Heart Failure: Part 2, Update on Therapeutic Options

Recently updated clinical guidelines reflect major changes in our understanding of and approach to heart failure.^1,2 In my previous article (CONSULTANT, July 2007), I reviewed the latest developments in diagnosis and disease staging. Here I discuss key shifts in focus in the management of heart failure. These include:

•The need for prompt titration of lifesaving neurohormonal antagonists.
•The benefits of treating underlying and comorbid diseases.
•Strategies for monitoring patients over time.
•The evolving role of device-based therapy.

NEUROHORMONAL ANTAGONISTS

Back in the 1980s, randomized clinical trials showed the potential benefits of hydralazine and isosorbide dinitrate in the treatment of chronic heart failure. In the 1990s, several pivotal trials demonstrated the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and b-blockers in patients with chronic heart failure. Today, ACE inhibitors and b-blockers are recommended for all patients with stage C or stage D heart failure (and for select patients with stage A or B) unless clearly contraindicated. These drugs can be initiated after optimization of volume status (even while the patient is still in the hospital). However, do not start them in patients who have recently undergone aggressive diuresis with relative intravascular volume depletion (azotemia or hypotension might be triggered) or in the presence of other factors that could hinder drug titration.

The rationale for starting ACE inhibitors first is largely historical. Recent clinical data show that ACE inhibitors and b-blockers are equally effective as initial therapy.³ The goal is to have patients take both drugs at their target (or maximally tolerated) dosages. This usually takes 1 to 3 months to achieve, although the duration and intensity of follow-up visits needed to attain optimal dosages of both agents vary widely, depending on the self-care ability and adherence of the patient.

It is customary to up-titrate a single drug at each visit (unless blood pressure is poorly controlled) to allow better assessment of drug intolerance. The effectiveness of a systematic "start low, go slow" approach to up-titration has been clearly demonstrated. Still, the pace of this titration is largely tailored to the individual patient's tolerance and need. For example, a patient with significant hypertension might receive maximal drug doses within a few weeks, whereas a patient with marginally elevated blood pressure might take months to adapt to a relatively modest drug dose.

NEWER APPROVED AGENTS

Other therapeutic options for heart failure have emerged in recent years. However, the guidelines indicate that these agents should be considered primarily in patients with underlying left ventricular systolic dysfunction who have persistent or progressively worsening symptoms despite optimal therapy.

Aldosterone receptor antagonists. These drugs significantly reduced mortality in patients with advanced chronic heart failure in the RALES trial⁴ and in those with post-infarction heart failure in the EPHESUS trial.⁵ However, broad use of these otherwise beneficial agents has led to a high rate of hyperkalemia and renal insufficiency in real- world settings. Thus, vigilance is mandatory when using these drugs.

In general, when aldosterone receptor antagonists are initiated, patients should have estimated glomerular filtration rates of greater than 30 mL/min, serum potassium levels below 5.0 mEq/L, and no diarrhea or history of serious hyperkalemia. In addition, advise patients to discontinue potassium supplements and NSAIDs.

Except in cases of persistent fluid retention, spironolactone is rarely up-titrated beyond 25 mg/d, whereas the dosage of eplerenone is usually between 25 and 50 mg/d. The recommended monitoring protocol, which helps guard against hyperkalemia and renal insufficiency (especially important in elderly patients), includes checking potassium levels and renal function at 2 to 3 days and 1 week following drug initiation, and afterwards at least monthly for the first 3 months.

Angiotensin receptor blockers (ARBs). Several mega-trials have illustrated the relative equivalence of ARBs (such as valsartan and candesartan) and ACE inhibitors when an ARB is substituted for a drug in the latter class. However, the potential cardiovascular benefits of add-on therapy with ARBs were recently demonstrated with candesartan in the CHARM-Added trial.⁶ Still, risks of hyperkalemia and hypotension are important limitations to the use of ARBs—especially when these are used in addition to an ACE inhibitor—and potassium levels and blood pressure should be carefully monitored. The safety of using an ARB in addition to both an ACE inhibitor and an aldosterone receptor antagonist is supported only by limited data.

Fixed-dose combination of hydralazine and isosorbide dinitrate. This combination pill is recommended as add-on therapy to be used along with an ACE inhibitor or ARB.It is used primarily in African American patients with symptomatic systolic heart failure, after reduced mortality was observed in this population in the A-HeFT study.⁷ As with ARBs, associated hypotension and other adverse effects can limit the use of this therapy.

VASODILATORS AND DIURETICS

Optimal systemic and right-sided pressures (achieved with vasodilators and diuretics) remain important treatment goals, especially in the advanced stages of heart failure. Many cardiologists add vasodilators to the regimen to optimize afterload reduction and improve perfusion. Diuretics may still be needed even in patients who are no longer "congested"—especially those who have reached target dosages of neurohormonal antagonists.

