- Email: [email protected]
Management of refractory congestive heart failure
Management
of Refractory Failure Robert J. Cody,
Despite recent advances in the treatment of congestiie heart failure (CHF), many patients continue to present with symptoms refractory to digoxhr, diuretic, and vasodilatory therapy. Since it is unlikely that thCs population will decrease in the near future, practiil approaches to management of refractory CHF are reviewed. Refractory CHF here is defined as NewYork Heart Association (RYHA) functional class IIW heart failure, despite maximal drug therapy. Before such a diagnosis is made, the patiint should be treated with diioxin, diuretics, and a vasodilator. Approach to therapy requires assessm ent of changing clinical status and pathophysiology, optimbing oral drug treatment, and provklie temporary parenteral support when indicated. SpecWic attention shoukl be given to factors that influence the optimal response to each of these 3 treatment classes. A theoretiil, but unproven, concept suggests that combined vasodilatory therapy may be appropriate as long as excessive hypotension is avoided. In the course of management, a decision is required as to whether further optlmizaion of therapy can be achieved on an outpatiint basis. Hospital-based intravenous inotropic support given for 2-4 days will often provide the opportuntty to restructure patient therapy. (Am J Cardiil1662;69:UlGl46G)
From the Division of Cardiology, Department of Medicine, The Ohio State University College of Medicine and Hospitals, Columbus, Ohio. Address for reprints: Robert J. Cody, MD, Division of Cardiology, The Ohio State University Hospitals, 611 Means Hall, 1654 Upham Drive, Columbus Ohio 43210.
Congestive
Heart
MD
ith much current interest in the management of mild congestive heart failure (CHF) and asymptomatic left ventricular (LV) dysfunction,rJ2 it is important to consider the other end of the spectrum, namely, the management of refractory CHF. The patient with refractory CHF presents a major therapeutic challenge, whether encountered in the outpatient setting or referral center. The purpose of this article is to define refractory CHF and to outline pragmatic approaches to management. It is unlikely that this population will decrease in the 1990s. In fact, it is conceivable that the CHF population will increase.3 A considerable number of patients who previously may have died following a myocardial infarction are today undergoing angioplasty or receiving thrombolytic therapy that often yields a dramatic favorable outcome. These modalities can limit the size of myocardial infarction and also reduce patient mortality; however, the remaining myocardial damage may still progress to CHF. Furthermore, the increasing elderly population in the United States, which comprised > 10% of the total population in 1984,4 will likely produce a concomitant increase in the incidence and complexity of heart failure.
W
DEFlNlTlON AND BASEUNE MANAGEMENT
For the purposes of this presentation, refractory CHF is defined as patients with New York Heart Association (NYHA) functional class III-IV heart failure, in whom symptoms have not improved, or have actually worsened, following recent attempts to escalate therapy. Typically, this patient population is likely to evidence substantial fluid retention and/or significantly reduced cardiac output (“lowflow state”). Treatment with digoxin, diuretics, and a vasodilator regimen should have been attempted prior to diagnosis; otherwise, it would not be reasonable to consider the CHF refractory. Even though several multicenter studies2,5,6 have reported favorable outcomes with combined digoxin, diuretic, and vasodilator therapy, the question may be asked: Can patients treated in this A SYMPOSIUM:
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manner still present with cardiac decompensation? The answer, in fact, is revealed in these same studies. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),6 for instance, many patients already receiving digoxin, diuretics, and a vasodilatory still had functional class IV failure. Despite the superiority of the combined regimen of digoxin, diuretics, and the angiotensin-converting enzyme (ACE) inhibitor enalapril over placebo in this study, the l-year mortality rate among enalapril-treated patients approximated 40%. In the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial of milrinone,7 entry criteria included evidence of recent functional class IV symptoms despite receiving digoxin, diuretic, and ACE-inhibitor therapy. More than 1,000 patients were enrolled. Similar observations can be drawn from the Vasodilator Heart Failure Trial II (V-HeFT II)5 and Studies of Left Ventricular Dysfunction (SOLVD).2 Against this background, the approach to the patient with refractory CHF consists of 3 major factors: assessmentof changing clinical status and pathophysiology, optimizing oral drug therapy, and providing temporary parenteral support when indicated. CHANGING CLINICAL PATHOPHYSIOLOGY
STATUS AND
In a patient with CHF who previously was well maintained on oral therapy, the appearance of refractory CHF should immediately raise questions regarding changes in clinical status and pathophysiology. Several factors influencing these changes are given in Table I. The first major factor is ongoing myocardial ischemia or infarction. In the United States, coronary artery disease is the major cause of CHF. Once a patient has experienced multiple myocardial infarctions or one large myocardial infarction, subsequent progression to CHF may change the focus of patient management to the extent that the importance of ongoing ischemia due to coronary artery disease can be overlooked. Even in the absence of clinically overt ischemia such as chest pain or new electrocardiographic changes, ongoing ischemia, particularly at the endocardial level, may result in progressive ventricular dysfunction and dilation. A new myocardial infarction, of course, would have self-evident consequences. More subtle, however, is the occurrence of ongoing ischemia that may compromise ventricular function. On a chronic basis, this could result in reduced LV systolic performance and diastolic 3.420
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TABLE I Factors Altering Clinical Status Refractory Congestive Heart Failure New myocardial
Diabetes Dietary
myocardial
controlled (particularly
sodium
Progressive Coexistent Patient-related
of
ischemialinfarction
New or progressive regurgitation) Inadequately
and Pathophysiology
mechanical
defect
(e.g., mitral
hypertension insulin-dependent)
indiscretion
renal failure disease
processes
drug therapy
(e.g., pulmonary) issues
dysfunction. Occurring more abruptly, it may cause complete cardiac decompensation and pulmonary edema. A new or progressive cardiac mechanical defect, most commonly mitral regurgitation, can often be masked on cardiac examination; the severity of mitral regurgitation is not necessarily reflected in the cardiac murmur. Therefore, it can function as an independent variable, modulating the extent to which CHF is expressed. Despite the large number of published studies focusing on CHF, few have been able to assessfully the direct impact of mitral regurgitation on ventricular function.8,9 Although clinical experience suggests that significant mitral regurgitation in essence provides a low-pressure escape for the failing ventricle, its long-term presence results in progressive dilation and worsening function of the ventricle, which is manifested symptomatically by pulmonary congestion and low cardiac output. Like myocardial ischemia, the presence of hypertension may lose its importance once the patient has developed functional class III or IV heart failure. If a patient has a history of hypertension that is no longer present, one might argue that this is not a cause for concern. However, if the patient continues to have a systolic blood pressure in the 130-180 mm Hg range, or a diastolic blood pressure in the 85-100 mm Hg range, one could argue that additional blood pressure control is necessary. Both severe hypertension and severe CHF are accompanied by comparable increases in systemic vascular resistance (Figure 1). The major hemodynamic difference is the status of ventricular function and cardiac output. However, when hypertension progresses to where severe systolic dysfunction occurs, or if it is superimposed on CHF of another etiology, both the LV dysfunction and excessiveLV wall stress due to the combination of these vascular disorders require particular attention. Even as the ventricle fails to the point where elevated systolic blood pressure is not generated (despite increased diastolic blood pressure), the long-standing hyperJUNE
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FIGURE 1. Comparative hemodynamic characteristics of patients with moderate to severe hypertension (HTN) and NWA functlonal class Ill or IV congestive heart fallure (CHF). Mean values are given, as is statiikz4l signiticance, comparing peak exercise responses. In the HTN group, whereas mean arterial pressure (MAP, mm Hg) was much higher than in the CHF group, cardiac performance, as judged by cardiac index (Cl, liters/min/nP), pulmonary wedge pressure (Pwp, mm Hg), oxygen consumption (VO,, mUmi@ and carbon dioxide production (VC&, mllmin), was mainteined, despite comparable systemic vascular resistance (SVR, dynesls/cn+). R = resting; 5X = exercise; NS = not stgniticant. *p ~0.01; **p co.05.
