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European Journal of Heart Failure 2002 4(4):515-529; doi:10.1016/S1388-9842(02)00041-7
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© 2002 European Society of Cardiology

The effectiveness and relative effectiveness of intravenous inotropic drugs acting through the adrenergic pathway in patients with heart failure—a meta-regression analysis

Simon Thackraya,*, Joanne Easthaughb, Nick Freemantleb and John G.F. Clelanda

a Department of Academic Cardiology University of Hull, Kingston upon Hull, UK
b Department of Primary Care University of Birmingham, Birmingham, UK

* Corresponding author E-mail address: simonthackray{at}hotmail.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Aims: To review systematically the use of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure.

Methods: Studies investigating the use of intravenous inotropes in patients with heart failure published between 1966 and 2000 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. In total, 21 trials, that included 632 patients receiving IV inotropic drugs, placebo or non-treatment control, were identified. Drugs of the following classes were included, the β-agonists; dobutamine, high-dose (>2.5 µg/kg/min) dopamine, dopexamine and the phosphodiesterase (PDE) inhibitors; amrinone, milrinone, enoximone and toborinone. Sixteen trials (474 patients) contributed data from acute invasive haemodynamic studies of symptomatically severe heart failure. Five trials (158 patients) were based on intermittent inotropic therapy in an outpatient context.

Results: With few exceptions, trials of intravenous inotropic agents were small and often failed to report clinically important outcomes. Compared to placebo, intravenous inotropic agents acting through the adrenergic system tended to increase mortality (odds ratio 1.50 (95% CI=0.51 to 3.92) but this did not reach significance and insufficient data were available to determine whether symptoms improved. There appeared to be little difference in the effect of beta-agonists compared to PDE inhibitors on patient outcomes but this could be attributed to the paucity of data.

Conclusions: Intravenous inotropic agents acting through the adrenergic pathway are often used in patients with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes and may not be safe. This highlights the need for further well designed randomised clinical trials.

Key Words: Intravenous inotropic drugs • Heart failure • Adrenergic pathway • Meta-analysis

Received October 20, 2001; Revised March 20, 2002; Accepted March 28, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Unlike other cardiovascular problems, the prevalence of heart failure is increasing [1]. Effective medical therapy is available in the form of ACE inhibitors, beta-blockers and spironolactone [2,3] but many patients still experience acute exacerbation of or chronic deterioration in heart failure necessitating hospital admission [1]. Heart failure may account for over 2000 admissions per annum in a typical large regional hospital serving a population of 500 000 people [1,4,5]..The short and medium term prognosis for these patients is extremely poor [1] and treatment strategies for decompensation of heart failure typically include intravenous diuretics and nitrates. In some centres, the use of intravenous inotropic agents is also common, as they offer a means of rapidly reversing some or all of the adverse haemodynamic sequelae associated with worsening pump failure [6,7].

Pharmacologically, significant differences between inotropic agents exist. Dobutamine is a synthetic sympathomimetic amine with predominant β1-adrenergic activity [8,9], through which it exerts an inotropic effect and increases heart rate [10–12]. The d-isomer of dobutamine exerts mild {alpha}-receptor blocking activity, but with a rather idiosyncratic vasodilator response [13]. Tachyphylaxis is marked, probably due to cardiomyocyte β-receptor down regulation or uncoupling [14] and may be more pronounced in advanced heart failure [15,16]. Dopamine, at low, so-called ‘renal’ doses (0.5–3.0 mcg/kg/min–1) stimulates type 1 and type 2 dopaminergic receptors [17,18] leading to an increase in renal blood flow, glomerular filtration and natriuresis [18]. At higher doses a β1-mediated inotropic effect predominates with similar chronotropic effects to dobutamine [19]. Dopexamine has a unique spectrum of action; it is relatively less β1 and proportionally 60 times more β2 active than dopamine or dobutamine with no substantial effect on {alpha} receptors and only a small effect on dopaminergic receptors [20]. Like dobutamine, it is a powerful inotropic agent [21] with vasodilator effects [22].

