GCR: Heart Failure Disease Specific Site

HEART FAILURE
Clinical Overview

Pharmacotherapy

Heart failure patients who present with fatigue or mild dyspnea on exertion (DOE) and no other signs of volume overload may be started on ACE inhibitor monotherapy.¹ Diuretics should be added if these symptoms persist. For those with moderate DOE, initiation of a diuretic along with initiation and titration of ACE inhibitor is recommended. Severe DOE or persistent symptoms of moderate DOE, usually warrants the addition of digoxin to both diuretics and ACE inhibitors.

The AHCPR guidelines state that asymptomatic patients who are found to have moderately or severely reduced LV systolic function (EF < 35-40%) should be treated with an ACE inhibitor to reduce the chance of developing clinical heart failure.¹Clinical studies have shown that even after patients have sustained a myocardial infarction (MI) and developed moderate-to-severe left-ventricular systolic dysfunction, it is still possible to slow or prevent progression to symptomatic heart failure (SAVE trial).⁶

This diagram depicts the mechanisms of action of ACE inhibitors.⁷ Their primary action is blocking the conversion of angiotensin I to angiotensin II (A-II). Angiotensin II is a potent vasoconstrictor as well as stimulator of aldosterone release.¹⁷ By decreasing circulatory levels of A-II, ACE inhibitors impair sympathetically mediated vasoconstriction and reduce noradrenaline overflow during exercise. ACE inhibitors also potentiate vasodilatory effects of bradykinins and prostaglandins, by reducing the breakdown of bradykinin (a vasodilator). These actions cause vasodilation in both arteries and veins, reducing preload and afterload.

ACE Inhibitors:Pivotal Clinical Trials

Trial Publication Timeline

This diagram depicts a time line for publishing dates of several pivotal trials evaluating the use of ACE inhibitors in heart failure. All trials listed here were randomized, controlled, and double-blind in design.

Reduction in mortality:

CONSENSUS I (Cooperative North Scandinavian Enalapril Survival Study) compared enalapril to placebo in patients who continued with their conventional pharmacotherapy. Enalapril showed a 27% risk reduction in mortality.⁸

The V-HeFT II (Veterans Administration Heart Failure Trial) found similar results when comparing enalapril to the combination hydralazine/isosorbide dinitrate (28% risk reduction).⁹

These two trials proved that the combination of diuretics and/or digoxin with the ACE inhibitor enalapril improves symptoms and prolongs life in patients with heart failure.

The SOLVD (Studies of Left Ventricular Dysfunction) trial compared enalapril to placebo in both treatment and prevention of heart failure. In the treatment arm enalapril showed a 26% risk reduction for death or hospitalization for worsening heart failure. In the prevention arm of the SOLVD trial results showed a 29% risk reduction for the combined endpoint of death or cases of symptomatic heart failure with enalapril.¹⁰

Low vs. high doses:
It has been observed that doses of ACE inhibitors used for heart failure in clinical practice are four to six times lower than those utilized in clinical trials. This may decrease the chances of patients achieving the best possible results from their ACE inhibitor therapy. The ATLAS (Assessment of Treatment with Lisinopril and Survival) trial ¹¹was designed to address low dose vs. high dose lisinopril therapy, using the primary endpoint of all-cause mortality. High-dose lisinopril resulted in a 12% reduction in death or hospitalization for any reason. High-dose therapy also resulted in a statistically significant 14% reduction in the composite endpoint of death or hospitalization for heart failure and a 24% reduction in hospitalization due to heart failure compared to low-dose therapy.

A study by van Velduisen and colleagues¹² examined the effects of low dose vs. high dose imidapril therapy in heart failure patients. They found that within 3 months of initiation of treatment, the patients in the high dose group showed greater improvement in exercise capacity.

Early initiation post-myocardial infarction (MI)
Additional studies have explored the effects of ACE inhibitors after myocardial infarction (MI) in the prevention of heart failure. SAVE (Survival and Ventricular Enlargement Trial) compared captopril to placebo. Captopril treatment resulted in a 21% risk reduction in death from cardiovascular causes, a 22% risk reduction for hospitalization due to heart failure, and a 25% risk reduction for recurrent MI.⁶

AIRE (Acute Infarction Ramipril Efficacy) compared ramipril vs. placebo. Ramipril treatment resulted in a 27% risk reduction in all cause mortality and a 19% risk reduction in secondary events such as severe/resistant heart failure, MI or stroke.¹³

Both ISIS-4 (the fourth International Study of Infarct Survival), which compared captopril to placebo in 50,000 patients, and GISSI-3 (Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico) which compared lisinopril to placebo in 20,000 patients, demonstrated increased survival in patients treated with ACE inhibitors within 24 hours of acute MI.¹⁴,¹⁵

The SMILE (Survival of Myocardial Infarction Long-term Evaluation) trial confirmed the benefit of early initiation of ACE inhibitor therapy (ISIS-4 and GISSI-3), especially for the high-risk population with Q-wave anterior acute MI.¹⁶