r
r
**
r
7
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7
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160
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tension does not suddenly disappear. In this regard, continued attention to blood pressure regulation is important. Of course, diabetes remains an additional major factor in progressive ventricular dysfunction and worsening of CHF. Typically, diabetes is considered a cause of LV dysfunction, rather than a factor that may contribute to intermittent LV dysfunction. This concept, however, may be revised within the next few years, based on accumulating evidence citing hyperinsulinemia as a persistent vascular insult.lO Both uncontrolled diabetes and perhaps even the adverse effects of chronic highdose insulin use may soon be considered risk factors. Dietary sodium indiscretion is an issue that continues to require attention. Patients with CHF frequently receive large doses of diuretics but, as described below, this does not obviate the need for ongoing dietary sodium management. Sodium intake is difficult to counsel and monitor. There are no firm guidelines regarding absolute sodium intake, but it would certainly be prudent to maintain sodium intake in the moderate range of 2-3 g. Progressive renal failure can also alter clinical status and pathophysiology. Although many CHF patients typically have a serum creatinine level in the range of l-l.5 mg/dL, which already reflects renal impairment (Figure 2) further progression to the range of 2.0-2.5 mg/dL induces a further, substantial reduction in renal function. This is particularly true in the elderly patient with CHF,il
Attention must also be given to intermittent, coexistent disease, particularly pulmonary function abnormalities or pulmonary disease. Pulmonary embolus, even to the periphery of the parenchyma, may produce marked cardiac decompensation. Chronic lung disease is not unusual in the heart
defined
FIGURE 2. Relation oFblood urea nttrogen (BUN, mg/dL) and serum creatlnlne (SCR, mg/dL) to glomerular filtration rate (GFR, mL/mln), as determlned by inulin clearance. Note that GFR may be substantially reduced even in patlents with relatively normal GUN and SCR.
as > 65
years
of age. In the heart
failure
population, renal dysfunction continues to be prevalent among the elderly, even when all other aspects of heart failure are equal.
70
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0
20
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40
60
100
80
120
160
140
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A SYMPOSIUM:
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1430
failure patient and is generally very difficult to differentiate from progressive heart failure. This is best done by the physician who follows the patient on a long-term basis. Pneumonia and other pulmonary and upper respiratory tract infections may also induce severe cardiac decompensation. Finally, patient-related drug therapy issues must be considered. Noncompliance with therapy is always a factor. In symptomatic heart failure patients, however, this may be less so than in hypcrtcnsive patients, where the perception of illness is less apparent. Trcatmcnt of heart failure requires using multiple drugs throughout the day. The patient may misunderstand the drug regimen and inadvertently alter therapy. In the elderly patient, confusion, memory deficit, and other central neurologic
* I I I
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I
I
I
-
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disorders may compromise with therapy.
the ability
to comply
OPTIMIZING ORAL MEDICAL THERAPY Dioxin: As more information accumulates,
the age-old debate on the role of digoxin therapy is increasingly favoring use of the drug in the majority of heart failure patients with normal sinus rhythm. This has been largely supported by investigative studies,” as well as by large multicenter trials showing favorable cffccts of digoxin therapy.‘“J4 Further, digoxin has additional therapeutic mechanisms, including suppression of the renin-angiotensin system (Figure 3),” and favorable resetting of autonomic tone.‘” In judging whcthcr digoxin is optimal for a given patient, factors to bc considered include determining the appropriate dose and indexing this to a specific strum digoxin concentration when appropriate. However, with progressive cardiac decompensation and subsequent refractory status, absorption can bc adversely affcctcd. Currently, the prospects for development of an altcrnative oral inotropic drug for long-term administration arc not good. Rcccnt data from the PROMISE trial suggest that agents such as the bipyridines actually increase morbidity and mortality in patients with functional class III-IV heart failurc7 Wureth therapy Although there is currently some debate regarding the appropriateness of diuretic use in patients with asymptomatic or mild LV dysfunction, there is no argument regarding such use in patients with refractory heart failure. With few exceptions, patients in this group will require diuretics. However, choosing the appropriate dose and deciding whether to use combined diuretic therapy require careful consideration. It is not unusual for a patient with CHF to become resistant to diuretics, and several variables such as renal insufficiency and aging can influence such resistance.11.‘7 As renal dysfunction gradually progresses, a diuretic response may become progressively attenuated. Concomitant therapy with noncardiac drugs that affect renal function can also mitigate the diuretic response. Such agents include nonsalicylated anti-inflammatory drugs and indomethacin. Edema of the gastrointestinal tract can reduce drug absorption, thereby limiting efficacy. Different diuretic agents may act at different sites within the nephron, so that combination therapy, as discussed later, may be appropriate in the patient with developing refractory heart failure. At the very least, a patient should not be considered refractory to diuretics if receiving only moderate oral doses of a loop diuretic. Several approaches JUNE
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can help optimize diuretic therapy in refractory heart failure patients resistant to such therapy.i7 A single large bolus of intravenous diuretics may substantially improve urinary flow and natriuresis. Alternatively, frequent administration of smaller effective intravenous doses might achieve a cumulative effect. Although not typically used in practice, continuous intravenous infusion of a loop diuretic may prove efficacious.‘s Perhaps the most versatile and effective approach to the management of such patients is administering the combination of a loop diuretic and thiazide diuretic. Long-term treatment with a loop diuretic can result in hypertrophy of the distal nephron segment,‘” producing enhanced sodium reabsorption. This can often attenuate the prcvious favorable response to a loop diuretic. To counter this, coadministration of a thiazidc diuretic acting at the distal nephron can substantially increase net sodium and water excretion. Intermittent administration of moderate doses of an intravenous loop diuretic to outpatients with sodium retention may promote sufficient diuresis to avoid hospitalization. l‘his would also be particularly effective in the holding area of an emergency department. Continued moderation of sodium intake to avoid and/or manage refractory CHF should be emphasized. Animal studies’” have shown that the response to a loop diuretic is often mitigated in animals that continue to ingest sodium ad lib compared with animals in whom sodium intake is somewhat restricted. Insistence that the patient ingest a moderate sodium diet enables the patient to participate in the therapeutic process. If the patient remains resistant to diuretics, additional approaches may be considered, including further intcnsifjling combined therapy. This might entail combining up to 3 diuretics (e.g., a loop and a thiazidc diuretic and amiloridc or spironolactone) that potentially act at different nephron sites. At least 1 report2” in a limited number of patients suggests that spironolactonc can bc well tolerated even in combination with an ACE inhibitor. Although typically not required for refractory heart failure, ultrafiltration, hemofiltration,” hemodialysis, or peritoneal dialysis can be used for rapid removal of fluid. These modalities obviously will be important in treating cases of CHF accompanying chronic renal failure.22 Vasodilator therapy: In view of the results 01 recent trials, it now appears reasonable to treat any patient with functional class III or IV heart failure with an ACE inhibitor, hydralazine and isosorbide dinitrate, or a combination of these agents. Vasodi-
