Skip Navigation

European Journal of Heart Failure 2007 9(2):202-208; doi:10.1016/j.ejheart.2006.06.001
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Berger, R.
Right arrow Articles by Pacher, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Berger, R.
Right arrow Articles by Pacher, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© 2007 European Society of Cardiology

Levosimendan and prostaglandin E1 for uptitration of beta-blockade in patients with refractory, advanced chronic heart failure

Rudolf Berger*, Deddo Moertl, Martin Huelsmann, Anja Bojic, Roozbeh Ahmadi, Isabella Heissenberger and Richard Pacher

Department of Cardiology, Medical University of Vienna Waehringer Guertel 18-20, A-1090, Vienna, Austria Ludwig Boltzman Institute of Cardiovascular Research Vienna, Austria

* Corresponding author. Department of Cardiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090, Vienna, Austria. Tel.: +43 1404004616; fax: +43 14081148. E-mail address: rberger{at}gmx.at


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
Background: In advanced chronic heart failure (CHF) 20% of patients do not tolerate beta-blockers and 50% do not reach target doses.

Aim: To test whether levosimendan or prostaglandin E1 (PGE1) can facilitate uptitration of beta-blockers in advanced CHF.

Methods and results: Seventy-five advanced CHF patients (LVEF<35%, NYHA class IIIb or IV) intolerant to beta-blocker uptitration to target doses (10 mg bisoprolol/day) were randomised to a monthly 24 h infusion with levosimendan (n=39) or a chronic infusion with PGE1 (n=36) for 3 months. Bisoprolol was uptitrated following predefined criteria. At 12 weeks, bisoprolol dose increased from 4 mg to 10 mg in both groups. Heart failure worsening occurred in 29 levosimendan patients (74%) versus 16 PGE1 patients (44%, p=0.008). Uptitration was impossible in 9 levosimendan patients (23%) versus 2 PGE1 patients (6%, p=0.03). The combined endpoint of death or urgent heart transplantation or implantation of a ventricular assist device was reached by 12 levosimendan patients (31%) versus 4 PGE1 patients (11%, p=0.04). After 1 year, LVEF increased from 23±7% to 28±11% (p=0.0004), and BNP decreased from 994±806 to 659±564 pg/ml (p=0.03).

Conclusion: Levosimendan and PGE1 facilitate uptitration of beta-blockers in previously intolerant CHF patients. PGE1 treatment allowed uptitration in more patients and resulted in a better clinical outcome compared to levosimendan. This approach increased LVEF and decreased BNP after 1 year.

Key Words: Heart failure • Beta-blocker • Positive inotropes • Vasodilators

Received June 21, 2005; Revised April 20, 2006; Accepted June 5, 2006


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 References
 
The benefit of beta-blockers has been clearly proven in patients with chronic heart failure (CHF) of varying severity [1,2]. Since the improvements in left ventricular function and survival produced by beta-blockade are dose-related [3], high doses should be targeted. Sub-analyses of the COPERNICUS trial revealed that patients at highest risk had the greatest absolute benefit from treatment with carvedilol [4]. However, in about 20% of these patients carvedilol had to be permanently withdrawn, only 50% of these patients reached target doses and heart failure worsening was the major adverse event [4]. In order to achieve the benefits of beta-blocker therapy, it may be useful to stabilize these high-risk patients with additional therapies to make them tolerant to beta-blocker uptitration and to avoid cardiac decompensation.

According to a meta-analysis, the inodilator levosimendan seems to improve mortality compared to the conventional inotropic agent dobutamine, in severe CHF [5]. The positive inotropic effects of levosimendan are based on calcium sensitization of the cardiac myofilaments [6] and its vasodilatory effects result from opening of ATP-sensitive potassium channels [7]. Thereby, levosimendan increases cardiac output, lowers filling pressures and decreases systemic and pulmonary vascular resistance [8,9]. Moreover, anti-ischaemic effects via opening of potassium channels may improve myocardial performance in ischaemic cardiomyopathy [10]. Levosimendan exerts its effects via its active metabolites for up to 11 days [9].

