2005

Commonly Asked Questions
From Primary Care Physicians
Treating Systolic Heart Failure

Points to Remember

• Treat all patients with reduced ejection fraction (EF) (<40%) with angiotensin-converting enzyme (ACE) inhibitors and ß-blockers. Some experts extend this to patients with EF less than 50%.
• ACE inhibitors are first-line therapy.
  • Use angiotensin receptor blockers only if ACE inhibitors cause cough or angioedema.
  • Treat patients who develop hyperkalemia or worsening renal function with ACE inhibitors with a combination of hydralazine and isosorbide dinitrate.
• Patients who present with signs and symptoms of heart failure (HF) can have reduced EF (systolic HF) or normal EF(diastolic HF).
• ß-Blockade should be prescribed for NYHA class I-III patients as soon as HF symptoms and volume status are stable.
  • Start low (dose) and go slow (titrate dose upward every 2 weeks).
  • Aim for goal doses or maximal tolerated dose
• Digoxin and diuretics should be prescribed for symptom relief as needed.
  • Consider a lower therapeutic range for digoxin (0.5-0.8 ng/mL).
  • Adjust diuretic dose daily on the basis of patient weight.
• Many HF patients may qualify for and benefit from an implantable defibrillator.
• Consider referral to Mayo Clinic's Heart Failure Clinic for
  • Evaluation of etiology (eg, catheterization).
  • Difficulty up-titrating medications or persistent symptoms on standard therapy.
  • Patients who may qualify for transplantation, advanced or experimental therapies.

Heart failure (HF) is extremely common, and primary care physicians must treat it aggressively to improve symptoms and survival and, importantly, to avoid the need for frequent hospitalizations. Common questions include the following:

Should I treat a patient with reduced ejection fraction (EF) even if he or she does not have HF symptoms?
Patients with a history of coronary artery disease, hypertension, peripheral vascular disease, or cerebrovascular disease may undergo EF assessment for various reasons despite an absence of HF symptoms. Sometimes patients without known cardiovascular disease are noted to have electrocardiographic or chest x-ray abnormalities or an abnormal finding on physical examination and undergo assessment of their EF. Thus, not uncommonly, patients are found to have reduced EF even though they have no symptoms of HF. This is called asymptomatic ventricular dysfunction and is actually quite common. Seven different population-based studies have now shown that 1% to 2% of the adult population has a reduced EF but no symptoms of HF. Other studies have shown that these patients are at high risk for HF progression and premature death. Indeed, even a mild reduction in EF (an EF of 40%-50%) is associated with a high risk of HF progression and premature death. Unfortunately, there is no cost-effective way to screen the general population for the presence of asymptomatic ventricular dysfunction. However, in a patient with asymptomatic ventricular dysfunction, American College of Cardiology/American Heart Association guidelines recommend treatment with angiotensin-converting enzyme (ACE) inhibitors and, in most instances, with ß-blockers to delay the progression to HF and to improve mortality. Use of digoxin and diuretics in these patients would generally not be warranted, because digoxin appears to affect only symptoms, not survival. Patients also need to undergo evaluation to clarify the cause of their systolic dysfunction and to be followed closely for onset of HF symptoms that would warrant additional therapy.

Should I prescribe ACE inhibitors or an angiotensin receptor blocker (ARB) as first-line therapy for symptomatic HF patients?
Three large clinical trials (ELITE II, OPTIMAAL, and VALIANT) have now demonstrated that ACE inhibition should be used as first-line therapy for symptomatic HF. ACE inhibitors are available in generic form and are considerably less expensive than ARBs. Use of an ARB offers no advantages over ACE inhibitors in reducing mortality or HF admissions. In fact, a trend in 2 of the trials suggested that ACE inhibitors were better as first-line therapy. In patients who develop a cough while taking an ACE inhibitor, an ARB is an effective and proven alternative therapy. When a patient develops angioedema due to an ACE inhibitor, results of the recent CHARM study suggest that angioedema will recur in only a few patients when they are switched from an ACE inhibitor to an ARB. For these patients, an ARB is an attractive option. For patients who cannot tolerate an ACE inhibitor because of worsening renal function, ARBs are equally likely to cause worsening renal function or hyperkalemia. These patients should be considered for treatment with a combination of hydralazine and isosorbide dinitrate.

