© 2005 European Society of Cardiology
Design of therapy for advanced heart failure
Cardiovascular Division, Brigham and Women's Hospital 75 Francis St., Boston, MA 02115, United States
* Tel.: +1 617 732 7406; fax: +1 617 264 5265.
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Advanced heart failure has been defined as persistent symptoms (NYHA class III–IV) that limit daily life despite routine therapy with agents of known benefit. Although these symptoms can occur both with low and preserved ejection fraction, the majority of reported experience is with low ejection fraction, usually <25%. For this population with expected one year mortality of 30–50%, over twice the mortality of the landmark trials of medical therapy, there is little trial data to guide management, which is based largely on collected experience. Once the disease has progressed to this stage, therapy focuses upon the twin goals of symptom relief and prolongation of survival and is guided according to the hemodynamic profiles defined by clinical assessment. As symptoms at this stage relate largely to the congestion, therapy is targeted to reduction of elevated pulmonary venous and/or systemic venous pressures to near normal levels. The most common obstacle to relief of congestion is the increasingly recognized cardio—renal syndrome, for which both understanding and therapy are currently limited. Design of the outpatient regimen for advanced heart failure must be tailored to the individual patient. Many patients with advanced heart failure cannot tolerate "target" doses of neurohormonal antagonists, and spironolactone should be used only when clinical and renal function are sufficiently stable and frequently monitored in order to avoid life-threatening hyperkalemia. The clinical benefit of bi-ventricular pacing is substantial for the small proportion of patients likely to benefit. The vast majority of patients will never be eligible for cardiac transplantation or ventricular assist devices. To derive maximal benefit from all available therapies, heart failure disease management with collaboration of physicians and specialized nurses offers the greatest benefit to the greatest number of patients with advanced heart failure.
Key Words: Advanced heart failure • Therapy • Cardio–renal syndrome • Beta blockers
Received June 4, 2004; Revised October 26, 2004; Accepted January 10, 2005
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1. Introduction |
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TopAbstract1. IntroductionReferences |
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Widespread use of ACEI and beta adrenergic blocking agents have improved the prognosis of heart failure in mild–moderate stages. For many, however, heart failure remains a progressive disease, eventually leading to decompensation. The incidence of unexpected sudden death has been decreased by systematic application of these therapies, and further decreased by implanted defibrillators. More patients now survive to become severely limited by symptoms of heart failure.
Advanced heart failure has been defined as persistent symptoms that limit daily life despite routine therapy with agents of known benefit [1].This corresponds to New York Heart Association Class III/IV symptoms, and to the newer classification of Stage D heart failure [2]. Most patients have had at least one recent hospitalization. Although these symptoms can occur both with low and preserved ejection fraction, the majority of reported experience is with low ejection fraction, usually <25%.
There is little data from trials to guide management of most patients with advanced heart failure. The expected mortality, particularly with recent hospitalization, is in the range of 30–50% or higher at one year, which is over twice the mortality of the landmark trials of medical therapy. Even the trials of "severe" heart failure with beta blockers have mortality in the range of 15–20% at one year [3]. The highest mortality in a medical trial was in the demonstration of the benefit of spironolactone [4]. At the other extreme is the trial of left ventricular assist devices, with a one year mortality of 75% for the medical arm [5].
For the most part, management of advanced heart failure is guided by reported and personal experience. Contemporary observation and synthesis remains critical, as experiences from ten years ago are of diminishing relevance to a population that has survived longer periods.
Much attention has been devoted to the replacement options of transplantation and mechanical cardiac support devices. Increasing awareness of these possibilities has attracted patients previously uncounted in small communities where they were considered end-stage. The concentration of these patients in centers has allowed advances in their medical care and formation of dedicated medical management programs, which continue to offer the most relevant options for most patients with advanced heart failure.
1.1. Importance of fluid balance
Before symptoms of heart failure ever appear, progression of disease is already influenced by the contribution of subtle increases in wall stress and filling pressures. When symptoms later dominate the picture, they are primarily symptoms of congestion, related to excess circulating volume. Key to the initial and ongoing evaluation of advanced heart failure is careful attention to assessment and management of volume status [2]. Many patients considered to have refractory heart failure can return to a reasonable level of comfort and function when fluid balance is restored and maintained [6]. This is repeatedly emphasized as a Level I recommendation in guidelines for management of heart failure [2]. Like many recommendations for disease of this severity, however, the evidence is based largely on consensus. When the immediate impact of a therapy to improve clinical status is apparent, it is not feasible or ethical to do randomized trials with placebo therapy.
