Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure: Title and subTitle BreakThe SURVIVE Randomized Trial FREE

Acute decompensated heart failure (ADHF) remains a common cause of hospitalization worldwide but it is not clear how patients admitted for clinical deterioration should be managed. Patients are generally treated with diuretics and vasodilators, while patients with evidence of peripheral hypoperfusion also may receive positive inotropes, usually dobutamine or milrinone. These positive inotropic agents improve hemodynamics and symptoms by increasing intracellular cyclic adenosine monophosphate within the failing heart but have been associated with an increased risk of death and other cardiovascular events.^{1 - 2}

Levosimendan is a pharmacological agent that exerts positive inotropic effects by binding to cardiac troponin C in a calcium-dependent manner, sensitizing myofilaments to calcium.^{3 - 4} Levosimendan also has vasodilatory properties due to its facilitation of an adenosine triphosphate–dependent potassium channel opening⁵ and anti-ischemic effects.⁶ In clinical studies, levosimendan increased cardiac output and lowered cardiac filling pressures and was associated with reducing cardiac symptoms, risk of death, and hospitalization.^{7 - 9} Unlike other positive inotropic agents, the primary actions of levosimendan are independent of interactions with β-adrenergic receptors.^{10 - 11} Compared with the β-adrenergic agonist dobutamine in the Levosimendan Infusion versus Dobutamine (LIDO) trial,¹² levosimendan exerted superior hemodynamic effects and in secondary and post hoc analyses was associated with a lower risk of death after 31 and 180 days.

Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) was the first survival trial performed in patients with ADHF, to our knowledge. The SURVIVE trial assessed the effect of short-term intravenous infusions of levosimendan or dobutamine on long-term survival.

The SURVIVE trial was conducted at 75 centers in Austria, Finland, France, Germany, Israel, Latvia, Poland, Russia, and the United Kingdom. The study protocol was approved by independent ethics committees and was conducted in accordance with the Declaration of Helsinki¹³ and applicable regulatory requirements. This trial was designed, implemented, executed, and overseen by the study sponsor and steering committee. An independent data and safety monitoring board had access to unblinded data and periodically reviewed the safety results.

The study enrolled patients aged 18 years or older who provided written informed consent and were hospitalized with ADHF. All patients had an ejection fraction of 30% or less within the previous 12 months and required intravenous inotropic support, as evidenced by an insufficient response to intravenous diuretics and/or vasodilators, and at least 1 of the following at screening: (1) dyspnea at rest or mechanical ventilation for ADHF; (2) oliguria not as a result of hypovolemia; or (3) pulmonary capillary wedge pressure of 18 mm Hg or higher and/or cardiac index of 2.2 L/min per m² or less.

Exclusion criteria included severe ventricular outflow obstruction; systolic blood pressure persistently lower than 85 mm Hg or heart rate persistently at 130/min or higher; intravenous inotrope use during the index hospitalization (except dopamine ≤2 μg/kg per minute or digitalis); history of torsade de pointes; and serum creatinine level higher than 5.1 mg/dL (450 μmol/L) or dialysis.

SURVIVE was a randomized, double-blind, multicenter, parallel-group study. Randomization was performed by a 2-step procedure (Figure 1). First, vials containing study drug were assigned a number using randomly permuted blocks. Second, patients were randomized centrally, using an interactive voice response system, to receive levosimendan or dobutamine at a ratio of 1:1. Randomization was stratified using a biased coin algorithm with previous ADHF and country as factors.

During the treatment period, patients were randomized to receive 2 double-blind intravenous infusions: levosimendan and placebo for dobutamine in the levosimendan group or dobutamine and placebo for levosimendan in the dobutamine group. A loading dose of levosimendan (12 μg/kg) or placebo for levosimendan was administered over 10 minutes, followed by an infusion (0.1 μg/kg per minute) for 50 minutes; the rate was increased to 0.2 μg/kg per minute for an additional 23 hours as tolerated. The infusion of dobutamine or placebo for dobutamine was initiated at a rate of 5 μg/kg per minute and could be increased at the discretion of the investigator to a maximum rate of 40 μg/kg per minute. The infusion was maintained as long as clinically appropriate (minimum of 24 hours) and was tapered according to each patient's clinical status.

Plasma B-type natriuretic peptide (BNP) levels were measured after 1, 3, and 5 days. Hospitalization or death was noted for the 180-day period. If patients required additional inotropic support during the study period, the intention was to maintain the blind by readministering the patient's original assigned study drug and dosing regimen. However, this was not mandated so failure to do so was not considered a protocol violation. If readministration occurred within 7 days of initial infusion, levosimendan was administered without a loading dose and at 0.1 μg/kg per minute.

The primary end point of the study was all-cause mortality during the 180 days following randomization. Secondary end points included all-cause mortality during 31 days, change in BNP level from baseline to 24 hours, number of days alive and out of the hospital during the 180 days, change in patient-assessed dyspnea at 24 hours, patient-assessed global assessment at 24 hours, and cardiovascular mortality through 180 days.

