Impairment of hemodynamics is one of the hallmarks of chronic heart failure (CHF), leading to neurohumoral activation and autonomic dysfunction (1). Phosphodiesterase (PDE) inhibitors have been shown to possess beneficial hemodynamic effects, but during long-term treatment, they were found to be associated with an adverse outcome (2). Two potential explanations for increased mortality during PDE-inhibitor treatment are the positive inotropic effects of these drugs and their neurohumoral activating influence (3,4).
Saterinone (BDF 8634) is a potent, selective PDE type III inhibitor, with additional α1-blocking properties (5,6), which was developed by Beiersdorf in Germany. Experimental studies have shown that the drug primarily acts as a vasodilator with mild positive inotropic properties; in addition, the drug inhibits platelet aggregation (6). In healthy volunteers, saterinone was found to induce peripheral vasodilatation, and the drug exerted a positive inotropic effect, whereas there was a dose-dependent increase observed in left ventricular ejection fraction (7,8). However, in isolated papillary muscle strips from patients with moderate to severe CHF, saterinone did not increase force of contraction, which might imply that the drug did not exert a significant positive inotropic effect in patients with CHF (9). In the only clinical study in patients with CHF, saterinone increased cardiac index (CI) and decreased filling pressures, but this uncontrolled, open-label study was published only in abstract form (10).
Saterinone therefore has a different mechanism of action than conventional PDE inhibitors, and it may thus have a different hemodynamic and autonomic profile. Because the effects of saterinone have not been well established in patients with CHF, we conducted a double-blind, placebo-controlled study, in which both the hemodynamic and the neurohumoral effects of this compound were examined. For the purpose of this study, patients with moderate to severe CHF, New York Heart Association (NYHA) functional class III-IV, were eligible. Invasive hemodynamic measurements, by using right-heart catheterization were performed, as well as measurement of plasma neurohormones and analysis of heart rate variability (HRV), to study drug influences on neurohumoral activation and autonomic tone.
Patients (aged 18-75 years) were eligible for the study if they had clinically stable NYHA class III-IV CHF, despite maximal CHF medication including angiotensin-converting enzyme (ACE) inhibitors, diuretics, digoxin, short-acting nitrates, or a combination of these. In addition, pulmonary capillary wedge pressure (PCWP) during right-heart catheterization (i.e., before the start of infusion) had to be >10 mm Hg. Exclusion criteria were recent (<3 months) cardiovascular surgery or myocardial infarction, unstable angina, symptomatic valvular dysfunction, presence of clinically significant ventricular arrhythmias, conduction disturbances, pacemaker, or any other relevant systemic illness. Patients with severe hypertension [diastolic blood pressure (DBP) >114 mm Hg] or hypotension [systolic blood pressure (SBP) <90 mm Hg] also were excluded. No washout period was required for ACE inhibitors, diuretics, and digoxin, to avoid hemodynamic deterioration, but short-acting nitrates were not allowed to be taken on the morning of the study. The protocol was performed according to the guidelines established in the Declaration of Helsinki and was approved by the Institutional Review Board of the three participating hospitals. Written informed consent was obtained from each patient before the study.
The protocol was a randomized, double-blind, placebo-controlled, parallel-group comparison. The ratio of patients with active medication to placebo was 2:1, and randomization was performed in blocks of six. Saterinone was administered in a dose of 2 mg/kg/min i.v. for 180 min. This dose was chosen on the basis of previous studies in humans (8,10). On the day of the study, blood pressure was measured, and baseline blood samples were taken for routine laboratory tests, saterinone plasma concentrations, and plasma neurohormones. Thereafter, a Swan-Ganz thermodilution catheter was introduced and advanced into the pulmonary circuit (11). An intraarterial catheter also was inserted for blood pressure monitoring. Subsequently, patients were left to recover before baseline hemodynamic measurements were taken. Hemodynamic measurements included HR, arterial SBP and DBP, right atrial pressure (RAP), and PCWP. Cardiac output (CO) was determined by the thermodilution technique and was automatically computed and recorded. Cardiac index (CI), stroke volume (SV), pulmonary vascular resistance (PVR), and systemic vascular resistance (SVR) were derived by conventional formulae. Hemodynamic measurements were performed at baseline and during drug infusion at 30, 60, 120, and 180 min after the start of the study. After 180 min, drug administration was discontinued.
Blood samples for plasma norepinephrine, epinephrine, and plasma renin activity were taken at baseline and 30, 120, and 180 min after the start of infusion, and again 60 and 180 min after the end of infusion. Plasma norepinephrine and epinephrine concentrations were measured by using high-pressure liquid chromatography with electrochemical detection after prior extraction. Plasma renin activity was determined by using a competitive binding 125I-radioimmunoassay (RIA) of angiotensin I with a commercial kit (Incstar, Stillwater, MN, U.S.A.). All measurements were performed in a blinded manner in a central core laboratory (Kerckhoff Klinik, Bad Nauheim, Germany). Normal values in this laboratory were 133-283 pg/ml for plasma norepinephrine, 26.9-76.9 pg/ml for plasma epinephrine, and 0.08-3.26 ng/ml/h for plasma renin activity.