The most obvious symptom of elevated left-sided filling pressures is dyspnea. While the dyspnea that occurs only after moderate exercise may reflect anaerobic metabolism from inadequate cardiac output reserve, immediate dyspnea on light exertion (IDLE), such as dressing or walking to the bathroom, is generally related to elevated resting filling pressures. Breathlessness is complex, and occurs earlier in the setting of underlying lung disease. Orthopnea is elevated filling pressures unless proven otherwise. Some patients have a cough equivalent to immediate dyspnea or orthopnea. Another common symptom complex is gastrointestinal symptoms related to elevated systemic venous (right-sided) pressures.
For patients with advanced heart failure, it has been helpful to classify patients into 4 basic hemodynamic profiles, depending on the presence and absence of congestion and the apparent adequacy of clinical perfusion [7] (Fig. 1). The symptoms described above provide strong evidence of congestion. For the physical examination, it is critical to recognize that rales occur rarely in chronic heart failure, due to compensatory hypertrophy of the lymphatics, which keep the airspaces clear but allow fluid to accumulate in the interstitium, causing increased work of breathing and sensations of dyspnea. The most useful physical sign of elevated left-sided filling pressures is jugular venous distention [8,9]. Effective examination of the neck veins requires dedication and persistence, as there is currently no non-invasive substitute.
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Appreciation of the relationship between right- and left-sided filling pressures is critical to effective therapy of fluid status in heart failure. In 1000 patients studied previously with advanced heart failure, the pulmonary capillary wedge pressure was usually over twice the right atrial pressure [10]. In this case, therapy can generally be tailored to reduce both, with the assumption that left ventricular filling pressures will be in the optimal range of 14–18 mmHg when the right atrial pressures were in the range of 5–8 mmHg. As the duration of survival with left heart failure lengthens, secondary right ventricular enlargement and failure may become more prominent. With a growing prevalence of equivalence between right- and left-sided filling pressures, therapy to normalize right-sided pressures may not be possible. In these patients, refractory signs and symptoms of right heart failure may dominate in the advanced stages of heart failure, although the primary abnormality was most often left ventricular injury or dysfunction.
Achieving optimal volume status is the most common intervention made successfully by specialized heart failure programs in patients considered to have failed therapy elsewhere. The goals are to eliminate or minimize all the evidence of congestion as described above, beyond the level of initial symptomatic relief. Patients with chronic volume overload often perceive incorrectly that they are back to baseline, when in fact considerable further clinical improvement, including better exercise tolerance, can be achieved with further therapy to normalize filling pressures. For the "wet and warm" patients (profile B), this generally can be achieved with high doses of intravenous diuretics administered two to three times daily, and may be more effective with continuous intravenous infusion. Addition of a thiazide or metolazone potentiates diuresis by inhibiting reabsorption in the distal tubule.
For patients who are "wet and cold" (profile C), the general concept is that they need to "warm up" before they can "dry out" (Fig. 2). Identification of this subset is more problematic, and may correspond more to a clinical group than to specific hemodynamic numbers. Addition of intravenous vasodilators such as nitroprusside [12,13], nitroglycerin, more recently nesiritide [14] may be useful. Intravenous inotropic agents at low doses such as 1–3 µg of dobutamine are also helpful for facilitating diuresis, but are associated with higher risk of arrhythmias, ischemia, and troponin leak than vasodilators [15].
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When should hemodynamic monitoring be performed in patients with advanced heart failure? This remains the subject of active investigation both in the United States and in the United Kingdom. Assessment and therapy for most patients can be performed clinically without invasive measurement. For patients with recurrent hospitalizations, hemodynamic information may be helpful when it guides therapy to decrease filling pressures and relieve symptoms. Determining the baseline hemodynamic profile invasively may clarify targets of therapy for patients with complicating non-cardiac conditions such as pulmonary or intrinsic renal disease, or patients with additional cardiac conditions such as intermittent ischemia or primary valve disease. Patients not responding as hoped, particularly those developing severe hypotension or renal dysfunction during diuresis, should be re-evaluated as to whether they may have higher right-left filling pressure ratio than anticipated, or intrinsic vasodilation such that further vasodilation is excessive. After initial diuresis of obvious volume reservoirs, the wet and cold patient may benefit from ongoing hemodynamic monitoring to allow simultaneous adjustment of volume status and peripheral resistance as the oral regimen is designed. Patients should not be considered dependent on intravenous inotropic infusions until attempts have been made to wean onto oral therapy with hemodynamic guidance if necessary.
