COMPELLING INDICATIONS TO TREAT HYPERTENSION

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