Newer trials:
Several large controlled trials are currently examining the long-term anti-ischemic and cardiovascular protective effects of ACE inhibitors; in patients at risk of cardiovascular event, HOPE (Heart Outcomes Prevention Evaluation); in patients with normal cardiac function, PEACE (Prevention of Events with ACE inhibition); in patients with coronary artery disease irrespective of cardiac function, EUROPA (EUropean trial of Reduction Of cardiac events with Perindopril in stable Artery disease).¹⁷

Contraindications

Absolute

Angioedema
Known renal artery stenosis

Relative

History of intolerance or adverse reaction
Serum potassium > 5.5 mEq/L
Symptomatic hypotension
Serum creatinine > 3.0 mg/dL
Creatinine clearance < 30mL/min

Patients with heart failure due to left ventricular systolic dysfunction should be given a trial of ACE inhibitors unless specific contraindications exist.¹ History of intolerance or adverse reaction to these agents, serum potassium greater than 5.5 mEq/L that cannot be reduced, or symptomatic hypotension are some contraindications to treatment with ACE inhibitors. Caution and close monitoring are also required for patients who have a serum creatinine greater than 3.0 mg/dL or have an estimated creatinine clearance less than 30 mL/min; half the usual dose should be used in this setting.¹

Use in Special Situations

Low Blood Pressure
Moderate renal insufficiency
Mild Hyperkalemia

Dosing should be initiated under the direction of a physician with expertise in dosing of ACE inhibitors when patients in high-risk populations, such as systolic blood pressure less than 90 mmHg, serum creatinine greater than 3.0 mg/dL, or an estimated creatinine clearance less than 30 mL/min, need ACE inhibitor therapy. These patients may also obtain the most benefit from ACE inhibitor use and the AHCPR panel recommends referral of these patients to physicians experienced in these situations.¹

Adverse Reactions

Hypotension	SBP > 90 mmHg acceptable if no orthostatic hypotension
Renal Insufficiency	For Scr >3.0, use with caution and titrate dose up slowly to half the usual maintenance dose
Cough	evaluate if from ACE inhibitor or pulmonary congestion
Angioedema	usually mild discontinue if oropharyngeal region
Dizziness	usually mild
Fatigue

Side effects of ACE inhibitors, particularly reduction in blood pressure, increase in serum potassium (K⁺), and/or increase in serum creatinine (SCr) are common, and should be monitored appropriately. Patients with low blood pressure should be carefully monitored and in the absence of orthostatic hypotension, asystolic blood pressure of 90 mmHg is acceptable.¹If SCr is 3.0 mg/dL or greater, ACE inhibitors should be used with caution and titrated up slowly to a maximum of half the usual maintenance dose. Potassium-sparing diuretics should be stopped in all patients started on ACE inhibitors. These agents may be restarted if a patient remains hypokalemic on full therapeutic doses of ACE inhibitors.¹

Cough is common in patients taking ACE inhibitors but is also common in heart failure patients. Those reporting cough should be evaluated to determine whether this is the result of pulmonary congestion before discontinuing therapy.¹ Dizziness and angioedema can also occur, but symptoms are usually mild and do not require discontinuation of the ACE inhibitor. Angioedema of the oropharyngeal region is an absolute contraindication to further use of an ACE inhibitor.

Initiating Therapy

Reducing Adverse Effects of First-Dose Hypotension

Risk Factors:

initial low blood pressure
severe heart failure
high doses of diuretics
low serum sodium
other vasodilators

Precautions:

omit the morning dose of diuretic (if needed, give later)
start with low dose ACE inhibitor
administer to patient who is and remains sitting for 2-3 hrs (bladder emptied first)
patient should not be alone
if patient become hypotensive, lie them down and elevate legs

Dosing:

Assess baseline volume status
Start with small dose of short-acting agent in special situations
Monitor test dose
Titrate after test dose

Note: some newer longer-acting ACE inhibitors cause less first-dose hypotension

First-dose hypotension is a common side effect with the initiation of ACE inhibitor therapy. The above table, adapted from an article by Haffner et al,¹⁸ lists the risk factors for development of first dose hypotension and precautions to follow when initiating ACE inhibitor therapy in these patients. Dosing guidelines are also included in the table.

Patients should be assessed for volume depletion before ACE inhibitor therapy is initiated (orthostatic hypotension, prerenal azotemia) and if depletion is evident, diuretics should be withheld for 24-48 hours until condition resolves.Monitoring of the test dose is indicated for patients starting on ACE inhibitor therapy, regardless of risk. For those at high risk for first-dose hypotension a small dose of a short-acting agent should be given. Patients over the age of 75 years may also be at an increased risk for hypotension, and may be started on lower initial first doses.

