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European Journal of Heart Failure 1999 1(3):263-268; doi:10.1016/S1388-9842(99)00016-1
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© 1999 European Society of Cardiology

Ambulatory vasodilator therapy in heart failure: systematic review of the literature and personal observational experience

Richard Pacher and Brigitte Stanek*

Department of Cardiology, University of Vienna Waehringer Guertel 18–20, A-1090 Vienna, Austria

* Corresponding author. Tel.: +43-1-404004616; fax: +43-1-4081148

Key Words: Dobutamine • Milrinone • Prostaglandin E1 • Ambulatory therapy

Accepted March 15, 1999


   1. Introduction
Top
 1. Introduction
2. Dobutamine
 3. PDE-inhibitors
 4. Prostaglandins
 References
 
Heart failure is a pressing medical problem, particularly when patients become refractory to standard oral outpatient medication and are referred to specialized centers. Once dyspnea and extreme fatigue at rest persist despite optimized oral medications the dilemma over parenteral therapy begins. The possibility of a future heart transplant as such does not offset the physical suffering. Much of the experience to provide sufficient pharmacological support to the failing left ventricle has been with short-term catecholamine and phosphodiesterase (PDE) inhibitor infusions in an intensive care unit allowing treatment to be continued in an outpatient setting [1–3]. Outpatient infusions show promise for their potential to improve patient comfort and decrease hospitalizations and costs. To increase independence further, patients who safely tolerate this therapy while displaying some measure of either symptomatic, functional, or hemodynamic improvement in the hospital, can be given parenteral therapy at home. The goal to use home infusions is a strategy to buy time either to improve symptoms until heart transplantation (HTx) or to extend the proportion of the terminal phase of the illness spent at home. Studies to date have used different drugs, dosages and administration schedules and their results require individual consideration.

In this article relevant case studies and clinical trials of long-term ambulatory intravenous inodilator or vasodilator therapy for refractory congestive heart failure are selected, the possible benefit is described, and recommendations for this treatment are debated.


   2. Dobutamine
Top
 1. Introduction
 2. Dobutamine
3. PDE-inhibitors
 4. Prostaglandins
 References
 
The β adrenergic agent dobutamine on an outpatient basis has been in use for over 15 years. Early published reports showed consistent improvement in 77 patients treated with multiple infusions of dobutamine (Table 1) [1]. The initial excitement over its use as home therapy was soon lessened because of problems in a controlled trial (mean dose 8.1 mcg/kg/min) in 60 patients which was terminated prematurely because of increased adverse outcomes [4]. Despite an increase in exercise duration, 40% of the patients treated with dobutamine died (half of which were sudden deaths). Also in the 21 patients treated by Applefield [5] there was a significant improvement of symptoms, but 20 patients died (four of them sudden). However, these earlier studies preceded the era of angiotensin-converting enzyme (ACE) inhibitors. Contemporary studies report no excess mortality (Table 1) [6–11]. In contrast to the previous policy, low dose dobutamine (max. 5 mcg/kg/min vs. max. 15 mcg/kg/min) is preferred now and is understood to exert a predominantly vasodilatory effect. An Australian study [10] of all patients listed for HTx reported mean 70% reduction in hospital bed occupancy. No death was sudden. The authors attributed this to the use of amiodarone in 50% of their patients given for high grade ventricular ectopy.


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  		Table 1 Chronic parenteral inotrope/inodilator infusion in end-stage heart failure

 

