting CCBs traditionally have
been viewed as alternatives
to β-blockers in chronic stable angina.
For acute coronary syndromes
(non–ST-segment elevation myocardial
infarction and unstable
angina), first-line therapy should consist
of a β-blocker and an ACE inhibitor.
This regimen will lower BP, control acute
ischemia, and reduce cardiovascular risk. Diuretics can be added thereafter if
the goal BP is not achieved with first-line therapy.
CCBs (especially the
nondihydropyridines diltiazem and verapamil)
and β-blockers lower BP and reduce myocardial oxygen demand
in patients with hypertension
and high coronary disease ris.
However, cardiac stimulation
may occur with dihydropyridine CCBs
or β-blockers with intrinsic sympathomimetic activity, making these
agents less desirable.
Therefore, β-blockers with
intrinsic sympathomimetic
activity should be avoided, and
CCBs (especially dihydropyridines)
should be reserved as second-
or third-line therapy.
There has been concern that
overtreating high BP in patients with
coronary artery disease may
bring about more harm than good (termed
the J-curve phenomenon). Since coronary blood flow occurs during
diastole, the rate of flow is
directly influenced by the DBP. Therefore,
excessively reducing DBP may
compromise coronary perfusion, especially
in patients with fixed coronary
artery stenosis, and lead to
myocardial infarction. This
concern has been theoretical based on retrospective
analyses, and prospective
studies have not found a J-curve
until DBPs were very low (<60 mm Hg). However, this
controversy
has resurfaced because a
post-hoc subgroup analysis of the INVEST
study has shown a J-curve in
patients with DBP less than 84 mm Hg.
Diabetes Mellitus
The BP goal in
diabetes is less than 130/80mmHg, and five antihypertensive
agents have
evidence supporting their compelling indications
in diabetes (see
Fig. 13–3). All these agents have been shown
to reduce
cardiovascular events in patients with diabetes..
8 All
patients with diabetes and hypertension should be treated
with an
antihypertensive regimen that includes either an ACE
inhibitor or an
ARB.
Pharmacologically, both these agents shoul provide
nephroprotection owing to vasodilation in the efferent arteriole of the kidney.
Moreover, ACE inhibitors have overwhelming data
demonstrating cardiovascular risk reduction in patients with established forms
of heart disease.
Evidence from outcome studies has demonstrated
reductions in both cardiovascular risk (mostly withACE inhibitors) and the risk
of progressive kidney dysfunction (mostly with ARBs) in patients with diabetes.
Some evidence indicates that ACE inhibitors and ARBs may increase
insulin sensitivity. A few case reports have associated hypoglycemia with ACE
inhibitor use in patients with diabetes taking oral hypoglycemic agents.
While such effects could be problematic in
some patients, the fact that ACE inhibitors improve insulin sensitivity is of
limited clinical significance in diabetes.
β-Blockers have been shown to reduce cardiovascular risk in
patients with diabetes, and
these agents should be used when needed.
β-Blockers have been shown in at
least one study to be as effective
. However, β-blockers (especially nonselective agents)maymask
the signs and symptoms of hypoglycemia in patients with tightly controlled
diabetes because most of the symptoms of hypoglycemia (i.e., tremor,
tachycardia, and palpitations) are mediated through the sympathetic nervous
system. Sweating, a cholinergically mediated symptom of hypoglycemia, still
should occur during a hypoglycemic episode despite β-blocker therapy. Patients also may have a delay in
hypoglycemia recovery time because compensatory recovery mechanisms need the
catecholamine input that is antagonized
by β-blocker therapy.
Finally, unopposed α-receptor stimulation during
the acute hypoglycemic recovery
phase (owing to endogenous
epinephrine release intended to
reverse hypoglycemia) may result
in acutely elevated BP from
vasoconstriction. Despite these potential
problems, β-blockers are highly beneficial in
diabetes after ACE
inhibitors/ARBs and diuretics.