Although most experts interpreted the results of the recent ESCAPE study as showing no benefit from hemodynamic assessment with a pulmonary artery catheter in "equipoise" patients admitted for acute decompensated heart failure,⁸ select patients (particularly those with end-organ compromise or symptoms refractory to existing medical regimens) may still benefit from hemodynamic assessment and tailored medical therapy in experienced heart failure centers.

TREATMENT OF UNDERLYING AND COMORBID DISEASE

As we continue to delay the progression of heart failure with drugs, patients are presenting with a greater number of comorbidities. Earlier recognition and prompt treatment of these comorbidities may lead to improved survival. However, clinical studies are still needed to demonstrate that targeting comorbid conditions has a direct impact on long-term clinical event rates in patients with heart failure.

Sleep-disordered breathing may contribute to the progression and symptom burden of heart failure. Alterations in breathing patterns (eg, Cheyne-Stokes respiration) are common in end-stage heart disease and during impending decompensation. However, both obstructive and central sleep apnea are increasingly noted in patients with chronic heart failure as well. Any patient with symptoms suggestive of sleep apnea should be evaluated with a formal sleep study. Once recognized, either type of sleep apnea should be corrected with positive airway pressure therapy.

Comorbid mood and cognitive disorders are often underrecognized. Their treatment may yield significant improvements in morbidity.

Renal insufficiency is a leading risk factor for mortality associated with heart failure.⁹ It has been recognized only recently that overzealous use of conventional loop diuretics can induce renal insufficiency and heighten morbidity and mortality risks in patients with heart failure. In fact, to minimize the risk of azotemia, the diuretic dosage in many patients is now being reduced to the lowest end of the recommended dosing range. However, down-titration of diuretic therapy should be attempted only in euvolemic (or hypovolemic) patients, in a stepwise fashion with careful monitoring, and after having weighed the risks and benefits.Although the underlying mechanisms of the cardio-renal connection in heart failure remain elusive, several promising therapeutic strategies include renal preservation as one of their objectives.

Anemia is common in patients with heart failure; it results from a combination of hemodilution, neurohormonal up-regulation, chronic inflammatory and metabolic derangements, and other unknown factors. In most patients, a reversible cause of anemia can be identified and treated (eg, GI bleeding, iron or nutritional deficiency, renal insufficiency). Erythropoietin supplementation has been shown in small mechanistic studies to improve signs and symptoms of heart failure; larger, more definitive studies are currently under way to determine the potential efficacy of this therapy before it is broadly adopted.

Diabetes mellitus is common in patients with heart failure; however, several drugs used to lower blood glucose levels can present challenges in the setting of heart failure. Thiazolidinediones and insulin may lead to fluid retention, and in patients with both heart failure and renal insufficiency, metformin may cause lactic acidosis.

LONGITUDINAL MONITORING

The optimal strategy for longitudinal monitoring of heart failure has not yet been determined. Even the latest guidelines do not specify how often patients should be evaluated and tested or what parameters are appropriate.

Biomarkers. The possibility of using a biomarker such as the B-type natriuretic peptide (BNP) level to guide therapy has been very attractive. In many diseases, clinicians rely on surrogate markers to titrate therapy (eg, glycated hemoglobin [HbA_1c] and blood glucose levels in diabetes, thyroid-stimulating hormone level in hypothyroidism). However, insufficient data support such an approach in heart failure; the majority of biomarkers have proved more useful in risk stratification than as the basis for therapeutic targets.

Early studies indicate that the use of natriuretic peptide testing by emergency department physicians significantly affects the length of hospital stay and the cost-effectiveness of heart failure treatment.¹⁰ The results of several preliminary randomized controlled trials show that plasma natriuretic peptide levels track with observed changes in clinical status and that lowering of natriuretic peptide levels correlates with a reduced risk of adverse clinical outcomes.¹¹ Larger prospective randomized studies are ongoing to identify the best way to use plasma natriuretic peptide levels to guide medical therapy in the outpatient setting.

Impedance cardiography (ICG). Impedance is a measurement of the resistance of different tissue types to an alternating current. Fluctuations in impedance allow the gross estimation of hemodynamics and body volume status. Although early results of the use of ICG to monitor heart failure therapy have been promising, ICG remains controversial because most data that support its use have focused on correlations with other surrogate markers rather than with clinical presentations or outcomes. Also, the different algorithms provided by different ICG vendors impede the establishment of a single diagnostic process. Nevertheless, the noninvasive nature of this strategy is an attractive advantage. A post hoc analysis of a recent clinical trial yielded a promising algorithm for the use of ICG monitoring along with clinical parameters in the risk stratification of patients with heart failure.¹² Validation of this algorithm in prospective clinical studies will be necessary before it is ready for widespread use in patient management.

