© 1999 European Society of Cardiology
Tailored therapy to hemodynamic goals for advanced heart failure
Brigham and Women's Hospital, Cardiovascular Division 75 Francis St., Boston, MA 02115, USA
Key Words: Heart failure • Hemodynamics • Vasodilators • Mitral regurgitation
Accepted March 3, 1999
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1. Tailoring to something |
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 TopNotes 1. Tailoring to something 2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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Our therapies for heart failure are prescribed to address at least one of three goals: survival, quality of life, and prevention of the disease progression that would threaten the first two goals. All therapy is tailored to something, even if it is to a uniform ‘target dose if tolerated’ from a megatrial. It seems unlikely, however, that ‘one size fits all’, many patients perhaps responding best to a dose that is higher or lower, with the absence of side effects being only one aspect of fit. Tremendous energy has been devoted to developing new drugs and ‘winning’ with a mortality or disease progression endpoint. The roster of victorious drugs, however, far outreaches our understanding about how to select and use them for an individual patient.
We lack surrogate endpoints for heart failure that will predict in time whether therapy is likely to improve survival or prevent disease progression. Once heart failure is advanced, however, the remaining goal of symptom relief represents an endpoint in itself as a major determinant of quality of life. Furthermore, symptoms represent one intermediate endpoint for therapy to improve survival. Although some therapies improve symptoms and worsen survival ([1–3]), the severity of symptoms determines the New York Heart Association classification, which, despite its crudity, remains one of the most robust predictors of outcome for patients receiving a current regimen of ACE inhibitors, digoxin, and diuretics [4]. Ambulatory patients with persistent Class IV symptoms have a 1-year mortality that approaches 50%, while those who can maintain relief from congestion regain a prognosis more like that for Class III, with a 1-year mortality of approximately 20–25% [5].
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2. Why not hemodynamics? |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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If we accept that symptoms are a worthwhile target of therapy, we also have to consider hemodynamics. For patients with advanced heart failure, the symptoms correlate qualitatively with hemodynamics within individual patients, despite inter-patient variability in the perception of symptoms. Most symptoms in Class IV heart failure result from congestion, the elevated filling pressures from the pulmonary or systemic venous circulation (orthopnea, immediate dyspnea on light exertion, abdominal discomfort and anorexia, anasarca). The elevation of filling pressures also correlates with other deleterious features of advanced heart failure, such as cachexia [6], sympathetic system activation [7], and disordered sleep patterns [8].
To relieve these symptoms requires reduction of elevated filling pressures. In addition, even at levels below the symptom threshold, elevations of pulmonary capillary wedge and right atrial pressures have been consistent predictors of worse outcomes, [9–11] particularly when measured after therapy tailored to reduce them to near-normal levels. Once limited by concern that cardiac output would be further compromised, such therapy has become more enthusiastic since recognition that cardiac output is actually improved when filling pressures are reduced to the range of 15–18 mmHg [12]. This benefit results largely from reduction of the mitral regurgitant orifice [13,14] but may reflect decreased myocardial energy requirements and improved coronary perfusion. In addition to relieving congestive symptoms, aggressive reduction of filling pressures leads to immediate direct reduction of neurohormonal activation [15], improvement in peripheral vasodilation to exercise [16], and increased exercise performance [17–20].
Why did hemodynamics previously fall out of fashion for guidance of therapy? Early drug studies often measured only one dose response and percent improvement rather than systematic achievement of more ambitious absolute goals for filling pressures. Probably the main reason for disillusion, however, arose from the emphasis on cardiac output as the main target of therapy for a condition with decreased contractility. Unfortunately, the agents that increased cardiac output through increasing contractility had no sustained hemodynamic benefit and led to increased mortality [21]. Subsequently, some vasodilator agents led to initial improvement that was not sustained, due to drug tolerance for prazosin [22] and refractory fluid retention with minoxidil [23]. Interestingly, beta blockers improve neither hemodynamics nor symptoms initially, while both are improved during longer follow-up, thus strengthening rather than disproving the ultimate relationship between hemodynamics and symptoms [24].
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3. When should we measure hemodynamics? |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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Once the hemodynamic target of elevated filling pressures has been selected, it is not clear how it should most efficiently be assessed or addressed. The initial identification of elevated filling pressures, for the critical distinction between ‘wet’ and ‘dry’, can usually be made by careful clinical assessment for history of orthopnea and immediate dyspnea on light exertion (IDLE), and for elevation of jugular venous pressure (in some cases facilitated by abdominal compression), hepatomegaly, and more obvious signs of fluid overload (Fig. 1). The Valsalva maneuver can also be useful in experienced hands. These clinical clues rely heavily upon the relationship between right and left sided filling pressures, which are reliable in up to 80% of patients with a primary diagnosis of heart failure and low ejection fraction (Drazner M, personal communication). The error rate is magnified by a recent lapse of training in clinical assessment of the jugular venous pulse [25]. Sometimes regarded as arcane, this skill has recently been emphasized as mandatory for the effective care of patients with diminishing function not only of the heart, but of other vital organs as well, which are characterized by dysregulation of volume status.