PDE inhibitors enjoy widespread use as inotropic agents. PDE inhibitors prevent degradation of cyclic AMP, increasing myocardial intracellular concentrations, leading to an increase in calcium ion concentration and therefore contractility [23–25]. They have powerful vasodilator as well as inotropic effects [26–29]. Trials of oral preparations, not included in the current analysis, have shown an adverse effect on survival [30,31]. Consistent, peripheral, vasodilator effects, lusitropic effects [32–34] and persistent effects despite beta-blockade [35], may give PDE inhibitors an important advantage over beta-agonists.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Objective
Our objective was to evaluate the effectiveness and relative effectiveness of intravenous inotropic agents acting through the adrenergic signalling pathway in patients with heart failure. Cardiac glycosides and a new class of agent, calcium sensitisers, were excluded unless these agents also had important effects on the adrenergic pathway. The primary outcome was all cause mortality. We also aimed to abstract data on length of hospital stay admissions/follow-up time, days alive and out of hospital and major morbidity (worsening heart failure, change of NHYA class, non-fatal myocardial infarction, and adverse events such as arrhythmia and hypotension). The estimates of effectiveness for different agents were compared using Forest Plots and nested meta-regression models.

2.2. Inclusion criteria
We included randomised trials that examined the clinical effectiveness of intravenous inotropic agents vs. placebo or alternative therapy in patients with heart failure. Where cross over trials were identified, the first period of therapy was treated as a simple randomised trial and data from that period included if the trial otherwise met the inclusion criteria. Trials conducted in the immediate post-operative period were excluded.

2.3. Search strategy
We conducted searches of MEDLINE (1966–2000 via OVID), EMBASE (1974–2000 via DIALOG), and the Cochrane Database of Trials. The reference list of each identified study was reviewed. We also examined existing bibliographies and reviews for relevant studies.

2.4. Data abstraction and appraisal of study quality
Data on the total number of patients randomised, dose, duration of treatment, loss to follow-up, level of blinding, concealment of allocation [36], specific study inclusion and exclusion criteria, duration of follow-up, deaths, re-infarctions, symptom severity (NYHA class, exercise testing and haemodynamic measures), quality of life, all cause hospitalisation, hospitalisations for worsening heart failure (including length of stay/days alive and out of hospital), other patient symptom data and adverse events such as hypotension and arrhythmias were abstracted where available. A second researcher abstracted data independently. The analysis plan included stratification for major variables such as severity of heart failure and reason for treatment (acute exacerbation of heart failure vs. chronic heart failure), dependent on available data.

2.5. Statistical methods and analysis plan
The treatment attributable effects on each main outcome for each trial are described. Pooled estimates of effect for each drug are also described.

We estimated pooled odds ratios using the fixed effect approach for binary data. Since, a priori, we anticipated systematic differences between the results of studies (heterogeneity); we also routinely estimated random effects pooled odds ratios. Standard random effects methods for meta-analysis (pooling the results of studies) [37,38] may provide unduly precise estimates of effect as they assume that the observed distribution of effects is the true treatment distribution, an assumption that may not be valid in sparse data [39–41]. Therefore, we used the full random effects approach, based upon Markov chain Monte Carlo numerical integration techniques, using appropriate uninformative priors and the ‘BUGS’ software described by Smith et al. [39]. Convergence was assessed using the methods described by Geweke [42] and visual inspection of convergence plots. As well as providing a more appropriate estimate of the precision of random effects estimates, this approach can account for trial groups that experience no events without resorting to crude fixes such as adding a value to each cell in order to estimate an individual odds ratio or its variance. A further advantage of this approach is that the effects of predictive factors may be examined. Our main protocol-defined, treatment-related covariates are drug classes that are examined using nested random effects logistic regression models. We also examined the effect of different treatment duration, to examine whether long term intermittent therapy is associated with different outcomes from that observed in short term rescue treatment.