DEVICE-BASED THERAPY AND MONITORING

Implantable cardioverter defibrillators (ICDs). The broad-based use of defibrillators and biventricular pacemakers in heart failure has been largely driven by a few pivotal clinical trials. A study of patients with ischemic cardiomyopathy (with a left ventricular ejection fraction [LVEF] of 30% or less),¹³ and another of patients with symptomatic heart failure of either ischemic or nonischemic origin (NYHA class II through IV, with an LVEF of 35% or less)¹⁴ demonstrated the effectiveness of prophylactic ICDs in reducing long-term mortality. However, the ability of ICDs to reduce mortality in patients with heart failure probably stems from the high risk of unexpected arrhythmic death in such patients. A strategy of "insuring" survival through widespread use of ICDs is exceedingly costly; moreover, the benefits of ICD therapy can be compromised by device malfunction. Thus, the risks and benefits of device therapy need to be weighed carefully. A useful tool for reviewing the risks and benefits of ICD therapy with patients is presented in Box II.¹⁵

Cardiac resynchronization therapy (CRT). Early mechanistic data identified an important role for dyssynchrony (both between the left and right ventricles as well as between different regions within the same ventricle) in the progression of heart failure. These observations were followed by clinical trials that dem- onstrated proof-of-concept diminishment of symptoms and ventricular remodeling with CRT (in which a pacer lead travels from the right heart, along the coronary sinus, to the left ventricular wall to provide simultaneous pacing). With longer follow- up and larger sample sizes, multicenter studies such as COMPANION and CARE-HF provided further evidence that CRT may reduce morbidity and mortality when used in carefully selected populations.^16,17

The established indications for CRT have been:

•Prolonged (more than 20 ms) QRS complex on ECG.
•Impaired LVEF (35% or less).
•Advanced heart failure symptoms (NYHA classes III and IV) despite optimal drug therapy.

What additional qualifications should be used to select those patients most likely to benefit from CRT—and what the underlying mechanisms are in those who do benefit—are the subjects of ongoing research.

Device-based hemodynamic monitoring. As increasing numbers of patients with heart failure (especially those who have impaired cardiac function) are receiving pacemakers or defibrillators, device-based monitoring is becoming more widely used.

At present, many defibrillators and pacemakers can identify the onset and duration of atrial fibrillation, detect changes in heart rate variability, calculate the percentage of beats paced, and even quantitate the average change in intrathoracic impedance across the lead and the device (as a surrogate marker for fluid accumulation). Other external devices can transmit patient information (such as weight, blood pressure, and clinical symptoms) to online reports. The available monitoring options largely depend on the make and function of the device and are offered in addition to the array of information already provided to help cardiologists maintain the device's primary defi-brillating or pacing function. There are various other telemonitoring devices and companies that offer similar monitoring capabilities via gadgets and telephone call-ins; however, lack of reimbursement remains a significant drawback.

Many ongoing prospective clinical trials are examining the utility of additional data in the management of patients with advanced heart failure. The greatest challenge with all implantable devices will be to provide a meaningful interpretation of the information collected, in a manner that is cost-effective and that does not unduly burden the caregiver.

ADVANCES IN SPECIALIZED THERAPIES

Advanced surgical procedures, such as left ventricular remodeling surgeries (Batista and Dor procedures) and mitral valve annuloplasty or repair surgeries, have significantly improved the treatment of heart failure. However, long-term clinical experience has indicated that these invasive procedures may not be appropriate for all patients with heart failure.^18,19 In many patients with stage D heart failure, cardiac transplantation remains the primary option. Moreover, early identification and stratification at experienced heart failure and transplant centers are the keys to improving outcomes for most patients, even though many cannot benefit from this strategy because their condition has progressed beyond "salvageable" by the time they reach such a center.

The permanent implantation of mechanical ventricular assist devices (VADs)—so-called destination therapy—in patients with end-stage heart failure who are not optimal candidates for cardiac transplantation has evolved over the past decade. In patients with end-stage heart failure (stage D) for whom cardiac transplantation is not an option, VAD implantation has been associated with better long-term survival than medical treatment alone.²⁰ However, infections of the device and driveline (the wires and tubes that connect the device to the external controllers), thrombosis, and strokes remain significant drawbacks. Even though newer-generation, non-pulsatile VAD designs are more compact and have smaller drivelines that allow better tolerability and portability, mechanical VAD support remains an expensive and labor-intensive venture whose results are still not on a par with the 90% average 1-year survival rate and 75% 5-year survival rate associated with cardiac transplantation.

CLINICAL PERSPECTIVES

Since the last guideline recommendations were published a decade ago, modest progress has been made in clarifying the optimal pharmacotherapeutic regimen for patients with heart failure. The primary focus of the latest guidelines remains therapy for patients with systolic heart failure; however, the emphasis is now on when and how drugs should be given rather than whether they are effective. Still, the bigger—and remaining—challenge is to delineate how heart failure differs from one patient to another and to determine whether tailoring drug regimens to correspond to different disease characteristics might improve outcomes. Resolution of this issue is desperately needed; new drugs are failing in clinical trials not because they target the wrong mechanisms but because the patients most likely to benefit from the drugs cannot be identified.

A thorough understanding of the pros and cons of specific drugs and devices is even more important. Without this, the adverse effects of an intervention may eclipse its intended benefit (as happened when spironolactone therapy was broadly adopted after publication of the RALES data).