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Although often unnecessary for identification of elevated filling pressures [26], actual measurement of the pressures can facilitate their effective reduction. This is neither just ‘afterload reduction’ with vasodilators, nor isolated ‘pre-load reduction’ with diuretics, both of which impact on each other. The end-diastolic pressures are a complicated function of circulating volume, impedance to ventricular ejection, valvular regurgitation, ventricular interdependence, myocardial ischemia, and coronary venous drainage, all of which will be influenced by therapies to change loading conditions. They are influenced also by inotropic state. Simultaneous measurement of filling pressures, cardiac output, and calculated vascular resistance may be most helpful in those patients for whom congestion is accompanied by evidence of hypoperfusion (Table 1) Some of these patients primarily need diuresis, while others return to near normal filling pressures from vasodilation alone, and most require adjustment of both.
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It should be emphasized that there is no indication for invasive monitoring in Class I–II patients without clinical evidence of resting hemodynamic compromise. As heart failure progresses, the majority of patients presenting with their first episode of congestive heart failure have adequate perfusion (‘wet and warm’), and can usually be managed without invasive measurement. Pulmonary artery catheters are more often employed during tailoring of therapy for recurrent or refractory congestion, congestion with systolic dysfunction plus another complicating cardiac or non-cardiac condition, and for the wet–cold patient as described previously.
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4. Current therapy tailored to measured hemodynamics |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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The tailored therapy approach has continued to evolve during experience with approximately 1500 patients at UCLA and Brigham and Women's Hospital (Table 2). Increasingly, obvious volume reservoirs such as anasarca or tense ascites are being reduced by aggressive diuresis prior to measurement of hemodynamics for finer tuning of loading conditions. This not only minimizes the time of invasive monitoring, but also avoids the problem of adjusting vasodilators to doses that may not be tolerated once the circulation is less distended and more responsive, particularly on the venous side. Once hemodynamics are known, the degree of elevation of systemic vascular resistance guides the use of vasodilators vs. diuresis to establish the target pulmonary capillary wedge pressure, usually approaching 16 mmHg [27]. In general, once the desired filling pressures are reached, there is less impact of reducing systemic vascular resistance further, and excessive reduction may activate the sympathetic nervous system and compromise renal function.
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Intravenous vasodilators allow rapid establishment of target hemodynamics. Currently nitroprusside and nitroglycerin are most commonly used, but the advent of newer vasodilators, such as natriuretic peptide infusion, may simplify this step while avoiding cyanide toxicity and nitroglycerin headaches. After a minimum of 24 h of stability, during which systemic neurohormonal stimulation is often reduced, oral agents are added as the intravenous infusions are weaned. My preference is for the captopril/isosorbide dinitrate combination, shown to lead to better survival than hydralazine/nitrates when both were titrated to the same hemodynamic goals [27]. (It is of note that the fixed target regimens of enalapril vs. hydralazine/isosorbide showed no difference in outcome for Class III–IV patients in the VHeFT II trial, while showing significant benefit for enalapril in the Class I–II patients [28].) Patients not tolerating ACEI are put on hydralazine/nitrate combinations, or in some cases high dose nitrates alone if hydralazine is not tolerated either. Hydralazine is sometimes added to the ACEI combination to maintain low filling pressures that are very sensitive to systemic vascular resistance. There is a dearth of other options for patients who cannot tolerate these agents. The angiotensin II receptor antagonists have a hemodynamic impact but have not been extensively tested during tailored therapy, and are in general not tolerated if the ACE intolerance is due to hypotension.
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5. Benefits observed with tailored therapy |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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Results of tailored therapy identified during the initial hospitalization include reduction of average pulmonary capillary wedge pressures average from 26 to 16 mmHg, and improvement of cardiac index from 2.1 to 2.6 l/min/m2. This is associated with a reduction in the mitral regurgitant flow from 47 to 14 cm3/beat (Table 3). An acute improvement in exercise capacity can sometimes be demonstrated also [19]. While this and other evidence indicate the benefit of reducing filling pressures, it is not known whether invasive measurement of the filling pressures is necessary for their effective reduction [29–31]. There is inconvenience and cost to an indwelling pulmonary arterial catheter for the 2–4 days necessary. Although there is concern about an increase in mortality with these catheters derived from a retrospective experience, no adverse impact was seen in patients with a diagnosis of heart failure [30].