To monitor safety, adverse events were collected for 31 days following initial study drug administration and during all blinded drug readministrations.

The sample size was based on the objective of assessing differences in all-cause mortality between the levosimendan and dobutamine groups at 180 days. The trial was event-rate driven until 330 deaths had occurred, providing 85% power (α = .05) to detect a 25% relative risk reduction in mortality rates between the treatment groups, assuming the 180-day mortality rate was 25.3%. The originally targeted number of patients, based on LIDO,¹² was 700 but was increased to 1320 following a blinded review of mortality after 131 deaths to achieve the target number of 330 deaths.

To control the type I error due to 2 interim analyses, the Haybittle-Peto boundary was used and differences in risk between the 2 treatments at the end of the trial were considered significant at a P value of less than .05.

Analysis of survival was based on a patient's randomization in accordance with the intention-to-treat principle. Cumulative survival curves were constructed as time-to-event plots by Kaplan-Meier methods and differences were tested for significance by the Cox proportional hazard regression model, with treatment as the only covariate. The Cox model also was used to examine potential treatment × subgroup interactions using treatment, subgroup, and treatment × subgroup interaction as covariates. Prespecified subgroup analyses included the baseline variables of sex, age, previous ADHF, acute myocardial infarction at initial hospitalization, serum creatinine level, oliguria, β-blocker use, angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker use, systolic blood pressure, heart rate, dyspnea at rest, and mechanical ventilation for ADHF. The Cox model within subgroups was further considered if the interaction P value was .10 or less.

Comparison of categorical variables such as dyspnea assessment, patients' global assessment, and number of days alive and out of the hospital was performed using the Cochran-Mantel-Haenszel test with effect for treatment only. Changes in BNP levels were analyzed using the Kruskal-Wallis test. Comparisons between treatment groups for the incidence rates of adverse events were performed using a Fisher exact test and mean change from baseline of other variables were performed by analysis of covariance with baseline as a covariate. Treatment differences in mean change from baseline in electrocardiogram and vital signs were tested by analysis of covariance with baseline as a covariate. Statistical analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, NC) and significance was reported at a P value of .05 or less.

A total of 1327 patients hospitalized with ADHF were randomized between March 2003 and December 2004 to either the levosimendan group (n = 664) or the dobutamine group (n = 663). Of this intention-to-treat population, 1320 patients (660 in each group) received study drug and were included in the safety population (Figure 1).

Patients randomized to levosimendan or dobutamine were similar with respect to pretreatment characteristics (Table 1) and concomitant medications. Patients had increased BNP levels and the large majority (n = 1171; 88%) had previous ADHF.

After the initial hour that includes loading dose, levosimendan was continuously infused at a mean (SD) rate of 0.2 (0.02) μg/kg per minute for 23.4 (2.9) hours; dobutamine was infused at a rate of 5.9 (2.6) μg/kg per minute for 39.3 (44.4) hours. During the 180-day period, 102 (<8%) patients (48 in the levosimendan group and 54 in the dobutamine group) received blinded readministration of study drug. Also, during the study period, 75 (11%) patients in levosimendan group received open-label dobutamine (n = 72) or levosimendan (n = 3) while 79 (12%) patients in the dobutamine group received open-label dobutamine (n = 74) or levosimendan (n = 5).

During the 180 days after study drug infusion, there were 173 deaths (26%) in the levosimendan group and 185 deaths in the dobutamine group (28%) (hazard ratio, 0.91 [95% confidence interval, 0.74-1.13] P = .40; Figure 2). Analysis of all-cause mortality at 31 days and cardiovascular mortality at 180 days also showed no difference between the treatment groups (Table 2).

Plasma BNP levels decreased more in the levosimendan group than in the dobutamine group at 24 hours and at 3 and 5 days (all P<.001) (Figure 3). Other secondary variables were similar between the treatment groups (Table 2).

Subgroup analyses were performed to assess the influence of prespecified baseline characteristics on the difference in survival between patients in the levosimendan and dobutamine groups (Table 3 and Table 4). Most of the prespecified subgroup analyses showed no interactions. However, a prior history of heart failure at baseline did influence the between-group difference at 31 days (treatment × prior heart failure interaction, P = .05) but not at 180 days. At 31 days, in the 88% of patients with a prior history of heart failure, there was a trend for lower risk of death in the levosimendan group compared with the dobutamine group. However, in the subgroup of patients without a prior history of heart failure (12%), there was a numerical increase in the levosimendan group.

Systolic and diastolic blood pressure initially declined more in the levosimendan group than in the dobutamine group. Following cessation of the study drug infusions, these differences subsided (Figure 4). Heart rate increased more in the levosimendan group than in the dobutamine group (Figure 4) and remained elevated through 5 days.