Intravenous PGE1 therapy also has advantages compared to dobutamine, as it reduces the risk of further heart failure exacerbations [11]. The balanced vasodilator decreases ventricular filling pressures and systemic and pulmonary vascular resistance and, as a result, indirectly increases cardiac output. In patients with decompensated CHF, intravenous PGE1 infusions improve haemodynamic status, reduce excessive neurohumoral activation and alleviate heart failure symptoms [12,13]. Furthermore, PGE1 exhibits angiogenetic effects in the human myocardium and less cardiac fibrosis has been found in patients chronically treated with PGE1 [14].

These properties make both levosimendan and PGE1 potentially useful agents to clinically stabilize refractory, advanced CHF patients. The aim of this prospective, randomised, open study was to investigate whether repeat infusions of the long-acting levosimendan or chronic infusions of PGE1 could facilitate uptitration of beta-blockers in refractory, advanced CHF patients with intolerance to beta-blocker uptitration.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 References
 
2.1. Study design
A prospective, randomised, open, parallel group trial was designed to compare repeat infusions of levosimendan (every 4 weeks) with chronic infusions of PGE1, as a bridging therapy to uptitration of bisoprolol over a treatment period of 12 weeks in advanced CHF patients intolerant to uptitration of beta-blockers to target doses. The primary study endpoint was worsening heart failure defined as (1) worsening of NYHA class or (2) weight increase >2 kg within 1 week or (3) clinical signs of cardiac decompensation. The secondary endpoint was the combined negative endpoint of death, urgent heart transplantation or implantation of a ventricular assist device (VAD). In each study patient the need for surgical intervention was discussed weekly within an interdisciplinary council including two cardiologists and two cardiac surgeons, the final decision was made by the surgeons. B-type natriuretic peptide (BNP) levels and left ventricular ejection fraction (LVEF; by radionuclide ventriculography) were evaluated at baseline and after 3 and 12 months. Measurement of BNP and LVEF were performed in a blinded fashion. The investigation conforms with the principles outlined in the Declaration of Helsinki. The protocol was approved by the institutional ethics committee and all patients gave written informed consent prior to study participation.

2.2. Patients
Inclusion criteria were age 18 to 85 years, NYHA class IIIb or IV without oedema, LVEF <35% as determined by radionuclide ventriculography within 3 months before inclusion, pulmonary capillary wedge pressure >15 mm Hg, cardiac index <2.5 l/min/m2, increased BNP of >400 pg/ml or N-terminal atrial natriuretic peptide (N-ANP) of >6300 fmol/ml [15,16], and the intolerance to uptitration ofbeta-blocker to the target dose of 10 mg bisoprolol. Therapy had to be unchanged within the 2 weeks before randomisation.

Exclusion criteria were a systolic blood pressure <90 mm Hg in supine position, severe impairment of renal function (serum creatinine >2.5 mg/dl), severe reactive chronic obstructive pulmonary disease, myocardial infarction or coronary revascularization within 3 months prior to inclusion, signs of acute inflammatory reaction or infection, hypertrophic cardiomyopathy and severe obstructive valvular disease.

2.3. Study drugs
2.3.1. Levosimendan
Levosimendan (Simdax, Orion Pharma, Finland) has a short half-life of 1 h, but it exerts additional effects via its long-acting metabolites OR-1896 (half-life 81 h) and OR-1855 (half-life 70 to 80 h) up to 11 days [9]. To avoid accumulation of the metabolites the infusion was repeated every 4 weeks. The infusion was commenced with a loading dose of 12 µg/kg for 10 min if the patient had a blood pressure ≥95 mm Hg and then continued at an infusion rate of 0.1 µg/kg/min for 24 h. In case of a blood pressure <95 mm Hg and ≥90 mm Hg, levosimendan was started without loading dose at an infusion rate of 0.1 µg/kg/min for 24 h. Blood pressure was recorded at the beginning of the infusion and after 5, 10, 15, and 30 min, and then after 1, 2, 3, 6, 12, 18 and 24 h. This schedule was restarted after each change of dose. If blood pressure dropped to <90 mm Hg but ≥85 mm Hg during infusion, levosimendan was reduced to half of the infusion rate. If blood pressure dropped below 85 mm Hg, levosimendan was stopped. If the patient's blood pressure recovered within 30 min, levosimendan was restarted at half dose.