   3. PDE-inhibitors
Top
 1. Introduction
 2. Dobutamine
 3. PDE-inhibitors
4. Prostaglandins
 References
 
PDE III inhibitors (e.g. amrinone, enoximone, milrinone) enhance myocardial contractility by increasing levels of cyclic adenosine monophosphate. Enoximone has been added to dobutamine in pre-transplant patients referred for a mechanical bridge to HTx or urgent HTx who exhibited clinically significant renal, cerebral, or peripheral hypoperfusion in spite of maximal adrenergic support. In the USA 72 patients received parenteral enoximone for 24–48 h and oral enoximone thereafter [12]. In Germany a bolus of enoximone followed by a continuous infusion was given to 24 patients with 11 patients being weaned and continued on oral enoximone [13]. In France a prospective study was performed with an intravenous bolus given every 8 h in 52 patients with cardiogenic shock. Although the hemodynamic situation stabilized rapidly the effect vanished in many as they were waiting in the intensive care unit for a suitable donor [14]. In contrast to enoximone, milrinone was shown not only to improve hemodynamics acutely [15] but stabilize such patients for prolonged periods by weekly infusions in an outpatient clinic [16]. The effects of milrinone are presumed to be multifactorial in origin involving a peripheral vasodilating effect independent of its cardiotonic action. Case studies [17–19] and one clinical trial [20]suggest that patients with end-stage heart failure can safely tolerate home infusions of milrinone while displaying some measure of either symptomatic, functional, or hemodynamic improvement (Table 1). In such patients 0.25 mcg/kg/min milrinone infusion was added on dobutamine and increased gradually over 2 days to reach a target infusion rate of 0.5 mcg/kg/min. Patients were discharged when heart rate and blood pressure were stable for at least 12 h and urine output was satisfactory. If patients did not respond to 0.5 mcg/kg/min milrinone within 1–2 weeks a further increment (to 0.6 mcg/kg/min) was provided. Other patients received milrinone without dobutamine starting with a loading dose of 50 mcg/kg/min. In all, milrinone was administered for a period of 9–59 days. Few side effects were reported; one sustained VT and no deaths. None of the patients had worsening heart failure while they were being treated with infusions of milrinone [17]. Another series of continuous 3–4-month infusions of milrinone in 18 advanced heart failure patients who were unresponsive to conventional oral therapy yielded similar results [18]. An experience of intermittent milrinone infusions ranging from 6-h infusions on 3 days per week to 12-h-infusions on 5 days per week in 10 patients was reported recently [19]. Hospitalizations decreased from 18 during the 3 months before to four during the 3-month home infusions and there were no deaths during this period. Initial exposure to i.v. milrinone (with dobutamine added later when necessary) was found to reduce the need for mechanical intervention before HTx in a prospective comparison of the two drugs as primary i.v. therapy. Of the total of 71 patients 48 were successfully bridged to HTx, but the other 23 died from refractory heart failure [20].


   4. Prostaglandins
Top
 1. Introduction
 2. Dobutamine
 3. PDE-inhibitors
 4. Prostaglandins
References
 
In 1984 Dzau et al. [21] pointed out that prostaglandin system activation in advanced heart failure could counter excessive vasoconstriction. Indeed part of the benefit obtained with ACE inhibition could be derived from an increase in endogenous prostaglandin production [22]. Thus, exogenous prostaglandins such as prostaglandin E1 (PGE1, alprostadil) and prostacyclin (prostaglandin I2, epoprostenol or flolan) — in theory — should be beneficial. Prostaglandins have potent pulmonary and systemic vasodilator actions, and various ancillary properties such as inhibition of platelet adhesion and cell proliferation. An important pharmacological consideration in using these compounds therapeutically is their rapid metabolism, which generally results in loss of biological activity. There are, however, important differences between prostacyclin and PGE1 which might influence the results from either drug. While prostacyclin is inactivated by spontaneous hydrolysis in the entire circulation, PGE1 is in part metabolized to inactive products in the lung, which acts as a filter to protect the systemic circulation from prolonged vasoactive effects due to recirculation. Until recently, clinical experience with chronic prostaglandin therapy in heart failure was scarce, however, or even disappointing [23–28]. In one study 20 ng/kg/min PGE1 was administered in five ambulatory patients for 1–4 months and resulted in remarkable increments in left ventricular function [23]. Our own hemodynamic results with 48-h-PGE1 infusions (30 ng/kg/min) in advanced heart failure patients suggested that a substantial gain in flow can be achieved in addition to that already obtained with catecholamines [24] and that much lower dosages sustain a sufficient hemodynamic and clinical benefit [25]. We recently reported on 5 years’ experience with PGE1 coupled to dobutamine and dopamine in 32 patients and to dopamine only in 22 patients (Table 2) [26]. The majority (70%) had idiopathic aetiology of their dilated cardiomyopathy and had very low cardiac output (1.7 and 1.9 l/min/m2 on average) and were listed for HTx, 12 of them with enhanced priority. In an initial dose ranging test PGE1 was uptitrated until side effects appeared (29 ng/kg/min on average) when usually a sufficient hemodynamic response was observed. Fifty percent of the peak dose was used for chronic therapy and the dose of PGE1 was further reduced if side effects recurred. Fifty-four percent of patients could be discharged home with chronic therapy via a Hickman catheter connected to a portable pump. After 1 month, when PGE1 was reduced to a mean of 8 ng/kg/min, increases in cardiac output were sustained. In three patients PGE1 therapy was withdrawn because of an increase in serum creatinine and in one because of non-compliance. In total there were 15 cardiac deaths and 36 heart transplants, as well as three weanings from the transplant list among 54 attempts of PGE1-associated bridging.