lators continue to evolve. Newer vasodilators such as floscquinan offer promise in patients with CHF.2’ The different classes of vasodilators exert their effects by different mechanisms. This may account for some of the clinical findings in the VHeFT II,5 in which the ACE inhibitor enalapril produced a relatively lower mortality rate yet the combination of hydralazine-isosorbidc dinitrate improved exercise capacity and ejection fraction. More novel approaches to the use of these drugs in refractory heart failure may be necessary. Varying combinations of these agents can be used intermittently, in sequence, etc. A patient who has become refractory to an ACE inhibitor, for cxample, may be given hydralazinc-isosorbide dinitrate as a substitute, or vice versa. When the patient with refractory heart failure who is currently taking digoxin, diuretics. and a vasodilator requires alteration in therapy, several issues should be considered. The first is drug dose. There is often a tendency for a “minimalist” approach to the use of vasodilators in heart failure because of concerns regarding cxccssive hypotension. Although it is certainly true that hypotension is an adverse effect of vasodilator therapy and is frequently seen in patients receiving ACE inhibitors, at the same time a reduction in blood pressure is anticipated. Guidelines helping to define an acceptable level of blood pressure have not been created. It is not unusual, however, to observe systolic blood pressure approximating 90 mm Hg with such therapy, and in the absence of significant orthostatic hypotension, such pressure is certainly acceptable. Pressures below this level may be tolerated in some patients but not in others. The second issue is dosing interval. There is a perception that the once-a-day therapeutic philosophy that is advocated for treating hypertension is carried over for the treatment of the CHF population. It is important that vasodilator agents be given at the appropriate dosing interval. For ACE inhibitors such as captopril, therapy should be 3 times a day; for enalapril, therapy is typically twice a day, although once daily might be reasonable, particularly in the elderly paticnt.14 Likcwisc, hydralazinc therapy typically should be administered 3-4 times a day. Longer dosing intctvals may result in ineffective vasodilator therapy. Vasodilators that influcncc neurohormonal pathways (e.g., ACE inhibitors) may have a functional responsiveness related to these pathways. For instance, the extent of sodium restriction can have a considerable influence on response to an ACE inhibitor.‘” A SYMPOSiUM:
CONGESTIVE
HEART
FAILURE
i4wi
Clinicians may consider the use of combined vasodilator therapy. Combination therapy does not imply giving 2 classes of agent at substandard doses rather than 1 agent at an appropriate therapeutic dose. Moreover, it should be emphasized that the excessive hypotension often potentiated by combined vasodilator therapy poses a serious obstacle to the successful management of these patients. If single-agent therapy is insufficient for management, then combined vasodilator therapy is a conceivable option if excessive hypotension can be avoided. Therapy could be based on differences in mechanism of action. For example, a physician might elect to combine a direct-acting vasodilator with one that suppresses the neurohormonal axis (Figure 4). 26 Again, caution must be exercised, as excessive hypotension may be exacerbated by this combination. Combined vasodilator therapy can also be determined based on disease substrate. Not all refractory heart failure is of the same etiology. In coronary artery disease, for instance, one could conceivably combine an ACE inhibitor with a calcium antagonist. Although calcium antagonists
I 2 -0 = 2% 0-:, I2.80
r
0 Control
2.60
2.20 2.00
1.80
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1.60 2.40 1.40
I.;Zs--3 8 z!ti; E 2 c/J2 z= rid00 6)
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-
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2200 2000
1800 1600
-
30
-
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diRews8tmecha&ms.Meanarte1W represented on the horkontal
P----(mHg)b axls. In ii patlents wRh se-
vemchronkcoagestlveheartfalhre,captoprll?S~w8~ glwen oraMy. At peak responrs, nitropnmdde was tltered to reduce mean artefial pressure an additIonal lO% This redtedhturtJmrincreaseofcaMachdex(Wters/mln/ I&) and struke volume Index (ml/beat) and reductkm of systemkvascslarresistance OJynWsld) and pum0 Raywedgep(mn WI. mm-ted*from Am Heart I.“,
1466
have caused unexpected cardiac decompensation in some patients with functional class III or IV heart failure, their use, particularly at lower doses, in combination with an ACE inhibitor may represent a pragmatic approach to the management of patients with known coronary artery disease. Hypertension may be ongoing in many patients with heart failure. In such patients, combining an ACE inhibitor with virtually any vasodilator known to be effective in hypertension, including calcium antagonists, would be reasonable. As previously discussed, hypertension in the CHF setting should be treated aggressively. This means reducing systolic blood pressure to 120-130 mm Hg and diastolic blood pressure to a level well below 90 mm Hg when possible. Mitral regurgitation is a functional consideration that may be particularly important in patients with refractory CHF. In such cases, hydralazine would be effective. The marked reduction in systemic vascular resistance achieved by this agent can be greater than that observed with an ACE inhibitor and could conceivably have a much greater impact on reducing the regurgitant mitral fraction. With addition of sufficient ACE-inhibitor therapy to suppress the neurohormonal axis, hydralazine could become a mainstay of vasodilator therapy in such patients. It has been difficult, however, to calculate an appropriate end point for reduction of regurgitant fraction to serve as a guideline for therapeutic intervention. New modalities such as color-flow Doppler will be useful in this regard.
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port: When the refractory CHF patient does not respond to all of the careful attempts at modulation of clinical status and therapy as outlined above, it is reasonable to consider hospitalization and administration of short-term intravenous inotropic support. Current oral therapy can be discontinued or stabilized with an eye toward restructuring therapy prior to hospital discharge. One may also administer intravenous diuretics to manage excessive sodium retention. Intravenous inotropic support would consist of dobutamine infusions of 2.5-20 pg/kg/min. Typically, many patients respond to 7.5 or 10 kg/kg/ min.*’ This therapy can be continued for 3-4 days, at which time the patient may be discharged. Data are lacking regarding the use of intravenous amrinone under these circumstances. SUMMARY Despite advances in the therapy of CHF, many patients still present with refractory symptoms and
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findings. If a logical approach is taken in the management of such patients, heroic and less available forms of therapy such as cardiac transplantation can often be avoided or delayed. A logical approach, therefore, would include the following: Administration of digoxin, diuretics, and a vasodilator on a chronic basis to all patients with NYHA functional class LII-IV CHF, particularly those who continue to have symptoms. When a patient experiences cardiac &compensation despite this approach, the physician should assess the potentially changing clinical status and pathophysiology of the heart failure and optimize oral drug therapy. Should these 2 steps prove insufficient, hospitalbased intravenous inotropic support, often in combination with intravenous diuretic therapy, should be considcrcd to permit restructuring of a subscquent oral regimen. REFERENCES L Pfcffer M, Lamas G, Vaughn D. Parbi A. Braunwald E. Effect of captopril on progessive ventricular dilation after anterior myocxdial infarction. N f
l.6. Binklcy PF, Nunziata E, Cody RI. Digoxin-mediated reduction of sympathctic tone contributed to vawdilation in dilated cardiomyopathy. (Abhtr) CticuMm 1990$2(suppl 111):316. 17. Brater C. Resktancc to loop diuretics. Why it happens and what to do about it. Dogs 1985;30:427443. 18. Rudy D, Vockler J, Greene I’, Esparza F, Brawr C. Ioop diuretics for chronic renal insufiicicncj. A continuous infusion is more efficacious than bolus therapy. Ann Inrem Med lYYl;115:36&366. 19. Elliwn D, Velazqucr H. Wr@t F. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietq salt intake and chronic diuretic infusion. J C/in /mztr 1989;83: 113-126. 20. lkram H, Webster WI, Nicholls MG. Lewis GRJ, Richards AM, Crazier IG. Combined spironolactonc and comer@ ewymc inhibitor therapy for refractov heart failure. /trcvf NZ J !&frd lY86:16:61~~7. ZL Rimondini A, Cipolla C, Della Bella P. Grazi S, Sisillo E, Susini G. Guazzi X4. Hemotiltration as short-term treatment for refraao? congest& heart failure. Am J Med 1387;83:43-I8. 72. Ruhin RK, Ball R. Continuous ambulatory peritoneal dialysis as treatment of were congestive heart failure in the face of chronic renal failure. ,4rc/1 Infern Med lY86;146:153.%1535. 23. Corin W, Monrad S. Strom J, Giustino S, Sonnenblick E, LcJemtel T. Flosequinan. A vwxiilator with pwitivc inntnrpic activity. Am Ihn J 1~~~1;121: 537-540. 24. Cody RJ. Clinical pharmacolog of an&nensin converting enzyme inhibitors as a @de 10 their utilizxion in congcstivc heart failure. Am J Crrrdiol lY’X&5(suppl):7D13D. 2S.Ci?dy RJ, Covit AB, Schaer GL, Laragh JII, Scaly JE., reldschuh J. Sodium and water balance in chronic congest& heart failure. J C/in hwc.~~ lY&5:77:1441-1452. 26. tidy RJ, Franklin KW, Laragh JH. Combined vasodilator therapy of chronic congcstiw heart failure. ,&!I 1feo1rI 1983;105.575580. 27. lrier CV, Wehel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutaminc in patienl$ with severe cardiac failure. C~rcularion 1977;56:468-479.