Risk differences were calculated using standard random effects methods [38] and because comparison of risk differences between trials may be affected by different lengths of follow-up, also estimated a pooled incidence risk difference using the approach described by Ioannidis et al. [43]. This approach is less robust than the pooled odds ratio, but provides a practically interpretable estimate of absolute treatment effect derived directly from the trials [44].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Included trials
In total, 21 trials that included 632 patients receiving either intravenous inotropic drugs acting through the adrenergic pathway, placebo or non-treatment controls were identified. The included trials are described in (Table 1 Schemes 1–7) [7,20,26–28,32,45–59]. In 11 trials, comparison was with placebo or a non-treatment control, while in 9 trials the comparator was another inotropic agent (see Table 1). In 5 trials an intermittent regimen of dobutamine was compared with placebo or non-treatment control. In all other cases treatment with intravenous inotropic drugs was a short-term treatment strategy.


Figure 1
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3.2. Effect of intravenous inotropic drugs on mortality compared with placebo or non-treatment control
Intravenous inotropic drugs were associated with a non-significant increase in all cause mortality across the trials—odds ratio 1.50 (95% CI=0.51 to 3.92). Eleven trials provided data for this comparison for calculation of odds ratios and estimation of confidence intervals (see Fig. 1). Only 4 trials of intermittent dobutamine had events in both the treatment and control groups (and thus are described in the figure). The majority of deaths occurred in chronic intermittent trials using dobutamine, with less data available on acute single doses. There was insufficient data regarding comparison of PDE III inhibitors with placebo or non-treatment control to draw any useful conclusions.


Figure 8
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  		Fig. 1 Effect of dobutamine or high-dose dopamine compared to control or placebo on mortality.

 
No differences were identified between dobutamine and alternative inotropic agents on mortality, odds ratio 1.37 (95% CI 0.23 to 8.46) (Fig. 2). Only limited data are available from which to estimate these effects, the degree of measurement error and uncertainty are reflected by wide confidence intervals.


Figure 9
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  		Fig. 2 Effect of phosphodiesterase inhibitors compared to dobutamine or high-dose dopamine on mortality (random effects model was not available due to sparse data).

 
3.3. Effect of intravenous inotropic drugs on discontinuation
There was a non-significant increase in discontinuation of allocated treatment associated with not receiving intravenous inotropic drugs in 11 trials—odds ratio 0.52 (95% CI=0.11 to 2.3). This may reflect the investigators knowledge of haemodynamic change. In active-comparator studies, discontinuation was slightly greater in dobutamine treated patients, odds ratio 0.46 (95% CI 0.083 to 2.29) (Fig. 3).


Figure 10
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  		Fig. 3 Effect of phosphodiesterase inhibitors compared to dobutamine or high-dose dopamine on death or discontinuation of therapy (random effects model was not available due to sparse data).

 
3.4. Effect of intravenous inotropic drugs on NYHA score
Treatment with intravenous inotropic drugs was associated with an improvement in NYHA score—standardised effect size –0.75 (95% CI=–1.42 to –0.08), equivalent to an average improvement of approximately 2/3 of a point on the NYHA scale (Fig. 4). This outcome was reported in only two trials and consequently it was not possible to develop a full random effects model, or to analyse results according to ‘acute’ vs. ‘chronic’ intervention.


Figure 11
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  		Fig. 4 Effect of dobutamine or high-dose dopamine compared to control or placebo on symptoms (NYHA Class) (random effects model was not successful).