Once optimal fluid status has been restored, maintenance of fluid balance is the challenge. There are no solid bases of evidence on the best way to do this. Patients should be instructed in daily weights and given a specific routine for temporary enhancement of diuretics (often advised to double loop diuretic dose or adding metolazone or another thiazide). Once furosemide dose is over 200 mg daily, it may be helpful to change to the loop diuretic torsemide, with more consistent gastrointestinal absorption and bioavailability, particularly in patients with some right heart failure. Sodium restriction is generally to 2 grams, although a lower level can be feasible and beneficial for occasional highly-motivated patients. Once patients have had repeated episodes of fluid retention despite high-dose maintenance diuretics, it may be helpful to restrict fluid intake, but there is no basis of evidence other than collective experience to support this. Generally restriction to 2 l is feasible and adequate. Often patients find fluid restriction very difficult for the first 4–6 weeks but will re-equilibrate to a lower set point and eventually find 2 l to be manageable. Some patients with lifelong excessive fluid intake of over a gallon a day may need particular help to gradually reset their own fluid consumption.
1.2. The cardio–renal syndrome
The most common reason for truly refractory congestive symptoms among the advanced heart failure population is the recently recognized cardio–renal syndrome [16,17]. As patients live longer before developing severe symptoms, renal function is increasingly compromised from chronically decreased perfusion. The cardio–renal syndrome may be defined as worsening of renal function during diuresis despite persistently elevated circulating volume and symptoms of congestion. This occurs most commonly in patients with underlying renal dysfunction, older patients, and long duration of fluid retention. Whether defined on the basis of increased absolute creatinine or proportional increase, the cardio–renal syndrome occurs in over 25% of patients hospitalized with heart failure.
At one time, it was assumed that worsening renal function reflected excessive diuresis to a level where central cardiac output fell. When measured, however, filling pressures are usually still markedly elevated and cardiac output is not decreased below baseline prior to diuresis [16]. Cardio–renal interactions are complex, and may involve altering balance of vasodilator and vasoconstrictor hormones, and direct neural input from chronically distended cardiac chambers. Even small elevations in creatinine and BUN predict lower likelihood of maintaining freedom from congestion and higher risk of death [6].
At more advanced stages, there is no current information to guide therapy in patients for whom diuresis to the level of symptom relief is repeatedly accompanied by progressive worsening of renal function. Decrease or discontinuation of diuretics will usually improve renal function but at the price of exacerbating congestive symptoms. Inhibitors of the renin–angiotensin–aldosterone system may need to be discontinued. Maintaining systolic blood pressures may require decrease or discontinuation of other heart failure medication. Natriuretic peptide administration acutely or intermittently is currently under investigation. The risks and poor outcomes with inotropic infusions are discussed below. Occasional patients with adequate blood pressure may be considered for chronic dialysis.
1.3. The outpatient regimen
For each patient, it is crucial to determine the most limiting symptom, and the hierarchy of goals regarding comfort, activity, and survival. Based on these goals, therapy should be individualized for each patient. Multiple medications have been shown to cause a statistically significant improvement in some measured outcome in a strictly defined patient population according to a defined protocol that limits adjustment of investigational and background therapies. In daily practice, many patients fall outside the trial criteria, and there are many opportunities to refine therapy based on clinical responses in each patient.
The major purposes of therapies for mild–moderate heart failure are to decrease disease progression (often measured as hospitalization) and prolong survival. As the disease becomes more advanced, the goal of symptom relief begins to dominate. A therapy that decreases symptoms or improves functional capacity does not have to prolong survival if symptoms and functional impairment were severe enough for a benefit to be observed. Traditionally, these therapies should not worsen survival, but it is debatable how precisely the excess mortality needs to be excluded.