CCBs are useful add-on agents for BP
control in hypertensive patients
with diabetes. Several studies
have compared an ACE inhibitor
with either a dihydropyridine
CCB or a β-blocker. In the
studies comparing
a dihydropyridine with an ACE
inhibitor, the ACE inhibitor
group had significantly lower
rates of cardiovascular end points, including
myocardial infarctions and all
cardiovascular events.73 These
data do not suggest that CCBs
are harmful in diabetic patients but indicate
that they are not as protective
as ACE inhibitors. While data are
limited, nondihydropyridine
CCBs (diltiazem and verapamil) appear
to provide more kidney
protection than the dihydropyridines.30
Based on the weight of all
evidence
, ACE inhibitors/ARBs are preferred
first-line agents for controlling hypertension in diabetes.
The need for combination therapy should
be anticipated, and thiazide
diuretics should be the second
agent added in most patients to lower BP.
Based on scientific evidence, β-blockers and CCBs are useful
evidenced-based agents in this
population but are considered add-on
therapies to the aforementioned
agents.
Chronic Kidney Disease
Patients with
hypertension may develop damage to either the renal
tissue (parenchyma)
or the renal arteries. Chronic kidney disease
presents initially
as microalbuminuria (30–299 mg albumin in a
24-hour urine
collection) that can progress to macroalbuminuria and
overt kidney
failure. The rate of kidney function deterioration is accelerated
when both
hypertension and diabetes are present.30,75
Once
patients have an
estimated glomerular filtration rate (GFR) of less
than 60 mL/m2 per
minute or macroalbuminuria, they have chronic
kidney disease, and
the risk of cardiovascular disease and progression
to severe chronic
kidney disease increases.1 Strict BP control to a goal
of less than 130/80
mm Hg can slow the decline in kidney function.
This strict control
often requires two or more antihypertensive agents.
In addition to
lowering BP,
ACE inhibitors and ARBs reduce intraglomerular
pressure, which can provide additional benefits in further reducing the decline in renal
function.
ACE inhibitors and ARBs have been shown
to reduce progression of chronic kidney disease in patients with diabetes and
in those without diabetes.
One of these two agents should be used
as first-line therapy to control
blood pressure and preserve
kidney function in patients with chronic
kidney disease. Some data
indicate that the combination of an ACE
inhibitor and an ARB may be
more effective than either agent alone.
However, routine use of this
combination in all patients with chronic
kidney disease is
controversial. Since these patients typically require
multiple antihypertensive
agents,
diuretics and a third antihypertensive drug
class (β-blocker or CCB) often
are needed. Thiazide diuretics can be used but may not be as effective as loop
diuretics when creatinine clearances are below 30 mL/min.
Patients may experience a rapid and
profound drop in BP or acute
kidney failure when given an
ACE inhibitor or ARB. The potential
to produce acute kidney failure
is particularly probematic in patients
with bilateral renal artery
stenosis or a solitary functioning kidney
with stenosis. Patients with
renal artery stenosis are usually older,
and the condition is more
common in patients with diabetes or those
who smoke. Patients with renal
artery stenosis do not necessarily have
evidence of renal disease
unless sophisticated tests are performed.
Starting with low dosages and
evaluating renal function shortly after
starting the drug (in 2 to 4
weeks) can minimize this risk.
Recurrent Stroke Prevention
Attaining goal BP
values in patients who have experienced a stroke is
considered a
primary modality to reduce the risk of a second stroke.
However, BP
lowering should be attempted only after patients have
stabilized
following an acute cerebrovascular event. One clinical trial,
the PROGRESS trial,
showed that an ACE inhibitor in combination
with a thiazide
diuretic reduces the incidence of recurrent stroke in
patients with a
history of stroke or transient ischemic attacks.47 Reduction
in recurrent stroke
was seen with this combination therapy,
even in those with
BP values less than 140/90 mm Hg. These data
are consistent with
other evidence demonstrating reduced cardiovascular
risk with ACE
inhibitor therapy in high-risk patients at goal BP