Electrocardiographic (ECG) Holter monitoring
Holter monitoring was performed 24 h before the study and again during the study to score the number of supraventricular and ventricular ectopic beats. In this manner, we were able to compare similar time points for 6 h during the study day (3 h during infusion and 3 h thereafter) with the same time span of the previous day. To evaluate possible proarrhythmia, the Morganroth criteria were used (12). Holter ECGs were recorded on a three-channel (V1, V5, and aVF) Holter recorder Series 8500 (Marquette Electronics Inc. Milwaukee, WI, U.S.A.).
HRV analysis was performed on a Holter analysis system (Marquette Series 8000; Marquette Electronics), as previously described in detail (13), according to recently published guidelines (14). In short, recordings of patients who had sinus rhythm and <15% of ectopic beats or noise could be analyzed. The data file of RR intervals was transported to a personal computer, and a software packet was used for HRV analysis, analyzing HRV divided in 5-min segments. Before calculation of HRV, episodes with noise and ectopic beats were substituted by keeping the previous normal-to-normal interval constant throughout that period. Time-domain parameters were calculated by using standard methods. The average value of the interval series was subtracted before spectral analysis was performed by using a discrete Fourier transformation algorithm. Total-frequency power was calculated as the power between 0.04 and 0.40 Hz. Low-frequency power was defined as the power between 0.04 and 0.15 Hz, and high-frequency power as the power between 0.15 and 0.40 Hz. Normalized low and high frequency was calculated as low (or high) frequency × 100/total frequency, and is expressed in normalized units (nu) (Table 1). HRV analysis was performed in a central core laboratory (University Hospital Groningen, The Netherlands) by one single analyst, who was unaware of the study medication.
For hemodynamic, neurohumoral, and electrophysiologic changes over time, repeated analysis of variance (ANOVA) was used, with last-value-option substitution of missing values. For comparison of end-point and baseline HRV values, a t test for paired samples was used, and for the between-groups HRV comparison, a t test for independent samples. A p value of <0.05 was considered statistically significant. Data are presented as mean ± standard deviation.
The study was conducted in three clinical centers (Northwick Park Hospital, Kerckhoff Klinik, University Hospital Groningen), and 36 patients (saterinone, n = 24; placebo, n = 12) were included in the study. CHF was caused by coronary artery disease in most patients. At baseline, there were no significant differences between the two groups with respect to demographic parameters; mean age of patients was 59 ± 10 years, and there were 31 men and five women. Of the 36 patients, 35 had sinus rhythm, and one had atrial fibrillation. Six patients did not complete the study according to the protocol and were prematurely withdrawn from the study (saterinone, n = 6, placebo, n = 0). All these six patients had clinically significant hypotension, which prompted the attending physician to discontinue study medication. In three of them, this occurred 30-60 min after start of saterinone infusion, and in the three others, symptoms did not appear until 2-2.5 h after the start. Because these symptoms (intolerable decrease of blood pressure) were most probably caused by saterinone and had to be considered typical side effects, these patients have been included in the data analysis. Other side effects were not observed during and after the study.
Saterinone plasma concentrations
A general linear tendency to increased plasma concentrations during the infusion period was observed. Saterinone plasma concentrations increased to 133 ± 37 ng/ml after 30 min, to 141 ± 41 ng/ml after 1 h, and to 193 ± 58 ng/ml after 3 h of infusion. Saterinone plasma concentration decreased to 35 ± 15 ng/ml at 3 h after the end of infusion.
As compared with placebo, SVR significantly decreased (Table 2) with saterinone, which was accompanied by a decrease in blood pressure (Fig. 1). After saterinone infusion. CO was found to be slightly increased (0.3 L/min; p = NS), but because of the rather large differences between patients, the changes in CO, CI, and SV did not reach statistical significance in the group comparison. Filling pressures also decreased after saterinone, but this was statistically significant only for PCWP, not for RAP. HR tended to increase with saterinone (Fig. 2; p = 0.05).
With plasma norepinephrine, a considerable variance between the patients was observed (Fig. 3). In the placebo group, plasma norepinephrine increased from 240 ± 319 to 371 ± 269 pg/ml at the end of infusion and decreased again to 300 ± 336 at 24 h after the start of infusion (p = NS). In the saterinone-treated patients, baseline plasma norepinephrine was 212 ± 217 pg/ml, increased to 281 ± 251 pg/ml at the end of infusion, and remained at 279 ± 326 pg/ml at 1 day after the start of saterinone infusion (p = NS). Plasma epinephrine concentrations were not elevated at baseline. During the infusion, epinephrine slightly increased in both groups (p = NS vs. baseline, and between groups). Plasma renin activity was elevated in both groups at baseline (placebo, 16 ± 19 ng/ml/h; saterinone, 13 ± 16 ng/ml/h). During infusion, plasma renin activity decreased in both groups (p = NS vs. baseline) and returned to baseline values thereafter (p = NS between groups).