If a major goal is to treat the symptoms, therapies should be reviewed in that context. As discussed above, establishment of good fluid balance addresses most of the symptoms that occur at rest or with minimal exertion. ACEI and beta blockers remain cornerstones of therapy even when heart failure becomes advanced, but re-evaluation of their role for individual patients becomes necessary. ACEI and beta blockers have clearly been shown to impact disease progression and survival, but benefit on current symptoms has been very difficult to demonstrate. In mild–moderate heart failure the differences are more often prevention of symptom worsening over the next year rather than actual improvement [18]. In the absence of clear trial data on symptom relief, it is critical to regard each patient as his own valid experiment.
Inhibition of the sympathetic nervous system helps to decrease progression of heart failure but is associated with initial worsening of hemodynamic status. This is most likely to lead to clinical decompensation in patients in whom the sympathetic system is markedly activated in more advanced disease. Thus patients should be sufficiently stable to be able to tolerate slight elevation of filling pressures and decrease of cardiac output. Patients with resting evidence of congestion should generally not be started or uptitrated on beta blocking agents, although patients previously tolerating a stable dose can usually maintain it if diuresis is effective. Patients with evidence of impaired resting perfusion often have the dose of beta blockers decreased or stopped until compensation is restored.
Although some patients require decrease of ACEI and/or slight increase in diuretics when beta blockers are initiated, most patients who will ultimately tolerate beta blocking agents do not experience major clinical deterioration upon initiation. Doses should be increased in smaller and less frequent increments than for patients with mild disease. Initial fatigue, sleepiness, and lack of initiative are common during initiation and uptitration, and generally resolve within the first 6 weeks after each change. For patients who can tolerate the medication, the later benefit is clearly established in terms of survival, hemodynamic improvement and reverse remodeling. However, some patients who can tolerate the medication in terms of blood pressure, heart rate, and renal function nonetheless have persistent fatigue and listlessness that compromises overall quality of life. There is no specific outcome data regarding whether or not these patients, in whom cardiac reserve may be impaired, derive the same benefit as patients who feel well on beta blockers. Regular exercise itself appears to be beneficial for heart failure outcomes, so a diminution related to medication merits concern. For patients with advanced heart failure and apparent adverse effects on beta blockers, the goals of therapy should be reviewed. It may be appropriate to diminish the dose below that which is "tolerated" by trial criteria, and occasionally to stop beta blockers completely. In clinical heart failure practices where beta blocker therapy is aggressively pursued, approximately 30% of patients are considered to be intolerant of beta blocker therapy [19].
Similar considerations apply for ACEI, although they are usually tolerated until later in the course of disease (Fig. 3). Progressive renal dysfunction and symptomatic hypotension may lead to discontinuation of ACEI in patients previously able to tolerate them. In these patients, angiotensin receptor blockers are likely to be limited as well. There is currently no data on when ACEI should be decreased or stopped for renal dysfunction and hypotension. It is clear, however, that patients who develop circulatory-renal limitations to ACEI have a very poor prognosis, with mortality over 50% at 1 year [20].
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Spironolactone has been shown to decrease hospitalizations and mortality by 35% in patients with severe heart failure, with placebo 1-year mortality over 20% [4]. Addition should strongly be considered in these patients who have adequate potassium handling. Serum creatinine over 2.0 mg/dl or high dose diuretics without need for potassium replacement connote at higher risk of hyperkalemia during spironolactone administration. Renal function and potassium levels should be closely monitored during initiation, but even after stabilization, hyperkalemia can occur later, particularly with changing renal function and volume status, such as during an episode of gastroenteritis. Potentially life-threatening hyperkalemia after addition of spironolactone in clinical practice has been reported to be over 20% [21].
Patients with persistent symptoms of exertional dyspnea may benefit from addition of nitrate therapy [22], either in addition to the other agents or in patients who cannot tolerate ACEI. Although often used with hydralazine, nitrates are very effective as single agents also, and have recently been associated with beneficial remodeling effects as well as improvement in exercise capacity. There is a general suspicion that nitrate therapy may improve symptoms more than any other vasodilator medication, lack of multicenter data reflecting only the absence of industry sponsorship. As with nitrates, hydralazine may be added to ACEI for patients with persistent vasoconstriction or hypertension. It is generally not given as monotherapy, although may be used in some patients unable to tolerate either ACEI or nitrates.