2.4. PGE1
Due to its short action, PGE1 (Alprostapint, Pint Pharma, Austria) has to be infused continuously to achieve sustained effects [12]. Over the last 10 years, we have used a side-effect-guided approach for uptitration of PGE1 [11,13]. In our experience, PGE1 side effects led to a dose reduction to <5 ng/kg/min followed by further decreases over the following months in most patients [11,13]. Thus, to prevent early side effects we used a fixed low dose of 2.5 ng/kg/min in this study. For chronic application, a Hickman catheter was placed via the subclavian vein and the medication was infused continuously using a portable pump [11].

If the blood pressure decreased to values below 90 mm Hg but above 85 mm Hg during infusion, PGE1 was reduced to half of the dose (1.25 ng/kg/min). In case of a blood pressure drop below 85 mm Hg or a creatinine increase of more than 0.5 mg/ml compared to baseline, PGE1 was stopped and volume was substituted. Moreover, dose of diuretics was reduced in the absence of signs of decompensation. Blood pressure and serum creatinine were reevaluated after 48 h, the PGE1 dose was then adjusted as described and maintained until the next visit. In case of side effects, PGE1 was reduced to half dose. If the side effects disappeared, the half dose was maintained; if the side effects were ongoing, the infusion was stopped. Re-start or dose increase to the normal dose was performed in accordance with the patient and dependent on the extent of side effects.

2.5. Bisoprolol target dose
The MOCHA trial clearly demonstrated that in patients with CHF receiving treatment with beta-blockers the improvements in LVEF and reduction in mortality are dose-related [3]. Bisoprolol is a beta-1 selective adrenoceptor blocker, which produces dose-related (up to 20 mg/day) effects on blood pressure, resting and exercise heart rate [17,18]. Although at higher doses (20 mg/day) a partial loss of beta-1 selectivity occurs, the antagonism of beta-2 adrenoceptors is far less than with non-selective beta-blockers [18]. Therefore, the recommended maximum dose of bisoprolol in the treatment of hypertension is 20 mg/day.

2.6. Clinical monitoring and dose titration of bisoprolol
A clinical evaluation was performed before treatment commenced and then 48 h, 1, 2, 3, 4, 8, 12 weeks and 12 months after the start of randomised treatment. During the levosimendan infusions (weeks 4, 8, 12) a clinical evaluation was performed prior to and 48 h after the start of the infusion; the dose of bisoprolol was increased 48 h after start of the infusion. Patients were eligible for dose increase if they had a systolic blood pressure >85 mm Hg, heart rate >60 bpm, serum creatinine <2.5 mg/dl and no signs of heart failure worsening as described above. The dose of bisoprolol was increased according to the following titration steps—0.6, 1.25, 2.5, 3.75, 5, 6.25, 7.5, 8.75, 10, 12.5, 15, 17.5, 20 mg/day.

2.7. Statistical analysis
Results are expressed as mean±standard deviation (S.D.). For group comparisons Student's t-test was used for continuous variables and Fischer's exact test for categorical data. Paired t-tests were performed to estimate changes over time. Kaplan-Meier analysis (log-rank test) was used to compare the levosimendan and PGE1 groups as regards heart failure worsening and the combined endpoint. Differences were considered significant at p<0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 References
 
3.1. Patient characteristics
The baseline characteristics were comparable between the two patient groups (Table 1).


View this table:
[in this window]
[in a new window]