Arrhythmias during ambulatory ECG monitoring
Compared with the baseline Holter, the incidence of ventricular ectopic beats remained unchanged in the placebo (2.51 and 2.09%; p = NS) and in the saterinone group (2.95 and 2.98%; p = NS). The incidence of supraventricular ectopic beats also was unaffected by placebo (0.86 and 0.94%) and by saterinone (1.73 and 1.34%). When the Morganroth criteria were applied, three patients had a greater than threefold increase in the number of ectopic beats and were thus classified as having proarrhythmia (saterinone, n = 2; placebo, n = 1; p = NS).
In 24 patients analysis of HRV (Fig. 4) was possible (saterinone, n = 15; placebo, n = 9). In the other 12 patients, HRV analysis was technically impossible. HRV parameters at baseline were impaired in all patients. During saterinone infusion, both time-domain and frequency-domain parameters were not significantly affected. HRV parameters in the placebo group were also not significantly changed, when compared with its baseline. However, when the two treatment groups were compared, saterinone and placebo were significantly different for several HRV parameters measured.
Our data show that saterinone, a new PDE inhibitor with additional α1-blocking properties, reduces filling pressures and systemic blood pressure in patients with moderate to severe CHF. This hemodynamic effect is not accompanied by an adverse effect on the autonomic nervous system, as demonstrated by assessment of plasma neurohormones and HRV analysis. In particular, the HRV data suggest that the hemodynamic influence of saterinone is not related to an increase in sympathetic tone (LFnu) or a decrease in parasympathetic tone (HFnu), despite a nonsignificant increase of HR. Further, the dose of saterinone used in this study led to significant hypotension, leading to drug discontinuation in six (25%) of the 24 patients treated. This potentially detrimental blood pressure reduction was possibly related to the relatively high dosage of saterinone infusion (2 mg/min/kg) in this study.
The observed hemodynamic changes are consistent with a potent vasodilator effect, which is the result of the combined α1-blocking and PDE-inhibiting properties of the drug. After saterinone infusion, a significant decrease of SBP, DBP, and SVR was observed, but the CI remained unchanged. Further, HR tended to increase, particularly in the later stages of the study. In a previous uncontrolled clinical trial in patients with CHF (10), HR increased (from 98 to 105 beats/min) only when plasma saterinone concentrations reached levels >300 ng/ml. In our study, saterinone concentrations increased gradually during infusion, but the highest mean plasma level measured was <200 ng/ml, whereas HR tended to increase. Further, in the previous study (10), CI significantly increased, but this effect was mostly found with the higher plasma concentrations (maximal effect, 2.3 to 2.9 L/min/m2). Effects on filling pressures and BP were similar in the two studies.
Heart rate trended to increase in our study, whereas HRV was not affected. These somewhat paradoxical findings were reported before in a similar study with flosequinan (15). In the study of Binkley et al. (16), flosequinan significantly increased HR, while at the same time HRV, especially the high-frequency component (which reflects parasympathetic tone) increased. The authors of the flosequinan study suggested a direct chronotropic effect of flosequinan, which may possibly also be the case in our study with saterinone. HRV parameters in patients with CHF are related to the degree of hemodynamic impairment and clinical severity of the disease (16). Improvement of hemodynamics might be expected to lead to improvement or normalization of HRV parameters (17,18). In our study, HRV parameters were impaired at baseline, but despite an effect on filling pressures, saterinone failed to have a favorable effect on HRV. In fact, placebo-treated patients tended to improve in the course of the study, which finding may be related to other, nonpharmacologic factors (such as a reduction in stress). Interestingly, in a previous study from our institution with a similar compound, isomazole (a PDE inhibitor with calcium-sensitizing properties) was found to improve HRV parameters, but in that study, cardiac output significantly increased (19). As impairment of HRV is reported to be correlated with increased mortality in CHF (20), it might be speculated that if a beneficial effect of a particular drug on HRV can be proven, this may correlate with a favorable long-term effect. Therefore, assessment of HRV effects is potentially important when new drugs are introduced for CHF treatment.
In our study, only one dose of saterinone was examined, and it cannot be excluded that other doses might have had a more pronounced hemodynamic and autonomic effect. Further, although we do not have a certain explanation for the observed HRV improvement in the placebo group, modification of autonomic balance caused by 3 h lying flat may be at least partly responsible. Still, this finding emphasises the importance of placebo control groups in clinical studies.
PDE inhibitors are not used any more for the long-term treatment of patients with CHF because of their reported negative effects on mortality (2). The increased mortality may be related to the additional neurohumoral activation caused by PDE-inhibitor treatment. In our study, saterinone was found not to aggravate autonomic dysfunction, although it tended to increase HR and exerted potent vasodilator effects. Further (comparative) studies with the currently used medications, like dobutamine and dopamine, and conventional PDE inhibitors would be required to determine whether saterinone may have a place in the (short-term) treatment of acute CHF.
Acknowledgment: This study was supported by a grant from Beiersdorf-Lilly GmbH, Hamburg, Germany.
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