Regular exercise in small trials has decreased both hospitalizations and deaths. This may relate to effects of exercise training to decrease baseline sympathetic stimulation as measured by sympathetic nerve recordings [23]. Although under-appreciated as a component of the medical regimen for neurohormonal inhibition, this is sufficiently important to form a major part of the ongoing education for heart failure patients.
1.4. Heart failure disease management
Discussed elsewhere, heart failure management is mentioned here to underscore its importance as part of the medical regimen. The benefits of heart failure management to decrease hospitalization and improve quality of life exceed that of any individual medical therapy. For patients with advanced heart failure, the frequency of patient contact, both routine and patient-initiated, is so high that specialized nurses can become overburdened. As an indication of the intensity of therapy, for patients discharged from first hospitalization after referral with refractory symptoms to a heart failure program, an average of 7 calls and 2 clinic visits per patient were made during the next three months (Shah M, Duke University, personal communication, manuscript submitted, Fig. 4). Although some adjustments were made in ACEI and beta blockers during this period, 80% of changes were in diuretic therapy, with an average of 3 changes in dose/patient. It is estimated that for patients with active issues as reflected by hospitalization within the past year, an experienced nurse specialist can handle education and follow-up for approximately 150 patients. More patients can be taken into the caseload later as initial patients gain facility at self-management. If the US-Medicare reimbursed costs of approximately $5000 are used for calculation, a reduction of the order of only 20 hospitalizations annually is needed to favorably impact the overall cost of caring for heart failure.
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1.5. Bi-ventricular pacing for resynchronization
As heart failure progresses, the ventricles further enlarge and conduction may become further impaired. The delay in activation between the septum and postero-lateral left ventricular wall diminishes the efficiency of contraction and aggravates functional mitral regurgitation. A QRS duration over 120 ms may be present in 25–40% of patients with advanced heart failure by symptoms and ejection fraction, as defined above. The most common conduction abnormality with both ischemic and non-ischemic cardiomyopathy is left bundle branch block, but many conduction patterns are atypical. Technology has developed to allow transvenous insertion of both ventricular pacing leads for many patients with wide QRS complexes. This therapy was approved on the basis of clinical improvement for over half of patients undergoing implantation [24]. Unlike other therapies shown to be beneficial for heart failure, there was consistent improvement shown in symptoms, quality of life, and exercise capacity. Individual patients often noted large improvement. Benefit may be conceived as moving heart failure between Class III and IV to a symptomatic level between Class II and III. Systolic blood pressure often increases by 10–15 mmHg in responding recipients, which may allow higher doses of neurohormonal antagonists.
Patients with marked inter-ventricular dysynchrony as measured by non-invasive imaging may derive the greatest benefit, but there is no current agreement about how this should be measured. Wide QRS does not always mean marked dysynchrony, and occasional patients will have severe dysynchrony without severely prolonged QRS. Nonetheless, the QRS width, as used in the trials, is currently the most convenient descriptor for patients for whom biventricular pacing should be considered. Trial inclusion criteria have generally specified QRS interval >120 or 130, but patients demonstrating symptomatic benefit have generally had median QRS duration in the 150–170 range. Ambulatory patients with early exertional symptoms most typically show benefit. While many patients have been able to come off lists for cardiac transplantation after bi-ventricular pacing, there is general agreement that patients with severe resting symptoms are unlikely to benefit, particularly if they are in a low output state or requiring continuous inotropic infusions. Resynchronization pacing is not "rescue therapy".
1.6. Minor role for current replacement therapies
Cardiac transplantation currently offers 50% chance of 10-year survival and generally good quality of life for recipients [25]. Unfortunately, the limited supply of donor hearts restricts transplantation to less than 2% of patients with advanced heart failure. Patients with refractory heart failure symptoms who are otherwise in good health without significant non-cardiac comorbidity should be referred to regional transplant centers for evaluation. From an epidemiologic standpoint, however, transplantation does not represent a major option for the therapy of end-stage heart failure.