When should I add a ß-blocker?
ß-blockers should be used in all patients with HF (or asymptomatic ventricular dysfunction) as soon as the patient's condition has stabilized, and the patient is relatively euvolemic and has been started on an ACE inhibitor. Patients who are still markedly decompensated with marked volume overload or who need inotropic support should be treated first with an ACE inhibitor, diuretics, and digoxin to achieve compensation. Often at the end of hospitalization, a low dose of a ß-blocker can be added with subsequent up-titration as an outpatient. NYHA class IV patients who are euvolemic and who have not required recent intravenous therapy for HF can also be started cautiously on a ß-blocker.

Which ß-blocker should I use to treat HF?
Current guidelines recommend the use of extended-release metoprolol (Toprol XL) and carvedilol (Coreg). These are the only ß-blockers labeled for use in patients with congestive heart failure. These drugs have been shown in randomized trials to improve survival and decrease the combined end point of death and recurrent HF hospitalization. On average, patients with systolic HF who are treated with a ß-blocker achieve a 5% to 10% increase in their EF.

Normalization of EF with ß-blocker therapy is not uncommon, but the drug should not be discontinued if this occurs. While many physicians have chosen to use the less expensive immediate-release preparation of metoprolol, the appropriate dose or dosing interval has not been clearly established, and a head-to-head comparison between immediate-release metoprolol and carvedilol showed that carvedilol therapy increased survival and reduced hospitalizations more than immediate-release metoprolol. There has been no head-to-head comparison of extended-release metoprolol and carvedilol, and the choice between these 2 agents should be dictated by compliance issues (once-a-day dosing for extended-release metoprolol vs twice-a-day dosing for carvedilol) and the presence of reactive airways disease (extended-release metoprolol is is elective, whereas carvedilol is not). Both drugs are available in preparations that facilitate up-titrating the drugs in HF patients. Very low doses of carvedilol (3.125mg twice daily) and extended-release metoprolol (25 mg daily) should be used as initial therapy. The speed of titration should be adjusted to consider the severity of HF symptoms, the blood pressure, the heart rate, and the tolerance of previous dose increases. Older, more fragile patients with low blood pressure should undergo gradual up-titration. Up-titration can be faster in younger patients who have fewer symptoms and higher blood pressure. The dose is increased by 25% to 100% every 2 weeks while monitoring daily weight, blood pressure, heart rate, and symptoms. A goal dose of carvedilol is 25 mg twice a day (higher if weight >85 kg). A goal dose of extended-release metoprolol is 200 mg daily.

What if the patient cannot achieve goal doses of ß-blocker?
Does it do any good to continue therapy? Studies have now shown that, as long as the dose is titrated up to the maximal tolerated dose, a benefit is achieved. Dose-finding studies with carvedilol have shown that as little as 6.25 mg twice a day was associated with a beneficial effect on survival. Studies with extended-release metoprolol have shown that as long as the maximally tolerated dose is achieved, significant effects on mortality and hospitalization are seen. Limiting symptoms are usually bradycardia, hypotension, orthostatic lightheadedness, and fatigue. Worsening heart failure with ß-blocker up-titration can usually be handled by adjustment of the diuretic dose and slowing the rate of up-titration. Fatigue unassociated with worsening HF is quite common. Often this resolves with time if the patient agrees tostay on the therapy.

Should I still be giving HF patients digoxin and, if so, at what dose?
Digoxin remains an effective therapy for patients with severe systolic dysfunction and symptomatic HF, particularly if they have atrial fibrillation, but even if they are still in sinus rhythm. Although the DIG trial did not show an effect on mortality, it did confirm a significant effect on improving symptoms and reducing hospitalizations. As digoxin is devoid of hypotensive effects, it is often a good drug to add when the patient has persistent symptoms despite ACE inhibitors and ß-blockers or during the up-titration process when starting therapy. More recent analysis of the DIG trial results suggests that a lower dose may be more appropriate with digoxin levels in a target range of 0.5 to 0.8 ng/mL rather than 1.0 to 2.0 ng/mL.