DISCUSSION
Dr. Lewis: The deleterious effect of mitral regurgitation in patients with refractory congestive heart failure (CHF) is often a lot more extensive than one might have thought. I have seen many cases in which patients have not received optimal diuresis. They look a lot better, but they still retain IO-15 pounds of fluid. Sometimes it is worth pushing that modality until you arc sure you have reduced the mitral regurgitation as much as possible. Dr. Cody: One thing I have become impressed with in the color-flow Doppler era is how unreliable the mitral regurgitation murmur can be in quantitating mitral regurgitation. By physical examination, it is very difficult to estimate the severity of mitral insufficiency. In this patient population, I almost automatically conduct a color-flow Doppler study to see if there is severe mitral regurgitation and make that a major focus of therapy. Dr. Packer: Some studies’ have shown that much of the improvement in hemodynamics that occurs with direct-acting vasodilators is due to reversal of mitral regurgitation and not to an improvement in systolic ejection fraction resulting from a reduction and improvement in loading conditions. It is a consistent finding. This raises the question, what do you do with someone who has an ejection fraction of 1276, a A SYMPOSIUM:
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markedly dilated left ventricle (LV), and secondary but significant mitral regurgitation? We grapple with this all the time, almost invariably thinking of reasons not to recommend surgical procedures because of the risk and questionable benefit. I think there may be a certain percentage of people whom we doom to medical therapy when they might, in fact, better benefit from mitral valve replacement or repair. Dr. Gheorghiade: Mitral insufficiency in patients with severe systolic dysfunction is not so much related to size of the ventricle as to its shape.2 Shape of the ventricle is also important in determining prognosiG4 and an important determinant of hemodynamic response to inotropic therapy.Qj Since mitral regurgitation in these patients is a dynamic process, it is doubtful that replacing the valve is of benefit. Dr. Packer: Obviously, the assumption is that these patients are not surgical candidates, and we generally do not operate; but occasionally we have, and we have had significant postoperative success, enough to impress us that it is a question worth pursuing. Dr. Creager: Transplantation is another option, if a donor heart is available. However, I think it is important to attempt to identify patients at risk long before they get into such dire straits. Dr. Gheorghiade: Because of the severe shortage of donor hearts, it is important to identify patients with ischemic cardiomyopathy that might benefit from coronary artery bypass graft.7 In addition, mitral valve repair, rather than replacement, should be performed, since this may preserve LV function. Dr. Kellyz I think cardiologists and surgeons need to join in a prospective trial about whether preservation of papillary muscle with valve replacement really does make a difference in preserving LV function. The feeling among surgeons is that clearly it does. Dr. McCall: The key is to identify the patients who are going to do well with surgery. Dr. Yusti Engelmeier et al8 have shown that the use of B blockers dramatically improves the condition of even patients with severe heart failure. Few other groups have been able to reproduce these findings in patients with heart failure. One way of dealing with the mitral regurgitation problem may be by prolonging diastole and reducing the total period of systole by simply reducing heart rate with a B blocker. Dr. Cody: I think B blockers should probably be used more frequently in NYHA functional class I 1480
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and II heart failure. We certainly should reconsider using them in patients with LV dysfunction and following myocardial infarction, where calcium antagonists now appear to be favored for reasons that are not particularly clear. In functional class IV refractory heart failure we may still encounter more problems by using a p blocker, but this is under evaluation. Dr. Creager: My feeling is that we can be of great assistance in teaching our house staff and referring physicians to be much more aggressive with their use of diuretics. Most tend to back off from using these agents far too soon. Appropriate use of diuretic therapy can cause an impressive clinical response, whether by adding a thiazide diuretic to a loop diuretic or by hospitalizing the patient and giving parenteral diuretics. Particularly in this circumstance, it is important that physicians remain cognizant about electrolyte disturbances, particularly hypokalemia, hypomagnesemia, and hyponatremia. Dr. Cody: I find that to be particularly true with metolazone. I have had a bit more success with hydrochlorothiazide, but that is observational. However, there are very few primary studies in the heart failure literature on this issue. Dr. Kelly: It is important to administer a shortacting diuretic like furosemide sufficiently frequently to obtain the desired clinical effect. One needs to get tubular levels up to a threshold where diuresis-and natriuresis-can be sustained. Most physicians give furosemide once or perhaps twice a day, but it should normally be given at least twice a day. If it is only given once a day, pharmacodynamic effects will occur that diminish the drug’s effectiveness and a sustained negative sodium balance will not be obtained. On the other hand, as I believe Dr. Cody pointed out, you should not go below a 20-30 mEq sodium diet. If you go below that, hyponatremia ensues, followed by severe hypokalemia due to renin and aldosterone activation. Dr. eheorghiade: Many of so-called “refractoryto-therapy” patients will respond by combining two diuretics (a loop diuretic with a thiazide diuretic or metolazone) or vasodilators, and ACE inhibitors with hydralazine and nitrates. It should also be recognized that improving hemodynamics in patients with end-stage CHF may also prolong life.9 Also, patients with ongoing ischemia due to severe coronary artery disease and severe CHF may not respond to conventional therapy for heart failure.lO JUNE 4, 1992
REFERENCES 1. Weiland DS, Konstam MA, Salem DN, Martin ‘IT, Cohen SR, Zile MR, Das D. Contribution of reduced mitral regurgitant volume to vasodilator effect in severe left ventricular failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy. Am .I Car&l 1986;58:1046-1050. 2. Kono T, Sabbah H, Stein PD, Brymer JF, Khaja F. Left ventricular shape as a determinant of functional mitral regurgitation m patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol1991;68:355-359. 3. Meizlish JL, Berger HI, Plankey M, Errico D, Levy W, Zaret BL. Functional left ventricular aneurysm formation after acute anterior transmural myocardIal infarction. NEngl J Med 1984;311:1001~1006 4. Douglas PS, Morrow R, ioli A, Reich& N. Left ventricular shape, afterload and suwival in idiopathic dilated cardiomyopathy. JAm Co11Cmiiol1989;13.311315. 5. Borow K, Lang RM, Neumann A, Carroll JD, Rajfer S. Physiologic mechanisms governing hemodynamic responses to positive inotropic therapy in patients with dilated cardiomyopathy. Circuhtim 1988;77:625637.
6. Keren G, Katz S, Strom J, Sonnenblick E, LeJerntel T. Dynamic mitral regurgitation. An important determinant of the hemodynamic response to load alterations and inotropic therapy in severe heart failure. Circlllofion 1989;80:30& 313. 7. L&e HW Ischemic cardiomyopathy: criteria for coronary revascularization and cardiac transplantation. Circulation 1991;84(suppl3):29~295. 6. Engehneier RS, O’Connell JB, Walsh R Rad N, Scanion PJ, Gunnar RM. Improvement m symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Ciradanim 1985;72:53&546. 9. Stevenson LW, Tillisch JH, Hamilton M, Luu M, Chelim&-Fallick C, Morignchi J, Kobashigawa J, Walden J. Importance of hemodynamic response to therapy in predicting survival with ejection fraction <2.0% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990,66:13481354. 10. Cl&and JGF. Effect of captoplil, an angiotensin-convetis enzyme inhibitor, in patients with angina pectoris and heart faihw. J Am Coil Car&l 1991;17:733-739.
A SYMPOSIUM:
CONGESTIVE
HEART FAILURE
l&G
of Refractory Failure Robert J. Cody,
Despite recent advances in the treatment of congestiie heart failure (CHF), many patients continue to present with symptoms refractory to digoxhr, diuretic, and vasodilatory therapy. Since it is unlikely that thCs population will decrease in the near future, practiil approaches to management of refractory CHF are reviewed. Refractory CHF here is defined as NewYork Heart Association (RYHA) functional class IIW heart failure, despite maximal drug therapy. Before such a diagnosis is made, the patiint should be treated with diioxin, diuretics, and a vasodilator. Approach to therapy requires assessm ent of changing clinical status and pathophysiology, optimbing oral drug treatment, and provklie temporary parenteral support when indicated. SpecWic attention shoukl be given to factors that influence the optimal response to each of these 3 treatment classes. A theoretiil, but unproven, concept suggests that combined vasodilatory therapy may be appropriate as long as excessive hypotension is avoided. In the course of management, a decision is required as to whether further optlmizaion of therapy can be achieved on an outpatiint basis. Hospital-based intravenous inotropic support given for 2-4 days will often provide the opportuntty to restructure patient therapy. (Am J Cardiil1662;69:UlGl46G)
From the Division of Cardiology, Department of Medicine, The Ohio State University College of Medicine and Hospitals, Columbus, Ohio. Address for reprints: Robert J. Cody, MD, Division of Cardiology, The Ohio State University Hospitals, 611 Means Hall, 1654 Upham Drive, Columbus Ohio 43210.