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
Intravenous inotropes are perceived by some to increase mortality [60–63] when used to treat severe chronic heart failure, so it was pertinent to analyse efficacy and safety data in this context. Our analysis was unable to confirm this view, although a trend to excess mortality with inotropic therapy was observed, with no evidence that beta-agonists and PDE inhibitors were different in this respect. Trends to improved symptoms were noted with dobutamine, which might be used to justify therapy, but these trends were not significant and inadequate blinding to therapy and haemodynamic data could have accounted for much of this effect. In many of our analyses, it was not possible to fit a full random effects model given the sparse data. The fixed effects results should not be over-interpreted as it under-represents the variability in the results. Clearly, further trials demonstrating safety and efficacy are required before such treatment can be recommended in guidelines. Indeed, guidelines should consider contra-indicating conventional inotropic agents for worsening heart failure until such evidence is available.

The OPTIME-CHF trial [64], recently but incompletely reported and hence, not included in this review, randomised 951 patients hospitalised with worsening heart failure, in whom inotropic therapy was not felt to be mandatory, to a single 48-h infusion of milrinone or placebo. The study failed to show a benefit on morbidity or length of hospital stay. There was an increase in adverse events in the milrinone group, which may be explained by hypotension due to vasodilatation, but only a small, non-significant trend to an increase in mortality was observed. The OPTIME-CHF study casts further doubt on whether conventional inotropic agents have a role in the management of worsening heart failure. However, OPTIME-CHF provides no information on the safety or efficacy when used as intermittent ‘out-patient’ therapy.

Recently, a new class of agent, calcium-concentration-dependent calcium sensitisers, have become available. In contrast to the above, studies with these agents have not only randomised a substantial number of patients but have shown some evidence for symptomatic benefit with reductions in morbidity and mortality [65–67]. Moreover, in contrast to studies of oral inotropic agents of other classes, there was no evidence of an increase in mortality at higher doses [67]. Further outcome studies are underway which may finally establish some role for inotropic therapy in the management of patients with heart failure.

The relative effectiveness of agents may depend on the underlying aetiology of heart failure. Liang et al [54] described long-term improvements in functional class following a 72-h dobutamine infusion in 15 patients but excluded patients with coronary disease. Similarly, data from Hoit [32], Marcus [47], Anderson [26], Machii [59], and Gollub [20] included fewer than 20% of patients with underlying ischaemic aetiology and in many of the remaining studies, aetiological characteristics were not clear. The patients in these studies do not appear representative of common clinical practice.

In the UK, as in many other countries, inotropic agents are often reserved for cardiogenic shock and usually in the context of acute myocardial infarction. Relatively little of the data (3 trials, 75 subjects) meeting our inclusion criteria pertain to this patient group [7,48,57]. In this setting, inotropic therapy could also do more harm than good by exacerbating ischaemia, increasing infarction size [68] and possibly even by exacerbating hypotension [69]. IV inotropic agents had no significant effect on mean arterial pressure or heart rate when compared with placebo in the studies in this review. This was expected with PDE inhibitors, due to their vasodilator properties. For the studies of dobutamine, this may reflect the use of low doses, usually <10 mcg/kg/per min [50–53,59]. Use of these low doses may have avoided the provocation of more arrhythmias and led to an underestimate of the toxicity of these agents [28,57,58].

The interaction with chronic beta-blocker therapy may profoundly affect the choice of inotropic agent used and the anticipated clinical response. Few of the patients included in these studies were established on what would presently be considered as optimal pharmacotherapy [5]. Beta-blockers will reduce the inotropic response to beta-agonists, which may reduce both any benefit or harm from these agents. There is evidence [70–72] that chronic oral dosing with selective beta1-blockers leads to up-regulation in beta2-receptor density which may last for several days beyond the last dose. The clinical significance of this is unclear. On the other hand, the haemodynamic response to PDE inhibitors does not appear impaired in the presence of a beta-blocker [73].


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
Further trials are required to investigate the use of inotropes in the context of contemporary management of severe heart failure and of acute cardiogenic shock. These trials need to focus on clinical outcomes, including the effects on symptoms, morbidity and mortality. Moreover, such studies should not only consider the immediate outcome but also the longer-term consequences of treatment and the interaction with other treatments that have been proven to be effective for patients with heart failure.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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