Once I have a patient on an ACE inhibitor, a ß-blocker, and appropriate doses of diuretics and digoxin (if needed), should I add an ARB or analdosterone inhibitor such as spironolactone or both?
Evidence to support adding an ARB to ACE inhibitor treatment is relatively weak. Three large trials (Val-HeFT, VALIANT, and CHARM) compared outcomes in patients treated with an ACE inhibitor or the combination of an ACE inhibitor and an ARB. None of these 3 trials showed that adding an ARB to an ACE inhibitor reduced all-cause mortality. The Val-HeFT trial suggested a benefit in reducing HF hospitalization with combined therapy, but this was not observed in the VALIANT trial and was of borderline statistical significance in the CHARM trial. Bottomline: adding an ARB to an ACE might reduce hospitalizations but does not impact all-cause mortality. In contrast, adding an aldosterone antagonist such as spironolactone or eplerenone (Inspra) to ACE inhibitors and ß-blockers improved mortality, reduced symptoms, and reduced HF hospitalizations in 2 large trials. The RALES trial used spironolactone, and the results were positive, demonstrating reduced mortality, improved symptoms, and reduced HF hospitalization. Both HF deaths and sudden deaths were reduced by adding spironolactone. A more recent trial in patients with HF after myocardial infarction used a more specific aldosterone inhibitor called eplerenone. Eplerenoneis free of the adverse effect of gynecomastia, which may occur in patients using spironolactone. As in the RALES trial, the EPHESUS trial using eplerenone showed reduced all-cause mortality, reduced HF hospitalization, and improved symptoms. Unfortunately, eplerenone is much more expensive than spironolactone. Thus, the first drug to add once patients are on ACE inhibitors and ß-blockers is an aldosterone inhibitor. Such drugs should not be added, however, in the presence of extreme renalin sufficiency (creatinine>2.0 mg/dL) or in patients with known hyperkalemia. Potassium needs to be monitored carefully for some time after the addition of spironolactone. Potassium supplements should usually be stopped before adding spironolactone or eplerenone. Given the higher cost of eplerenone, a reasonable approach might be to start with spironolactone and switch to eplerenone if the patient complains of gynecomastia.

What can be done for the patient who remains symptomatic despite maximal medical therapy?
Referral to a cardiologist or HF specialist should be considered to help identify the cause of HF (eg,need for catheterization), when patients are not tolerating standard therapy or when they remain symptomatic despite goal doses of ACE inhibitors, ß-blockers, aldosterone antagonists, diuretics, and digoxin. Certain advanced therapies can be considered.

Potential transplant candidates should be referred before they develop severe symptoms because patients may spend 2 years or more waiting for their transplant. Transplantation may even bean option for some patients in their late 60s and early 70s if other organ function is preserved.

The indications for an implantable defibrillator have widened. Many, if not most, HF patients qualify for a defibrillator. As half of HF deaths occur because of arrhythmias, this important component of HF care should not be neglected. Referral to a cardiologist for consideration of a defibrillator is important for patients with reduced EF regardless of their level of symptoms.

Cardiac resynchronization therapy, or "biventricular pacing," can provide marked benefit to selected HF patients. Patients who have persistent symptoms despite medical management can be considered for this type of therapy, particularly if their QRS duration is wide (>120 ms). Left ventricular assist devices are often used as a bridge to transplantation in patients who have severe HF and who cannot survive until a transplantable heart becomes available. In addition, left ventricular assist devices are offered to some patients as "destination therapy," meaning that they will not receive a transplant but will use the assist device to improve their quality of life chronically. There is intense investigation in this area, and smaller and better systems to assist the heart are being developed and will expand the number of patients who may benefit from such therapy. The role of disordered breathing (sleep apnea) in worsening HF symptoms must be considered, evaluated, and treated. This is an extremely common cause of persistent symptoms in HF patients. A sleep study can make the diagnosis and guide therapy. A wide range of new drugs and devices are currently being tested for HF, including novel devices to augment the systolic function of the heart, devices to reduce the amount of mitral regurgitation related to dilatation of the heart, stem cell therapies, and a number of novel drugs. Patients may be interested in such studies and can learn more about them from an HF specialist.

General guidelines regarding use of defibrillators, cardiac resynchronization therapy, and cardiac transplantation or chronic left ventricular assist devices