  		Table 1 Patient characteristics

 
3.2. Bisoprolol dose increase
The bisoprolol dose increased from 4±4 mg to 10±6 mg in the 12-week completers of the levosimendan group (n=27; p<0.0001), and from 4±4 mg to 10±5 mg in the 12-week completers of the PGE1 group (n=32; p<0.0001). At a maximum number of 7 visits per patient, the total number of patient visits was 246 in the levosimendan group and 245 in the PGE1 group. Reasons for failure of bisoprolol uptitration in the levosimendan group were hypotension at 52 patient visits, HF worsening at 60 visits, elevated serum creatinine at 8 visits, and heart rate below 60 bpm at 6 visits. In the PGE1 group reasons for failure of bisoprolol uptitration were hypotension at 49 patient visits, HF worsening at 35 visits, elevated serum creatinine at 1 visit, and heart rate below 60 bpm at 6 visits. Dose increase of bisoprolol was never possible for 9 patients in the levosimendan group (23%) and 2 patients in the PGE1 group (6%) during the 3 month study period (p=0.03). These eleven non-responders did not significantly differ from the responders in any of the baseline characteristics (e.g. BNP levels 1189±628 versus 1153±1007 pg/ml). The furosemide dose was slightly reduced from 84±79 mg/day to 67±42 mg/day (p=0.08), the other concomitant medical therapy was kept stable during beta-blocker uptitration.

3.3. Outcome
During the 12-week-treatment period heart failure worsening occurred in 29 patients (74%) of the levosimendan group and in 16 patients (44%) of the PGE1 group (p=0.008). Kaplan-Meier analysis showed a significant difference in freedom from HF worsening between the groups over time (p=0.003; Fig. 1). Implantation of a VAD was performed in 7 (18%) patients of the levosimendan group compared to 2 (6%) patients of the PGE1 group (p=0.09). Three (8%) patients of the levosimendan group and no patient of the PGE1 group underwent heart transplantation (p=0.09). Two patients (levosimendan group: 5%; PGE1 group: 6%) died in each study group (n.s.). The combined endpoint of death or heart transplantation or implantation of a VAD was reached in 12 patients (31%) of the levosimendan group and in 4 patients (11%) of the PGE1 group (p=0.04). Kaplan-Meier analysis showed a significant difference between groups over time (p=0.03; Fig. 2).


Figure 01
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Kaplan-Meier analysis showing actuarial freedom from heart failure worsening during 3 months of treatment in the levosimendan group (n=39) and the PGE1 group (n=36) (p=0.003).

 


Figure 02
View larger version (10K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Kaplan-Meier analysis showing actuarial event-free 3-month survival in the levosimendan group (n=39) and the PGE1 group (n=36) (p=0.03).

 
3.4. Haemodynamic data, BNP levels and NYHA class
The 12 week follow-up data for haemodynamic parameters, BNP and NYHA class are given in Table 2a. In both study groups a significant decrease in heart rate wasdetectedand NYHA class improved by one class. Taking both groupstogether, the increase in LVEF reached statistical significance.


View this table:
[in this window]
[in a new window]

  		Table 2
 
3.5. Safety of repeat levosimendan infusions
Dose reduction due to hypotension was performed in 12 patients (9 patients, 8 patients, 4 patients), premature withdrawal was performed in 3 patients (3 patients, 3 patients, 0 patients) at baseline (weeks 4, 8, 12). Due to systolic blood pressure below 90 mm Hg the repeat levosimendan infusion could not be started in 3 patients (4 patients, 5 patients) at week 4 (weeks 8, 12).

3.6. Safety of chronic PGE1 infusion
In six patients PGE1 was withdrawn permanently after 46±11 days for various reasons (cholecystitis followed by sepsis, back-pain due to vertebral impression fracture, hypotension, catheter dislocation, mechanical catheter problem, catheter infection). In two patients PGE1 was withdrawn temporarily for 19±6 days due to diarrhoea. A permanent dose reduction after 41±14 days was performed in nine patients, in two patients due to hypotension and inseven patients due to prostaglandin side effects includingmyalgia, arthralgia and headache. A temporary dose reduction for 53±20 days was performed in four patients, due to hypertension (n=1) and other prostaglandin side effects (n=3). No patient suffered from a serious adverse event due to a catheter complication.