Several mechanical assist devices have become accepted as standard therapy for patients deteriorating while awaiting transplantation. More recently, the left ventricular assist device has been approved in the United States as permanent, or "destination" therapy for highly selected patients who are not transplant candidates [5]. Current reported survival with these devices is in the range of 50% at one year, so appropriate candidates are those whose anticipated mortality on medical therapy exceeds 50% at one year. The initial criteria for severity of disease are shown in Table 1. Quality of life according to heart failure scales has been described as between Class II and III, with other limitations perceived due to device noise, abdominal discomfort and fear of device failure. Continued technological improvements will improve both survival and comfort. Although they may ultimately increase the candidates for replacement therapies by an order of magnitude, it is not likely that devices will become the dominant mode of therapy. The resources required in direct finances and institutional commitments to provide dedicated implantation and follow-up limit applicability of this technology in the foreseeable future.
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Although the number of patients directly affected by replacement therapies is likely to remain small, the overall impact is magnified many-fold. As soon as expensive therapies are possible, other therapies with more modest cost and wider applicability become increasingly attractive. Thus, as many heart failure therapies evolved in patients referred for transplantation, there may be even greater incentive now to develop and support better therapies and outpatient management for heart failure.
1.7. Intravenous inotropic infusions—the "until" therapy
Intravenous inotropic therapy with dobutamine, dopamine, or less commonly milrinone is usually started with the intent of temporary support until some specific endpoint is reached [26]. Most commonly in this population, it is initiated to stimulate diuresis through improving cardiac output and renal perfusion. It is hoped that once the congestive state has resolved, stability will be restored without the need for ongoing inotropic therapy. It may be instituted for support until recovery from some other cardiac condition, such as stunning after myocardial infarction or ventricular tachyarrhythmic event, or some non-cardiac condition such as pneumonia, gastroenteritis, or recent surgery. A major use of longer-term intravenous inotropic therapy is until transplantation, with occasional use as partial palliation for symptoms until death at home.
There is an increasing prevalence of intravenous inotropic infusions that cannot be weaned without symptomatic hypotension, recurrent congestion, or renal dysfunction [27]. Dependence on intravenous inotropic infusions should not be declared until repeated efforts, often over 1–2 weeks, have been made to wean infusions, including hemodynamic monitoring to confirm filling pressures and systemic vascular resistance and discontinuation of other medications that decrease blood pressure and renal function. There is reluctant recognition that intravenous inotropic therapy with chronically indwelling central catheters may occasionally be reasonable for palliation of end-stage symptoms when no other therapies are available [2]. For the rare patients receiving these, 6 month mortality is in the range of 50% [26,28]. This therapy is not considered to be life-prolonging, and may be life-shortening, as suggested by previous trials of chronic oral inotropic therapy in patients with less severe compromise [29].
1.8. End-of-life care for heart failure
Twenty years ago, patients with heart failure usually died suddenly as the disease progressed, such that there were few patients suffering with refractory Class IV symptoms. As discussed above, fewer patients now die suddenly with heart failure. As more patients die with end-stage hemodynamic decompensation, increasing efforts are required to help them and their families face the end with comfort.
Many patients and their families have trouble accepting the likelihood of imminent death with heart failure, compared to cancer. This may in part reflect the wider range between good and bad days that continues to occur even in terminal heart failure, such that patients regard each good day as a contradiction of their impending fate. There is also much less public education and recognition of the wide prevalence and grim prognosis for heart failure than for cancer. Discussions regarding prognosis should be specifically instituted as the disease progresses. More specific plans regarding aggressive palliative therapies and potential modes of death may be triggered by re-hospitalization, progressive renal dysfunction, or recurrent implantable defibrillator events. Patient and family acceptance of the inevitability of death is culturally more difficult in the United States than in other countries.
Hospice organizations traditionally evolved for the end stages of cancer, and more recently for AIDS. The dyspnea of heart failure requires unique considerations, which have not been adequately considered in most hospice plans. However, the benefit of narcotics, and the common problems of insomnia, constipation, and restlessness are common themes for all of these diseases in the terminal stages.
As heart failure management matures, increasing integration will be required between the specialty nursing staffs for heart failure and for terminal care. Heart failure is now truly a chronic disease, with an undulating course of therapies for early stages, exacerbations, and late stages. Some patients now survive long enough to die of other diseases, whose course requires interdigitation with heart failure care. While many details of therapy are unique to different stages, the challenge for disease management is to recognize and integrate therapy and counseling to provide effective and compassionate care throughout the life of the patient with heart failure.
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