Compared with dobutamine-treated patients, levosimendan-treated patients were less likely to experience cardiac failure (P = .02) and more likely to experience atrial fibrillation (P = .05), hypokalemia (P = .02), and headache (P = .01) during the initial 31 days following study drug administration (Table 5). The treatment groups were similar with respect to frequency of hypotension, renal insufficiency, ventricular arrhythmias, or history of torsade de pointes. The QTc interval did not increase with levosimendan and did not differ between the 2 groups.

Patients hospitalized for ADHF carry a high risk of death and rehospitalization in the months following admission.^{14 - 15} Available evidence suggests that the short-term risk may be influenced by treatment¹⁶ because several therapeutic agents including dobutamine, milrinone, and nesiritide have been associated with an early increase in the risk of death.^{1 ,17 - 18} In this study, we compared levosimendan, which sensitizes the cardiac myofilament response to calcium and facilitates the opening of adenosine triphosphate–dependent potassium channels with minimal effect on intracellular cyclic adenosine monophosphate, to dobutamine, the most widely used therapy for ADHF, which predominately acts by increasing intracellular cyclic adenosine monophosphate. In the LIDO trial,¹² those assigned to levosimendan had a lower risk of death than those assigned to dobutamine but this benefit was not the primary end point of the study.

The SURVIVE study is the first prospective, randomized trial to monitor long-term survival in patients with ADHF. The results revealed no significant difference between levosimendan and dobutamine in all-cause mortality at 31 and 180 days after study drug infusion.

The SURVIVE study demonstrated that levosimendan-treated patients had marked decreases in BNP level compared with dobutamine-treated patients through 5 days. The contrast in the effects of levosimendan over dobutamine is congruent with the pharmacokinetics of both drugs; the active metabolite of levosimendan peaks approximately 3 days after the start of the infusion and has a half-life of 80 hours.¹⁹ In contrast, dobutamine has a shorter half-life and no known active metabolite. Therefore, it is noteworthy that in the SURVIVE trial numerical differences in survival between the 2 drugs were seen early in the trial immediately following the cessation of treatment (ie, hazard ratio, 0.72 [95% confidence interval, 0.44-1.16] at 5 days post hoc analysis) but these hazard ratio differences dissipated in the absence of continued therapy during long-term follow-up.

A second explanation for the lack of mortality difference between the treatment groups during long-term therapy is that levosimendan and dobutamine may differ in their survival effects only in a subgroup of ADHF patients. In SURVIVE, randomization was stratified by previous heart failure based on earlier evidence that it might influence ADHF mortality²⁰ and treatment differences. Therefore, it is noteworthy that a history of heart failure influenced the treatment differences we observed. Specifically, treatment differences in favor of levosimendan at 31 days were more apparent in patients with a prior history of heart failure than in those with recent-onset heart failure, possibly because of the greater use of β-blockers in patients with chronic heart failure. β-Receptor antagonists may interfere with the hemodynamic benefits of dobutamine^{21 - 22} or potentiate the circulatory actions of levosimendan^{12 ,23} or both.

A third explanation may be that a different dobutamine dosing strategy in the SURVIVE study prohibited the replication of the 180-day mortality in the LIDO study,¹² a hemodynamic study in which all patients had a pulmonary artery catheter inserted. In SURVIVE, the tailored approach was different from the dobutamine dosing regimen used in the LIDO study in which patients in the dobutamine group initially received 5 μg/kg per minute and were up-titrated to 10 μg/kg per minute if hemodynamic goals were not achieved. In the SURVIVE trial, the dobutamine dose could have been increased up to 40 μg/kg per minute to achieve clinical goals, however it was administered at a relatively low dose of 6 μg/kg per minute and for an average of 39 hours. The dobutamine dosing regimen was determined by the treating physician in a blinded fashion and according to the patient's needs. Additionally, the dobutamine infusion was discontinued after 24 hours in the LIDO study. The individualized dosing strategy adopted for dobutamine in the SURVIVE trial may have produced the 180-day mortality of 28% compared with 38% in the LIDO study. By contrast, levosimendan was given in a fixed manner in both the SURVIVE and LIDO studies with the same 180-day all-cause mortality rate of 26%. Accordingly, future trials should consider allowing the dose of levosimendan to also be individualized.

Compared with dobutamine-treated patients, levosimendan-treated patients were more likely to experience an initial decrease in systolic and diastolic blood pressure (Figure 4). The latter, likely related to the mode of administration of levosimendan and especially to the bolus dose, might be responsible for the occurrence of atrial fibrillation and possibly to other detrimental effects such as death. Accordingly, future trials should investigate the optimal mode of administration of levosimendan. Hypokalemia was consistently observed in SURVIVE as in other trials.^{7 ,12} Mechanism of hypokalemia remains to be elucidated.

In conclusion, the SURVIVE trial demonstrated no survival difference between levosimendan and dobutamine during long-term follow-up despite evidence for an early reduction of plasma BNP level for levosimendan. These findings may be related to the short duration of treatment in the trial, a selective effect of levosimendan in specific subgroups, or the lack of a true difference between the 2 drugs. Further studies are needed to distinguish between these possibilities.