3.7. One year follow-up
Beta-blocker treatment was continued after stopping iv treatment with levosimendan or PGE1 (Table 2b). One year after study start, the combined endpoint was reached by 20 levosimendan-treated patients (implantation of a VAD—10 patients, heart transplantation—4 patients, death—6 patients) and 15 PGE1-treated patients (implantation of a VAD—7 patients, heart transplantation—1 patient, death—7 patients) (n.s.). In both study groups the LVEF significantly increased by 5 to 6 percent points, and the NYHA class improved by 1.4 classes. Taking both study groups together, BNP levels decreased significantly.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 References
 
This prospective, randomised, open study demonstrates that both a monthly 24 h infusion with levosimendan and a chronic infusion with PGE1 facilitate uptitration of beta-blockers to target doses in advanced CHF patients with previous intolerance. Beta-blocker intolerance usually results from the negative inotropic effect of these agents—the decrease in LVEF during uptitration [19], which may lead to cardiac decompensation in patients with advanced CHF [4]. Therefore, by counteracting this beta-blocker induced deterioration in cardiac function during uptitration, with a pharmacological intervention known to increase cardiac output, we could successfully uptitrate beta-blocker therapy to target doses in most patients.

4.1. Selection of levosimendan and PGE1 for uptitration of beta-blocker
In contrast to catecholamines like dobutamine, levosimendan and PGE1 increase cardiac output by mechanisms other than stimulation of beta-receptors. As demonstrated in the LIDO-trial, pre-treatment with beta-blockers attenuates the effect of dobutamine on cardiac output and pulmonary wedge pressure, but does not reduce the effects of levosimendan [8]. Milrinone also does not exert its positive inotropic effects via beta-receptors. Indeed, chronic positive inotropic support with milrinone has been demonstrated to facilitate uptitration of beta-blocker therapy to target doses in patients who were intolerant before [20]. However, long-term therapy with oral milrinone increases the morbidity and mortality of patients with severe CHF [21].

Besides inotropic agents, intravenous vasodilators such as sodium nitroprusside and nitroglycerin are commonly used in patients with decompensated CHF. They decrease systemic vascular resistance by vasodilation and ventricular filling pressures, which correlates with improved symptoms and clinical outcome [22], and as a result indirectly increase cardiac output. PGE1 has haemodynamic advantages compared to the above-mentioned vasodilators [23] and, additionally, is not limited by the rapid development of tolerance [24] or toxic effects [25].

4.2. Beta-blocker therapy and advanced CHF
There are few data on the benefit and risk of beta-blocker therapy in very advanced CHF. One-year mortality, an indicator of the severity of disease in a given patient population, was 19% in the placebo group of the COPERNICUS trial which included predominantly patients in NYHA class IV [2]. However, there are patients with a much more advanced disease severity, like the enalapril group in the CONSENSUS trial (36%) or the medical therapy group in the REMATCH trial (75%). Sub-analyses of the COPERNICUS trial demonstrated that the patients at highest risk have the greatest absolute benefit from treatment with carvedilol [4]. However, in about 20% of these patients carvedilol had to be permanently withdrawn and only 50% of these patients reached target doses.

The inclusion criteria for our study were chosen to focus on this type of patient, with very advanced CHF, intolerant to beta-blocker uptitration. Due to these inclusion criteria (BNP>400 pg/ml, N-ANP>6300 fmol/ml [15,16]) our study patients were characterized by high BNP levels (mean 1100 pg/ml). These BNP levels reflect the advanced stage of disease, resulting in an extrapolated 1-year event rate (heart transplantation, VAD implantation, death) of 85%. Incomparison, in another study using BNP>400 pg/ml asinclusion criterion, 241 patients had a mean BNP of 750 pg/ml, an extrapolated 1-year event rate of 65%, and an extrapolated 1-year mortality rate of 38% [26].