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It has been shown that the benefits observed acutely can be maintained chronically [18]. (It should be noted that tailoring with invasive monitoring as described need rarely be performed more than once in a given patient.) The hemodynamic responses, the improvement in mitral regurgitation, amelioration of congestive symptoms, and improvement in exercise capacity have been demonstrated 6–8 months after tailoring [14,18,19]. Up to 30% of patients have been able to leave the transplant waiting list, despite meeting initial indications for disease severity [9].
As it is not clear that initial measurement of hemodynamics are necessary for early results, neither is it known whether such measurement is necessary for the chronic benefits observed. The programs providing tailored therapy also provide a multidisciplinary team for patient education about medications, daily weights, flexible diuretic regimen, exercise routine, and expert nursing specialists for regular phone contact [19,31]. This support may be responsible for much of the benefit observed after referral to heart failure centers, with or without therapy tailored during invasive hemodynamic monitoring [32]. These issues are being addressed in a pilot trial currently ongoing at Brigham and Women's Hospital and will be further studied in an NHLBI-sponsored multicenter trial, in which patients with at least two hospitalizations for systolic failure will be randomized to therapy guided by pulmonary artery catheters or clinical assessment, followed for 6 months to determine readmission rate, natriuretic peptide levels, peak oxygen consumption, and survival adjusted for patient preference.
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6. Beyond hemodynamically tailored therapy |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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Long-term therapy includes agents for which benefits are not detectable immediately. There would be no rationale for adjusting such therapy on the basis of invasive hemodynamic monitoring. To the extent that tailored therapy facilitates the reduction of congestion and maintenance of freedom from congestion, it may expand the population for which benefits from other therapies may be observed. This may be particularly true for therapy with beta adrenergic blocking agents, in whom current or recent clinical congestion is a contraindication for initiation of therapy. Other therapies, such as digoxin, are also associated with clinical benefit that may not be directly linked to early hemodynamic effects. Although digoxin causes a modest increase in contractility, its benefit may result more from its effect on autonomic function, and the risk may be highest in those patients in whom the drug is titrated up to maximal inotropic effect. Other potential adjunctive agents such as spironolactone are also postulated to have primarily non-hemodynamic effects, and should be adjusted independently of acute hemodynamics.
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7. Future evolution of tailored therapy |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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Better ways to monitor filling pressures may broaden the applicability of therapy tailored to reduce filling pressures. Mitral regurgitant flow patterns, estimated pulmonary artery pressures, and direct hemodynamic estimates from echocardiography may refine bedside and outpatient clinical assessment. As suggested by Dr Christian Hall, and recently described by Murdoch et al. [33]in milder heart failure, following natriuretic peptide levels may facilitate intermediate-term adjustment of therapy to filling pressures.
Increasing access to non-invasive hemodynamic assessment may also extend the principles of tailored therapy beyond the patient with low ejection fraction and refractory heart failure in whom aggressive intervention is appropriate. The challenge of controlling and monitoring loading conditions in the large population of elderly patients with heart failure and preserved ejection fraction may be lessened by serial non-invasive assessment of filling pressures. For early systolic dysfunction, we currently conceive of the Class I–II heart failure patient as not limited by hemodynamics; it is possible, however, that current lines of investigation will converge to indicate the importance of maintaining normal filling pressures even in asymptomatic patients, as fundamental processes such as altered myocyte gene expression, apoptosis [34], and sympathetic stimulation [7] can all be triggered by increased wall stress.
A major limitation to maintenance of patients at optimal volume status is the complex cardio–renal interactions that lead in a significant minority of patients to aggravated renal dysfunction at volume status that is otherwise optimal for symptom relief [35]. Experience with hemodynamic monitoring has revealed that this limitation is usually not due to ‘excessive diuresis’ from the standpoint of ventricular filling pressures. Greater insight and newer agents to directly improve renal function may embolden us to further reduce filling pressures and relieve ventricular wall stress.
In its broadest sense, the evolution of tailored therapy will continue, as we learn how to use multiple drugs to optimize outcome for individuals beyond that achieved for trial populations titrated to target arbitrary doses. The limits of patient compliance as well as expense will truncate the long roster of recommended drugs, each of which adds a significant but sometimes small benefit to the previous combination in the average patient. We will become mores elective and hopefully more adept at managing heart failure. This will require more doctors interested and experienced in treating this common syndrome [32].
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1 Tel.: +1-617-732-7406; fax: +1-617-278-6931
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References |
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TopNotes1. Tailoring to something2. Why not hemodynamics?3. When should we...4. Current therapy tailored...5. Benefits observed with...6. Beyond hemodynamically...7. Future evolution of...References |
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