Congestive
Heart
MD
ith much current interest in the management of mild congestive heart failure (CHF) and asymptomatic left ventricular (LV) dysfunction,rJ2 it is important to consider the other end of the spectrum, namely, the management of refractory CHF. The patient with refractory CHF presents a major therapeutic challenge, whether encountered in the outpatient setting or referral center. The purpose of this article is to define refractory CHF and to outline pragmatic approaches to management. It is unlikely that this population will decrease in the 1990s. In fact, it is conceivable that the CHF population will increase.3 A considerable number of patients who previously may have died following a myocardial infarction are today undergoing angioplasty or receiving thrombolytic therapy that often yields a dramatic favorable outcome. These modalities can limit the size of myocardial infarction and also reduce patient mortality; however, the remaining myocardial damage may still progress to CHF. Furthermore, the increasing elderly population in the United States, which comprised > 10% of the total population in 1984,4 will likely produce a concomitant increase in the incidence and complexity of heart failure.
W
DEFlNlTlON AND BASEUNE MANAGEMENT
For the purposes of this presentation, refractory CHF is defined as patients with New York Heart Association (NYHA) functional class III-IV heart failure, in whom symptoms have not improved, or have actually worsened, following recent attempts to escalate therapy. Typically, this patient population is likely to evidence substantial fluid retention and/or significantly reduced cardiac output (“lowflow state”). Treatment with digoxin, diuretics, and a vasodilator regimen should have been attempted prior to diagnosis; otherwise, it would not be reasonable to consider the CHF refractory. Even though several multicenter studies2,5,6 have reported favorable outcomes with combined digoxin, diuretic, and vasodilator therapy, the question may be asked: Can patients treated in this A SYMPOSIUM:
CONGESTIVE
HEART
FAILURE
l4lG
manner still present with cardiac decompensation? The answer, in fact, is revealed in these same studies. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS),6 for instance, many patients already receiving digoxin, diuretics, and a vasodilatory still had functional class IV failure. Despite the superiority of the combined regimen of digoxin, diuretics, and the angiotensin-converting enzyme (ACE) inhibitor enalapril over placebo in this study, the l-year mortality rate among enalapril-treated patients approximated 40%. In the Prospective Randomized Milrinone Survival Evaluation (PROMISE) trial of milrinone,7 entry criteria included evidence of recent functional class IV symptoms despite receiving digoxin, diuretic, and ACE-inhibitor therapy. More than 1,000 patients were enrolled. Similar observations can be drawn from the Vasodilator Heart Failure Trial II (V-HeFT II)5 and Studies of Left Ventricular Dysfunction (SOLVD).2 Against this background, the approach to the patient with refractory CHF consists of 3 major factors: assessmentof changing clinical status and pathophysiology, optimizing oral drug therapy, and providing temporary parenteral support when indicated. CHANGING CLINICAL PATHOPHYSIOLOGY
STATUS AND
In a patient with CHF who previously was well maintained on oral therapy, the appearance of refractory CHF should immediately raise questions regarding changes in clinical status and pathophysiology. Several factors influencing these changes are given in Table I. The first major factor is ongoing myocardial ischemia or infarction. In the United States, coronary artery disease is the major cause of CHF. Once a patient has experienced multiple myocardial infarctions or one large myocardial infarction, subsequent progression to CHF may change the focus of patient management to the extent that the importance of ongoing ischemia due to coronary artery disease can be overlooked. Even in the absence of clinically overt ischemia such as chest pain or new electrocardiographic changes, ongoing ischemia, particularly at the endocardial level, may result in progressive ventricular dysfunction and dilation. A new myocardial infarction, of course, would have self-evident consequences. More subtle, however, is the occurrence of ongoing ischemia that may compromise ventricular function. On a chronic basis, this could result in reduced LV systolic performance and diastolic 3.420
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TABLE I Factors Altering Clinical Status Refractory Congestive Heart Failure New myocardial
Diabetes Dietary
myocardial
controlled (particularly
sodium
Progressive Coexistent Patient-related
of
ischemialinfarction
New or progressive regurgitation) Inadequately
and Pathophysiology
mechanical
defect
(e.g., mitral
hypertension insulin-dependent)
indiscretion
renal failure disease
processes
drug therapy
(e.g., pulmonary) issues
dysfunction. Occurring more abruptly, it may cause complete cardiac decompensation and pulmonary edema. A new or progressive cardiac mechanical defect, most commonly mitral regurgitation, can often be masked on cardiac examination; the severity of mitral regurgitation is not necessarily reflected in the cardiac murmur. Therefore, it can function as an independent variable, modulating the extent to which CHF is expressed. Despite the large number of published studies focusing on CHF, few have been able to assessfully the direct impact of mitral regurgitation on ventricular function.8,9 Although clinical experience suggests that significant mitral regurgitation in essence provides a low-pressure escape for the failing ventricle, its long-term presence results in progressive dilation and worsening function of the ventricle, which is manifested symptomatically by pulmonary congestion and low cardiac output. Like myocardial ischemia, the presence of hypertension may lose its importance once the patient has developed functional class III or IV heart failure. If a patient has a history of hypertension that is no longer present, one might argue that this is not a cause for concern. However, if the patient continues to have a systolic blood pressure in the 130-180 mm Hg range, or a diastolic blood pressure in the 85-100 mm Hg range, one could argue that additional blood pressure control is necessary. Both severe hypertension and severe CHF are accompanied by comparable increases in systemic vascular resistance (Figure 1). The major hemodynamic difference is the status of ventricular function and cardiac output. However, when hypertension progresses to where severe systolic dysfunction occurs, or if it is superimposed on CHF of another etiology, both the LV dysfunction and excessiveLV wall stress due to the combination of these vascular disorders require particular attention. Even as the ventricle fails to the point where elevated systolic blood pressure is not generated (despite increased diastolic blood pressure), the long-standing hyperJUNE
4, 1992
FIGURE 1. Comparative hemodynamic characteristics of patients with moderate to severe hypertension (HTN) and NWA functlonal class Ill or IV congestive heart fallure (CHF). Mean values are given, as is statiikz4l signiticance, comparing peak exercise responses. In the HTN group, whereas mean arterial pressure (MAP, mm Hg) was much higher than in the CHF group, cardiac performance, as judged by cardiac index (Cl, liters/min/nP), pulmonary wedge pressure (Pwp, mm Hg), oxygen consumption (VO,, mUmi@ and carbon dioxide production (VC&, mllmin), was mainteined, despite comparable systemic vascular resistance (SVR, dynesls/cn+). R = resting; 5X = exercise; NS = not stgniticant. *p ~0.01; **p co.05.
r
r
**
r
7
rNS1
7
2400
5.00
160
5 ?800
G
2 M 2 120 80
**
3.00
R EX
1200
1 .oo
R EX
r-
r--*1
**
r-
1
1600
1600
0" > 800
g 800
**
1
N
R EX @i CHF(n=9)
n
R EX
R EX
R EX
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tension does not suddenly disappear. In this regard, continued attention to blood pressure regulation is important. Of course, diabetes remains an additional major factor in progressive ventricular dysfunction and worsening of CHF. Typically, diabetes is considered a cause of LV dysfunction, rather than a factor that may contribute to intermittent LV dysfunction. This concept, however, may be revised within the next few years, based on accumulating evidence citing hyperinsulinemia as a persistent vascular insult.lO Both uncontrolled diabetes and perhaps even the adverse effects of chronic highdose insulin use may soon be considered risk factors. Dietary sodium indiscretion is an issue that continues to require attention. Patients with CHF frequently receive large doses of diuretics but, as described below, this does not obviate the need for ongoing dietary sodium management. Sodium intake is difficult to counsel and monitor. There are no firm guidelines regarding absolute sodium intake, but it would certainly be prudent to maintain sodium intake in the moderate range of 2-3 g. Progressive renal failure can also alter clinical status and pathophysiology. Although many CHF patients typically have a serum creatinine level in the range of l-l.5 mg/dL, which already reflects renal impairment (Figure 2) further progression to the range of 2.0-2.5 mg/dL induces a further, substantial reduction in renal function. This is particularly true in the elderly patient with CHF,il
Attention must also be given to intermittent, coexistent disease, particularly pulmonary function abnormalities or pulmonary disease. Pulmonary embolus, even to the periphery of the parenchyma, may produce marked cardiac decompensation. Chronic lung disease is not unusual in the heart
defined
FIGURE 2. Relation oFblood urea nttrogen (BUN, mg/dL) and serum creatlnlne (SCR, mg/dL) to glomerular filtration rate (GFR, mL/mln), as determlned by inulin clearance. Note that GFR may be substantially reduced even in patlents with relatively normal GUN and SCR.
as > 65
years
of age. In the heart
failure
population, renal dysfunction continues to be prevalent among the elderly, even when all other aspects of heart failure are equal.