4.3. Possible advantages of PGE1 compared to levosimendan
Compared to levosimendan, treatment with PGE1 allowed uptitration of bisoprolol in more patients and was associated with a lower rate of heart failure worsening. Accordingly, significantly fewer patients treated with PGE1 reached the combined endpoint of death or HTx or VAD implantation compared to levosimendan-treated patients.

The following suggestions might explain these results. Due to their negative inotropic effect, beta-blockers initially decrease LVEF, but this returns to baseline levels after 1 month [19]. This initial decrease in cardiac function, which we tried to counteract with levosimendan, might have outlasted the haemodynamic effect of levosimendan, which lasts approximately 9-11 days. This explanation is supported by previously reported data on levosimendan-induced changes in BNP plasma levels. The initial decrease in BNP after 24 h of levosimendan infusion reflects reduced wall stress and, thereby, stabilization of cardiac function. However, BNP almost returns to baseline levels after 1 week suggesting that the positive effects of levosimendan on cardiac function are also diminished [27]. In contrast, in patients treated with a chronic infusion of PGE1, BNP is continuously decreased during 1 week of treatment. These observations might explain why continuous PGE1 infusion had a higher success rate in beta-blocker uptitration than monthly levosimendan infusions.

Although levosimendan is less effective than PGE1 for uptitration of bisoprolol, it has to be mentioned that levosimendan treatment is easier to administer, because it requires only 3 intravenous infusions compared to a chronic prostaglandin infusion (Hickman catheter with a portable pump). Nevertheless, scheduled repeat hospitalisations are necessary for levosimendan treatment.

4.4. Long-term benefit
Titration of bisoprolol up to 20 mg/day increased LVEF by about 3 percent points after 3 months and 4-5 percent points after 1 year in the study completing cohort. This increase in LVEF was similar in both study groups. The lack of reduction in BNP after 3 months can be explained by the fact that uptitration of bisoprolol increases BNP levels in the short term (6 weeks) [28]. However, 1 year after study start BNP was significantly lower compared to baseline in the whole study completing cohort, reflecting the improved prognosis of these patients [29]. It should be noted that, although the bisoprolol dose of 20 mg/day seems to work in clinical practice and is used in hypertension, such a high dose has not been evaluated in heart failure, to date.

4.5. Limitations
The time interval of 4 weeks for repeat levosimendan infusions was chosen for safety reasons, to avoid accumulation, but was not evidence-based. To date there are no recommendations for the repeat administration of levosimendan. Only one paper has reported a retrospective analysis of a few patients who received levosimendan repetitively at different time intervals (4 to 8 weeks) [30]. Therefore, repeat infusions using a 4-week interval are considered to be safe. Indeed, in our patients no significant decrease in blood pressure (despite uptitration of beta-blockers) or increase in heart rate could be detected. Shorter time intervals between repeat infusions might be more effective, but we cannot exclude that this benefit would be gained at the cost of a higher rate of side effects due to accumulation of the long-acting metabolites. This accumulation may result in a significant decrease of blood pressure and increase of heart rate [9]. An alternative strategy would be to reduce not only the time intervals between infusions from 4 weeks to weekly or biweekly intervals, but also the duration of infusion from 24 h to maybe 6-8 h. This approach might avoid hospitalisations and, thereby, reduce costs and improve quality of life.

As can be expected from administration of levosimendan or PGE1 in patients with advanced CHF, the most frequent side effect was hypotension. However, all cases of hypotension were easily treated with dose reduction and volume substitution and none of the side effects were fatal. On the other hand, uptitration of bisoprolol resulted in a significant increase in LVEF and decrease in BNP and was associated with clinical improvement. According to these considerations we believe that the benefits of this treatment by far outweigh the risk. However, this approach should be performed by heart failure specialists experienced in the use of these agents.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
References
 
Repeat infusions with levosimendan and chronic infusion with PGE1, both facilitate uptitration of beta-blocker therapy in advanced CHF patients who were previously intolerant to beta-blocker uptitration. A chronic infusion with PGE1 seems to stabilize patients more effectively during beta-blocker uptitration. One year after the start of uptitration LVEF was improved and BNP, a marker of prognosis, decreased significantly.