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  		Table 2 Chronic parenteral prostaglandin E1 infusion in heart failure

 
In the meantime intravenous home therapy by means of a portable infusion pump has gained popularity in advanced heart failure. Few patients with severe and persistent symptoms have the chance of a transplant. Therefore, a randomized open label parallel group trial comparing conventional therapy vs. conventional therapy plus prostacyclin was performed (the FIRST trial) [27]. Interim analyses were performed after every 50 patient deaths. At the time the trial was stopped there had been 95 deaths in the prostacyclin group and 76 deaths in the conventional therapy group. The excess in mortality which diverged from control in about the third month of therapy appeared to be a result of an excess of deaths related to progressive congestive heart failure in the prostacyclin group, with no significant differences in sudden deaths between groups. There did not appear to be a significant difference between prostacyclin and conventional therapy in exercise tolerance, worsening chronic heart failure, or requirements for intravenous inotropic therapy. Systemic pressures were significantly lower in the prostacyclin group; heart rates were slightly higher. The FIRST trial demonstrates that intravenous vasodilation can be a ‘double-edged sword’ in advanced heart failure and calls into question the ultimate utility of hemodynamic end points. One possibility is that vasodilation with prostacyclin caused a reflex deleterious increase in sympathetic tone. According to our observations this does not occur with PGE1 [25,28]. Thus, there is hope that failure of prostaglandin therapy in FIRST is not a class effect but rather associated with prostacyclin.

While the FIRST study was ongoing a prospective trial comparing the two prostaglandins, PGE1 and prostacyclin, with each other and with dobutamine in a randomized fashion was conducted in our center (Table 2) [29]. In contrast to FIRST we included only listed HTx candidates. All patients had to pass a challenge test at the intensive care unit before the respective study drug was used continuously. Patients in whom the drug was unsafe or ineffective were dropped. This was the case in eight consecutive patients allocated to prostacyclin therapy resulting in truncation of the prostacyclin arm. However, 13 patients failed the acute dobutamine test, seven because of tachycardia early after starting the infusion, although low doses were used and electrolytes were well controlled. A decrease in oxygen saturation was recorded in one patient on PGE1 (smoker) which returned to normal immediately after the infusion of PGE1 was stopped. In three other patients no satisfactory increase in cardiac output occurred. Due to these early drop-outs the number of patients entering the chronic outpatient phase in each arm varied widely with 26 patients on PGE1 and 17 patients on dobutamine. With PGE1, side effects occurred in the majority of patients but subsided in all but one after dose reduction. The main negative endpoint reached during ambulatory bridging was worsening heart failure (nine patients with dobutamine and five patients with PGE1). In two patients the dobutamine-bridge was interrupted in the outpatient phase because of arrhythmias and in one the PGE1-bridge because of pain. Fortunately death was a rare event in this trial. One patient died from an accident during catheter insertion and only one died from worsening heart failure. The basis for this low death rate was that every effort was made to stabilize patients until surgery with combined bridging (e.g. PGE1 plus dobutamine) or other measures. Designing a bridging study prospectively is a difficult task. A number of endpoints during the outpatient phase but also during the initial challenge test appear essential to provide safety and comfort during home therapy. Factors unrelated to the drug effects such as donor availability influence which patients undergo HTx, for example. Weaning is also highly subjective as long as proper protocols are missing. Accordingly, freedom from events rather than reaching HTx was the key approach in our trial. The data strongly suggested that a far larger study will be required to obtain evidence of superiority of one bridging drug over another. Clearly, prostaglandin therapy in heart failure has major limitations. The correct dosage is difficult to set. The symptom-guided dose finding procedure as used in the FIRST study (40% peak dose of prostacyclin for chronic infusion) and in our protocol (50% peak dose of PGE1 for chronic infusion) is empiric and based on the side effects elicited by these drugs (mainly pain). It is unclear if this initial ‘bolus’ dose (when pain becomes intolerable) is a prerequisite to obtain the desired subsequent clinical effects. Furthermore, the dose–effect relationship of PGE1 differs considerably between individual patients with heart failure. A small data base study suggested that even in patients who do not tolerate uptitration with the drug beyond 5 ng/kg/min because of pain PGE1 may include considerable hemodynamic benefits at small doses [30].

Clearly, these open-label studies with their limited patient numbers and inherent weaknesses are a preliminary solution to the problem. Patients with advanced heart failure were treated with carefully prescribed doses of various parenteral inodilator/vasodilator drugs to examine whether beneficial effects could be ascertained and toxicity avoided. There is, of course, no way to know this without a contemporaneous control group. Surprisingly, the well-documented arrhythmogeneity of dobutamine and milrinone caused little difficulty in recent studies. These low complication rates may be in part related to the careful scrutiny with which all study patients were monitored in the intensive care unit during the initial infusions. Additionally, some of the decrease in hospitalizations may be attributable to the excellent home nursing care that such patients received.


   References
Top
 1. Introduction
 2. Dobutamine
 3. PDE-inhibitors
 4. Prostaglandins
 References
 

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