70
1
0 0 y=55.303-.523x
0
20
0
+.002x~
r = 0.61
40
60
100
80
120
160
140
GFR 31 0
2.75
y =1.803-.01x
2.5
-5x*
r= 0.23
2.25
5 v)
+ 4.939E
1.75 1.5 1.25 1 .75 1
I
s, 0
, I0 , I 20
40
/ , 60
, I 80
, 100
, , 120
, 140
,
1 16C
GFR
A SYMPOSIUM:
CONGESTIVE
HEART FAILURE
1430
failure patient and is generally very difficult to differentiate from progressive heart failure. This is best done by the physician who follows the patient on a long-term basis. Pneumonia and other pulmonary and upper respiratory tract infections may also induce severe cardiac decompensation. Finally, patient-related drug therapy issues must be considered. Noncompliance with therapy is always a factor. In symptomatic heart failure patients, however, this may be less so than in hypcrtcnsive patients, where the perception of illness is less apparent. Trcatmcnt of heart failure requires using multiple drugs throughout the day. The patient may misunderstand the drug regimen and inadvertently alter therapy. In the elderly patient, confusion, memory deficit, and other central neurologic
* I I I
* * '--_ --1---ma__ I * PC.05 1'
I
I
I
-
10 0 6 4
Hours FlwRE3.Aalte respome of plasma aklostawe (PA) and plasma renin actlvtty (PRA) to bobs admhdstratlon of dlgoxh (0.50 I@) In patients nd remlvhg oral dtgoxln therapy.nteserem dlgoxln concsnbatkn Is also given. “p ~0.05. (Rqwlnteul from Am I Me&‘=)
1440
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disorders may compromise with therapy.
the ability
to comply
OPTIMIZING ORAL MEDICAL THERAPY Dioxin: As more information accumulates,
the age-old debate on the role of digoxin therapy is increasingly favoring use of the drug in the majority of heart failure patients with normal sinus rhythm. This has been largely supported by investigative studies,” as well as by large multicenter trials showing favorable cffccts of digoxin therapy.‘“J4 Further, digoxin has additional therapeutic mechanisms, including suppression of the renin-angiotensin system (Figure 3),” and favorable resetting of autonomic tone.‘” In judging whcthcr digoxin is optimal for a given patient, factors to bc considered include determining the appropriate dose and indexing this to a specific strum digoxin concentration when appropriate. However, with progressive cardiac decompensation and subsequent refractory status, absorption can bc adversely affcctcd. Currently, the prospects for development of an altcrnative oral inotropic drug for long-term administration arc not good. Rcccnt data from the PROMISE trial suggest that agents such as the bipyridines actually increase morbidity and mortality in patients with functional class III-IV heart failurc7 Wureth therapy Although there is currently some debate regarding the appropriateness of diuretic use in patients with asymptomatic or mild LV dysfunction, there is no argument regarding such use in patients with refractory heart failure. With few exceptions, patients in this group will require diuretics. However, choosing the appropriate dose and deciding whether to use combined diuretic therapy require careful consideration. It is not unusual for a patient with CHF to become resistant to diuretics, and several variables such as renal insufficiency and aging can influence such resistance.11.‘7 As renal dysfunction gradually progresses, a diuretic response may become progressively attenuated. Concomitant therapy with noncardiac drugs that affect renal function can also mitigate the diuretic response. Such agents include nonsalicylated anti-inflammatory drugs and indomethacin. Edema of the gastrointestinal tract can reduce drug absorption, thereby limiting efficacy. Different diuretic agents may act at different sites within the nephron, so that combination therapy, as discussed later, may be appropriate in the patient with developing refractory heart failure. At the very least, a patient should not be considered refractory to diuretics if receiving only moderate oral doses of a loop diuretic. Several approaches JUNE
4, 1992
can help optimize diuretic therapy in refractory heart failure patients resistant to such therapy.i7 A single large bolus of intravenous diuretics may substantially improve urinary flow and natriuresis. Alternatively, frequent administration of smaller effective intravenous doses might achieve a cumulative effect. Although not typically used in practice, continuous intravenous infusion of a loop diuretic may prove efficacious.‘s Perhaps the most versatile and effective approach to the management of such patients is administering the combination of a loop diuretic and thiazide diuretic. Long-term treatment with a loop diuretic can result in hypertrophy of the distal nephron segment,‘” producing enhanced sodium reabsorption. This can often attenuate the prcvious favorable response to a loop diuretic. To counter this, coadministration of a thiazidc diuretic acting at the distal nephron can substantially increase net sodium and water excretion. Intermittent administration of moderate doses of an intravenous loop diuretic to outpatients with sodium retention may promote sufficient diuresis to avoid hospitalization. l‘his would also be particularly effective in the holding area of an emergency department. Continued moderation of sodium intake to avoid and/or manage refractory CHF should be emphasized. Animal studies’” have shown that the response to a loop diuretic is often mitigated in animals that continue to ingest sodium ad lib compared with animals in whom sodium intake is somewhat restricted. Insistence that the patient ingest a moderate sodium diet enables the patient to participate in the therapeutic process. If the patient remains resistant to diuretics, additional approaches may be considered, including further intcnsifjling combined therapy. This might entail combining up to 3 diuretics (e.g., a loop and a thiazidc diuretic and amiloridc or spironolactone) that potentially act at different nephron sites. At least 1 report2” in a limited number of patients suggests that spironolactonc can bc well tolerated even in combination with an ACE inhibitor. Although typically not required for refractory heart failure, ultrafiltration, hemofiltration,” hemodialysis, or peritoneal dialysis can be used for rapid removal of fluid. These modalities obviously will be important in treating cases of CHF accompanying chronic renal failure.22 Vasodilator therapy: In view of the results 01 recent trials, it now appears reasonable to treat any patient with functional class III or IV heart failure with an ACE inhibitor, hydralazine and isosorbide dinitrate, or a combination of these agents. Vasodi-
lators continue to evolve. Newer vasodilators such as floscquinan offer promise in patients with CHF.2’ The different classes of vasodilators exert their effects by different mechanisms. This may account for some of the clinical findings in the VHeFT II,5 in which the ACE inhibitor enalapril produced a relatively lower mortality rate yet the combination of hydralazine-isosorbidc dinitrate improved exercise capacity and ejection fraction. More novel approaches to the use of these drugs in refractory heart failure may be necessary. Varying combinations of these agents can be used intermittently, in sequence, etc. A patient who has become refractory to an ACE inhibitor, for cxample, may be given hydralazinc-isosorbide dinitrate as a substitute, or vice versa. When the patient with refractory heart failure who is currently taking digoxin, diuretics. and a vasodilator requires alteration in therapy, several issues should be considered. The first is drug dose. There is often a tendency for a “minimalist” approach to the use of vasodilators in heart failure because of concerns regarding cxccssive hypotension. Although it is certainly true that hypotension is an adverse effect of vasodilator therapy and is frequently seen in patients receiving ACE inhibitors, at the same time a reduction in blood pressure is anticipated. Guidelines helping to define an acceptable level of blood pressure have not been created. It is not unusual, however, to observe systolic blood pressure approximating 90 mm Hg with such therapy, and in the absence of significant orthostatic hypotension, such pressure is certainly acceptable. Pressures below this level may be tolerated in some patients but not in others. The second issue is dosing interval. There is a perception that the once-a-day therapeutic philosophy that is advocated for treating hypertension is carried over for the treatment of the CHF population. It is important that vasodilator agents be given at the appropriate dosing interval. For ACE inhibitors such as captopril, therapy should be 3 times a day; for enalapril, therapy is typically twice a day, although once daily might be reasonable, particularly in the elderly paticnt.14 Likcwisc, hydralazinc therapy typically should be administered 3-4 times a day. Longer dosing intctvals may result in ineffective vasodilator therapy. Vasodilators that influcncc neurohormonal pathways (e.g., ACE inhibitors) may have a functional responsiveness related to these pathways. For instance, the extent of sodium restriction can have a considerable influence on response to an ACE inhibitor.‘” A SYMPOSiUM:
CONGESTIVE
HEART
FAILURE
i4wi
Clinicians may consider the use of combined vasodilator therapy. Combination therapy does not imply giving 2 classes of agent at substandard doses rather than 1 agent at an appropriate therapeutic dose. Moreover, it should be emphasized that the excessive hypotension often potentiated by combined vasodilator therapy poses a serious obstacle to the successful management of these patients. If single-agent therapy is insufficient for management, then combined vasodilator therapy is a conceivable option if excessive hypotension can be avoided. Therapy could be based on differences in mechanism of action. For example, a physician might elect to combine a direct-acting vasodilator with one that suppresses the neurohormonal axis (Figure 4). 26 Again, caution must be exercised, as excessive hypotension may be exacerbated by this combination. Combined vasodilator therapy can also be determined based on disease substrate. Not all refractory heart failure is of the same etiology. In coronary artery disease, for instance, one could conceivably combine an ACE inhibitor with a calcium antagonist. Although calcium antagonists
I 2 -0 = 2% 0-:, I2.80
r
0 Control
2.60
2.20 2.00
1.80
Hospital-based
1.60 2.40 1.40
I.;Zs--3 8 z!ti; E 2 c/J2 z= rid00 6)
+O
-
80--O-
2200 2000
1800 1600
-
30
-
15za
1400
1200
27g; 24
a$i
21=
E3 I8 gj 12
FlGUREADatafromacutestwRns~petent&lMdltlVS3htHK4RtOf-lIgVasodlatorSthataCtby
diRews8tmecha&ms.Meanarte1W represented on the horkontal
P----(mHg)b axls. In ii patlents wRh se-
vemchronkcoagestlveheartfalhre,captoprll?S~w8~ glwen oraMy. At peak responrs, nitropnmdde was tltered to reduce mean artefial pressure an additIonal lO% This redtedhturtJmrincreaseofcaMachdex(Wters/mln/ I&) and struke volume Index (ml/beat) and reductkm of systemkvascslarresistance OJynWsld) and pum0 Raywedgep(mn WI. mm-ted*from Am Heart I.“,
1466
have caused unexpected cardiac decompensation in some patients with functional class III or IV heart failure, their use, particularly at lower doses, in combination with an ACE inhibitor may represent a pragmatic approach to the management of patients with known coronary artery disease. Hypertension may be ongoing in many patients with heart failure. In such patients, combining an ACE inhibitor with virtually any vasodilator known to be effective in hypertension, including calcium antagonists, would be reasonable. As previously discussed, hypertension in the CHF setting should be treated aggressively. This means reducing systolic blood pressure to 120-130 mm Hg and diastolic blood pressure to a level well below 90 mm Hg when possible. Mitral regurgitation is a functional consideration that may be particularly important in patients with refractory CHF. In such cases, hydralazine would be effective. The marked reduction in systemic vascular resistance achieved by this agent can be greater than that observed with an ACE inhibitor and could conceivably have a much greater impact on reducing the regurgitant mitral fraction. With addition of sufficient ACE-inhibitor therapy to suppress the neurohormonal axis, hydralazine could become a mainstay of vasodilator therapy in such patients. It has been difficult, however, to calculate an appropriate end point for reduction of regurgitant fraction to serve as a guideline for therapeutic intervention. New modalities such as color-flow Doppler will be useful in this regard.
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imtropk
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port: When the refractory CHF patient does not respond to all of the careful attempts at modulation of clinical status and therapy as outlined above, it is reasonable to consider hospitalization and administration of short-term intravenous inotropic support. Current oral therapy can be discontinued or stabilized with an eye toward restructuring therapy prior to hospital discharge. One may also administer intravenous diuretics to manage excessive sodium retention. Intravenous inotropic support would consist of dobutamine infusions of 2.5-20 pg/kg/min. Typically, many patients respond to 7.5 or 10 kg/kg/ min.*’ This therapy can be continued for 3-4 days, at which time the patient may be discharged. Data are lacking regarding the use of intravenous amrinone under these circumstances. SUMMARY Despite advances in the therapy of CHF, many patients still present with refractory symptoms and
69
JUNE 4, 1992
findings. If a logical approach is taken in the management of such patients, heroic and less available forms of therapy such as cardiac transplantation can often be avoided or delayed. A logical approach, therefore, would include the following: Administration of digoxin, diuretics, and a vasodilator on a chronic basis to all patients with NYHA functional class LII-IV CHF, particularly those who continue to have symptoms. When a patient experiences cardiac &compensation despite this approach, the physician should assess the potentially changing clinical status and pathophysiology of the heart failure and optimize oral drug therapy. Should these 2 steps prove insufficient, hospitalbased intravenous inotropic support, often in combination with intravenous diuretic therapy, should be considcrcd to permit restructuring of a subscquent oral regimen. REFERENCES L Pfcffer M, Lamas G, Vaughn D. Parbi A. Braunwald E. Effect of captopril on progessive ventricular dilation after anterior myocxdial infarction. N f
l.6. Binklcy PF, Nunziata E, Cody RI. Digoxin-mediated reduction of sympathctic tone contributed to vawdilation in dilated cardiomyopathy. (Abhtr) CticuMm 1990$2(suppl 111):316. 17. Brater C. Resktancc to loop diuretics. Why it happens and what to do about it. Dogs 1985;30:427443. 18. Rudy D, Vockler J, Greene I’, Esparza F, Brawr C. Ioop diuretics for chronic renal insufiicicncj. A continuous infusion is more efficacious than bolus therapy. Ann Inrem Med lYYl;115:36&366. 19. Elliwn D, Velazqucr H. Wr@t F. Adaptation of the distal convoluted tubule of the rat. Structural and functional effects of dietq salt intake and chronic diuretic infusion. J C/in /mztr 1989;83: 113-126. 20. lkram H, Webster WI, Nicholls MG. Lewis GRJ, Richards AM, Crazier IG. Combined spironolactonc and comer@ ewymc inhibitor therapy for refractov heart failure. /trcvf NZ J !&frd lY86:16:61~~7. ZL Rimondini A, Cipolla C, Della Bella P. Grazi S, Sisillo E, Susini G. Guazzi X4. Hemotiltration as short-term treatment for refraao? congest& heart failure. Am J Med 1387;83:43-I8. 72. Ruhin RK, Ball R. Continuous ambulatory peritoneal dialysis as treatment of were congestive heart failure in the face of chronic renal failure. ,4rc/1 Infern Med lY86;146:153.%1535. 23. Corin W, Monrad S. Strom J, Giustino S, Sonnenblick E, LcJemtel T. Flosequinan. A vwxiilator with pwitivc inntnrpic activity. Am Ihn J 1~~~1;121: 537-540. 24. Cody RJ. Clinical pharmacolog of an&nensin converting enzyme inhibitors as a @de 10 their utilizxion in congcstivc heart failure. Am J Crrrdiol lY’X&5(suppl):7D13D. 2S.Ci?dy RJ, Covit AB, Schaer GL, Laragh JII, Scaly JE., reldschuh J. Sodium and water balance in chronic congest& heart failure. J C/in hwc.~~ lY&5:77:1441-1452. 26. tidy RJ, Franklin KW, Laragh JH. Combined vasodilator therapy of chronic congcstiw heart failure. ,&!I 1feo1rI 1983;105.575580. 27. lrier CV, Wehel J, Bush CA. The cardiovascular effects of the continuous infusion of dobutaminc in patienl$ with severe cardiac failure. C~rcularion 1977;56:468-479.