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

  1. Braunwald E. Expanding indications for beta-blockers in heart failure. N Engl J Med (2001) 344:1711–1712.[Free Full Text]
  2. Packer M., Coats A.J.S., Fowler M.B., et alfor the Carvedilol Prospective Randomized Cumulative Survival Study Group. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med (2001) 344:1651–1658.[Abstract/Free Full Text]
  3. Bristow M.R, Gilbert E.M., Abraham W.T., et alfor the MOCHA Investigators. Carvedilol produces dose-related improvements in left ventricular function and survival in subjects with chronic heart failure. Circulation (1996) 94:2807–2816.[Abstract/Free Full Text]
  4. Rouleau J.L., Roecker E.B., Tendera M., et al. Influence of pre-treatment systolic blood pressure on the effect of carvedilol in patients with severe chronic heart failure. J Am Coll Cardiol (2004) 43:1423–1429.[Abstract/Free Full Text]
  5. Cleland J.G., Freemantle N., Coletta A.P., Clark A.L. Clinical trials update from the American Heart Association: REPAIR-AMI, ASTAMI, JELIS, MEGA, REVVE-II, SURVIVE, and PROACTIVE. Eur J Heart Fail (2006) 8:105–110.[Abstract/Free Full Text]
  6. Haikala H., Kaivola J., Nissinen E., Wall P., Levijoki J., Linden I.B. Cardiac troponin C as a target protein for a novel calcium sensitizing drug, levosimendan. J Mol Cell Cardiol (1995) 27:1859–1866.[CrossRef][Web of Science][Medline]
  7. Yokoshiki H., Katsube Y., Sunagawa M., Sperelakis N. The novel calcium sensitizer levosimendan activates the ATP-sensitive K+ channel in rat ventricular cells. J Pharmacol Exp Ther (1997) 283:375–383.[Abstract/Free Full Text]
  8. Follath F., Cleland J.G., Just H., et al. Efficacy and safety of intravenous levosimendan compared with dobutamine in severe low-output heart failure (the LIDO study): a randomised double-blind trial. Lancet (2002) 360:196–202.[CrossRef][Web of Science][Medline]
  9. Kivikko M., Antila S., Eha J., Lehtonen L., Pentikainen P.J. Pharmacodynamics and safety of a new calcium sensitizer, levosimendan, and its metabolites during an extended infusion in patients with severe heart failure. J Clin Pharmacol (2002) 42:43–51.[Abstract]
  10. Kersten J.R., Montgomery M.W., Pagel P.S., Warltier D.C. Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg (2000) 90:5–11.[Abstract/Free Full Text]
  11. Stanek B., Sturm B., Frey B., et al. Bridging to heart transplantation: prostaglandin E1 versus prostacyclin versus dobutamine. J Heart Lung Transplant (1999) 18:358–366.[CrossRef][Web of Science][Medline]
  12. Stanek B., Pacher R. Intravenous therapy for advanced heart failure. Curr Opin Cardiol (2000) 15:156–160.[CrossRef][Web of Science][Medline]
  13. Frey B., Pacher R., Locker G., et al. PGE1 improves hemodynamics and neurohumoral activity in potential HTx candidates on long term. Chest (2000) 117:1713–1719.[CrossRef][Web of Science][Medline]
  14. Mehrabi M.R, Serbecic N., Tamaddon F., et al. Revascularization of myocardial scar tissue following prostaglandin E1-therapy in patients with ischemic heart disease. Pathol Res Pract (2003) 199:129–136.[CrossRef][Web of Science][Medline]
  15. Berger R., Huelsman M., Strecker K., et al. Prognostic power of neurohormones depends on the mode of death in patients with chronic heart failure—neurohormonal risk stratification of sudden death and pump failure. Eur J Clin Invest (2005) 35:24–31.[CrossRef][Web of Science][Medline]