Short-acting captopril should be monitored at least 1-2 hours post-dose, while longer-acting agents (e.g., enalapril, lisinopril, quinapril, fosinopril) should be monitored 3 hours or more. If tolerated, titration of ACE inhibitor can be started; for example, captopril 12.5 mg twice daily or three times daily or enalapril 2.5mg twice daily. With concomitant hypertension, captopril can be increased to 25mg three times daily and enalapril to 5mg twice daily as an appropriate starting dose.¹ The doses in the frail elderly, however need to be modified and a prolonged monitoring phase may be required.

Patients should be monitored carefully for the 48 hours following initiation of full dose ACE inhibitor therapy to assess for symptoms of hypotension such as dizziness or weakness.¹ Within 1 week of initiation, patients should be seen to monitor blood pressure, renal function, and serum potassium. Treatment may need to be modified if patient develops an increase in serum creatinine of 0.5 mg/dL or higher, increase of serum potassium of 5.5 mEq/L or more, or symptomatic hypotension. Those who develop renal insufficiency or hypotension should have volume status reassessed. Increases in dose should be made every 2-3 weeks, as tolerated, to target goals used in large-scale clinical trials. In the elderly, more prudent dosing protocols and diligent monitoring for all the above listed parameters are of the utmost importance.

ACE Inhibitors: Dosing

Agent	FDA Approved Indication	Initial Geriatric Dose (mg)	Initital Observation (h)
Captopril	hypertension/heart failure	6.25 - 12.5 TID	1 to 1.5
Enalapril	hypertension/heart failure	2.5 QD, BID	3 to 4.5
Fosinopril	hypertension/heart failure	10 QD	> 3
Lisinoril	hypertension/heart failure	2.5 QD, BID	3 to 6
Quinapril	hypertension/heart failure	2.5 - 5 QD	> 2
Ramipril	hypertension/heart failure post MI	2.5 - 5 QD	1 to 3

This table, adapted from the Geriatric Dosage Handbook and Facts and Comparisons, lists the available ACE inhibitors and their indications for use, as well as initial starting doses and observation time periods for first-dose administration.^2,19 This is important to be aware of especially in the elderly, who may already be on diuretics and consequently dehydrated.

A discrepancy has been observed between the doses of ACE inhibitors used in clinical trials and the doses that are actually prescribed in clinical practice. This may decrease the chances of patients achieving the best possible results from their ACE inhibitor therapy. Studies examining this problem are further discussed earlier in this section in the ACE Inhibitor Clinical Trial discussion.

Special characteristics of some ACE inhibitors

captopril

TID dosing

sulfhydryl group

metallic taste/rash

stimulate

prostaglandin synthesis

antiplatelet effects

enhances insulin sensitivity

fosinopril

QD dosing

renal and hepatic metabolism

efficiently taken up by the heart¹⁹

quinapril

QD dosing

inhibits lung and tissue-based ACE binding²⁰

The AHCPR guidelines do not recommend any individual ACE inhibitor over another. Although they differ in duration of action and side effect profile, it is generally thought that one ACE inhibitor is equal to another in effectiveness.¹

Because of captopril's short duration of action, its recommended administration is three times daily compared to twice daily for enalapril and once daily for lisinopril, quinapril, ramipril, and fosinopril. Compliance may be worse with the more frequent dosing of captopril, leaving patients exposed to adverse effects of renin-angiotensin-aldosterone activation.⁴

Differences in chemical structure may be important. Captopril has a unique sulfhydryl group which is responsible for side effects such as metallic taste and rash, but this group may also contribute to the stimulation of prostaglandin biosynthesis.¹ This is the postulated mechanism behind captopril's enhancement of insulin sensitivity. Captopril also has antiplatelet effects which could have helped in the reduction rate of recurrent myocardial infarction in the SAVE trial.⁶

Fosinopril is efficiently taken up by the heart, and it is postulated that conversion to a charged state "traps" fosinopril in the intracellular cytoplasmic environment, and therefore it accumulates in high concentrations in the heart.²⁰

The distribution of ACE inhibitors in plasma and tissue depends on the number of available binding sites, and a range of factors related to the ACE inhibitor and the tissue enzyme that enable interaction. Quinaprilat is one of the most potent inhibitors of lung and tissue-based ACE binding.²¹ The implications of tissue-based ACE are not completely understood at this time, and there is no evidence that differences in tissue binding contribute significantly to the clinical effects of the various ACE inhibitors. Well-controlled, prospective, comparative trials are needed to determine whether claims of class effects are valid.

Summary of Clinical Benefits

Reduce severity and frequency of symptoms
Prevent progression of symptoms
Improve survival
Improve functional status
Improve exercise tolerance

In summary, ACE inhibitors have been shown to reduce mortality in patients with mild, moderate and severe heart failure, as well as patients post-MI who are asymptomatic for heart failure. They reduce severity and frequency of symptoms, prevent progression of, and prolong survival in patients with heart failure. ACE inhibitors have been demonstrated to enhance functional status of patients, with an average improvement of 0.5-1 functional class.

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