DISCUSSION
Dr. Lewis: The deleterious effect of mitral regurgitation in patients with refractory congestive heart failure (CHF) is often a lot more extensive than one might have thought. I have seen many cases in which patients have not received optimal diuresis. They look a lot better, but they still retain IO-15 pounds of fluid. Sometimes it is worth pushing that modality until you arc sure you have reduced the mitral regurgitation as much as possible. Dr. Cody: One thing I have become impressed with in the color-flow Doppler era is how unreliable the mitral regurgitation murmur can be in quantitating mitral regurgitation. By physical examination, it is very difficult to estimate the severity of mitral insufficiency. In this patient population, I almost automatically conduct a color-flow Doppler study to see if there is severe mitral regurgitation and make that a major focus of therapy. Dr. Packer: Some studies’ have shown that much of the improvement in hemodynamics that occurs with direct-acting vasodilators is due to reversal of mitral regurgitation and not to an improvement in systolic ejection fraction resulting from a reduction and improvement in loading conditions. It is a consistent finding. This raises the question, what do you do with someone who has an ejection fraction of 1276, a A SYMPOSIUM:
CONGESTIVE
HEART FAILURE
1476
markedly dilated left ventricle (LV), and secondary but significant mitral regurgitation? We grapple with this all the time, almost invariably thinking of reasons not to recommend surgical procedures because of the risk and questionable benefit. I think there may be a certain percentage of people whom we doom to medical therapy when they might, in fact, better benefit from mitral valve replacement or repair. Dr. Gheorghiade: Mitral insufficiency in patients with severe systolic dysfunction is not so much related to size of the ventricle as to its shape.2 Shape of the ventricle is also important in determining prognosiG4 and an important determinant of hemodynamic response to inotropic therapy.Qj Since mitral regurgitation in these patients is a dynamic process, it is doubtful that replacing the valve is of benefit. Dr. Packer: Obviously, the assumption is that these patients are not surgical candidates, and we generally do not operate; but occasionally we have, and we have had significant postoperative success, enough to impress us that it is a question worth pursuing. Dr. Creager: Transplantation is another option, if a donor heart is available. However, I think it is important to attempt to identify patients at risk long before they get into such dire straits. Dr. Gheorghiade: Because of the severe shortage of donor hearts, it is important to identify patients with ischemic cardiomyopathy that might benefit from coronary artery bypass graft.7 In addition, mitral valve repair, rather than replacement, should be performed, since this may preserve LV function. Dr. Kellyz I think cardiologists and surgeons need to join in a prospective trial about whether preservation of papillary muscle with valve replacement really does make a difference in preserving LV function. The feeling among surgeons is that clearly it does. Dr. McCall: The key is to identify the patients who are going to do well with surgery. Dr. Yusti Engelmeier et al8 have shown that the use of B blockers dramatically improves the condition of even patients with severe heart failure. Few other groups have been able to reproduce these findings in patients with heart failure. One way of dealing with the mitral regurgitation problem may be by prolonging diastole and reducing the total period of systole by simply reducing heart rate with a B blocker. Dr. Cody: I think B blockers should probably be used more frequently in NYHA functional class I 1480
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and II heart failure. We certainly should reconsider using them in patients with LV dysfunction and following myocardial infarction, where calcium antagonists now appear to be favored for reasons that are not particularly clear. In functional class IV refractory heart failure we may still encounter more problems by using a p blocker, but this is under evaluation. Dr. Creager: My feeling is that we can be of great assistance in teaching our house staff and referring physicians to be much more aggressive with their use of diuretics. Most tend to back off from using these agents far too soon. Appropriate use of diuretic therapy can cause an impressive clinical response, whether by adding a thiazide diuretic to a loop diuretic or by hospitalizing the patient and giving parenteral diuretics. Particularly in this circumstance, it is important that physicians remain cognizant about electrolyte disturbances, particularly hypokalemia, hypomagnesemia, and hyponatremia. Dr. Cody: I find that to be particularly true with metolazone. I have had a bit more success with hydrochlorothiazide, but that is observational. However, there are very few primary studies in the heart failure literature on this issue. Dr. Kelly: It is important to administer a shortacting diuretic like furosemide sufficiently frequently to obtain the desired clinical effect. One needs to get tubular levels up to a threshold where diuresis-and natriuresis-can be sustained. Most physicians give furosemide once or perhaps twice a day, but it should normally be given at least twice a day. If it is only given once a day, pharmacodynamic effects will occur that diminish the drug’s effectiveness and a sustained negative sodium balance will not be obtained. On the other hand, as I believe Dr. Cody pointed out, you should not go below a 20-30 mEq sodium diet. If you go below that, hyponatremia ensues, followed by severe hypokalemia due to renin and aldosterone activation. Dr. eheorghiade: Many of so-called “refractoryto-therapy” patients will respond by combining two diuretics (a loop diuretic with a thiazide diuretic or metolazone) or vasodilators, and ACE inhibitors with hydralazine and nitrates. It should also be recognized that improving hemodynamics in patients with end-stage CHF may also prolong life.9 Also, patients with ongoing ischemia due to severe coronary artery disease and severe CHF may not respond to conventional therapy for heart failure.lO JUNE 4, 1992
REFERENCES 1. Weiland DS, Konstam MA, Salem DN, Martin ‘IT, Cohen SR, Zile MR, Das D. Contribution of reduced mitral regurgitant volume to vasodilator effect in severe left ventricular failure secondary to coronary artery disease or idiopathic dilated cardiomyopathy. Am .I Car&l 1986;58:1046-1050. 2. Kono T, Sabbah H, Stein PD, Brymer JF, Khaja F. Left ventricular shape as a determinant of functional mitral regurgitation m patients with severe heart failure secondary to either coronary artery disease or idiopathic dilated cardiomyopathy. Am J Cardiol1991;68:355-359. 3. Meizlish JL, Berger HI, Plankey M, Errico D, Levy W, Zaret BL. Functional left ventricular aneurysm formation after acute anterior transmural myocardIal infarction. NEngl J Med 1984;311:1001~1006 4. Douglas PS, Morrow R, ioli A, Reich& N. Left ventricular shape, afterload and suwival in idiopathic dilated cardiomyopathy. JAm Co11Cmiiol1989;13.311315. 5. Borow K, Lang RM, Neumann A, Carroll JD, Rajfer S. Physiologic mechanisms governing hemodynamic responses to positive inotropic therapy in patients with dilated cardiomyopathy. Circuhtim 1988;77:625637.
6. Keren G, Katz S, Strom J, Sonnenblick E, LeJerntel T. Dynamic mitral regurgitation. An important determinant of the hemodynamic response to load alterations and inotropic therapy in severe heart failure. Circlllofion 1989;80:30& 313. 7. L&e HW Ischemic cardiomyopathy: criteria for coronary revascularization and cardiac transplantation. Circulation 1991;84(suppl3):29~295. 6. Engehneier RS, O’Connell JB, Walsh R Rad N, Scanion PJ, Gunnar RM. Improvement m symptoms and exercise tolerance by metoprolol in patients with dilated cardiomyopathy: a double-blind, randomized, placebo-controlled trial. Ciradanim 1985;72:53&546. 9. Stevenson LW, Tillisch JH, Hamilton M, Luu M, Chelim&-Fallick C, Morignchi J, Kobashigawa J, Walden J. Importance of hemodynamic response to therapy in predicting survival with ejection fraction <2.0% secondary to ischemic or nonischemic dilated cardiomyopathy. Am J Cardiol 1990,66:13481354. 10. Cl&and JGF. Effect of captoplil, an angiotensin-convetis enzyme inhibitor, in patients with angina pectoris and heart faihw. J Am Coil Car&l 1991;17:733-739.
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