  16. Harrison A., Morrison L.K., Krishnaswamy P., et al. B-type natriuretic peptide predicts future cardiac events in patients presenting to the emergency department with dyspnea. Ann Emerg Med (2002) 39:131–138.[CrossRef][Web of Science][Medline]
  17. Davidov M.E, Sing S.P., Vlachakis N.D., et al. Bisoprolol, a once-a-day beta-blocking agent for patients with mild to moderate hypertension. Clin Cardiol (1994) 17:263–268.[CrossRef][Web of Science][Medline]
  18. Lipworth B.J., Irvine N.A., McDevitt D.G. A doe-ranging study to evaluate the β1-adrenoceptor selectivity of bisoprolol. Eur J Clin Pharmacol (1991) 40:135–139.[Web of Science][Medline]
  19. Hall S.A, Cigarroa C.G., Maroux L., et al. Time course of improvement in left ventricular function, mass and geometry in patients with congestive heart failure treated with beta-adrenergic blockade. J Am Coll Cardiol (1995) 25:1154–1161.[Abstract]
  20. Shakar S.F., Abraham W.T., Gilbert E.M., et al. Combined oral positive inotropic and beta-blocker therapy for treatment of refractory class IV heart failure. J Am Coll Cardiol (1998) 1336–1340.
  21. Packer M., Carver J.R., Rodeheffer J.R., et alfor the PROMISE Study Research Group. Effect of oral milrinone on mortality in severe chronic heart failure. N Engl J Med (1991) 325:1468–1475.[Abstract]
  22. Fonarow G.C. The treatment targets in acute decompensated heart failure. Rev Cardiovasc Med (2001) 2(Suppl_2):S7–S12.[CrossRef][Medline]
  23. Murali S., Uretsky B.F., Armitage J.M., et al. Utility of prostaglandin E1 in the pretransplantation evaluation of heart failure patients with significant pulmonary hypertension. J Heart Lung Transplant (1992) 11:716–723.[Web of Science][Medline]
  24. Elkayam U. Tolerance to organic nitrates: evidence, mechanisms, clinical relevance, and strategies for prevention. Ann Intern Med (1991) 114:667–677.[Abstract/Free Full Text]
  25. Friederich J.A, Butterworth J.F.t. Sodium nitroprusside: twenty years and counting. Anesth Analg (1995) 81:152–162.[Abstract]
  26. Vrtovec B., Delgado R., Zewail A., et al. Prolonged QTc interval and high B-type natriuretic peptide levels together predict mortality in patients with advanced heart failure. Circulation (2003) 107:1764–1769.[Abstract/Free Full Text]
  27. Moertl D., Berger R., Huelsmann M., Bojic A., Pacher R. Short term effects on hemodynamic parameters and B-type natriuretic peptide levels of levosimendan compared to prostaglandin E1 in patients withchronic decompensated heart failure. Eur J Heart Fail (2005) 7:1156–1163.[Abstract/Free Full Text]
  28. Davis M.E., Richards M., Nicholls G., Yandle T.G., Frampton C.M., Troughton RW. Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure. Circulation (2006) 113:977–985.[Abstract/Free Full Text]
  29. Anand I.S., Fisher L.D., Chiang Y.T., et al. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation (2003) 107:1278–1283.[Abstract/Free Full Text]
  30. Spargias K.S., Anifantakis A., Papadakis M., et al. Preliminary clinical experience with the repetitive administration of levosimendan in patients with end-stage heart failure. Ital Heart J (2003) 4:45S–49S.

Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in ISI Web of Science
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrow Search for citing articles in:
ISI Web of Science (1)
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Berger, R.
Right arrow Articles by Pacher, R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Berger, R.
Right arrow Articles by Pacher, R.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?