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Vol. 289, Issue 1, 565-571, April 1999
Division of Cardiology (H.P.B.-L., D.W., W.K.), Institute of Clinical Chemistry (F.E.M.), and Department of Internal Medicine (F.F.), University Hospital Zurich, Switzerland
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Abstract |
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 Top
 Abstract
 Introduction
Materials and Methods
Results
Discussion
References
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Angiotensin-converting enzyme (ACE) inhibitors are established as first-line therapy in chronic heart failure (CHF). However, little is known about the dosage-plasma-level relationship of ACE inhibitors in CHF and its relation to drug-induced adverse effects. We investigated 45 patients (age 55 ± 10 years) with stable CHF who presented with a maintenance dosage of enalapril of either 5 mg b.i.d. (E10, n = 16), 10 mg b.i.d. (E20, n = 18), or 20 mg b.i.d. (E40, n = 11). This dosage was changed three times to treat all patients with lower, higher, and, finally, the initial dosage for 4 weeks each. Patients were examined clinically, by questionnaire, and by spiroergometry. In addition, neurohormones (atrial and brain natriuretic peptide and norepinephrine), enalaprilat trough levels, and serum potassium and creatinine were measured. Enalaprilat trough levels differed significantly between the three groups at study entry but also varied markedly within each group. In addition to the dose of enalapril, serum creatinine, severity of CHF, basal metabolic rate, and body weight significantly influenced enalaprilat trough levels (R2 =.84, p < .001). Within-patient comparisons revealed that serum creatinine (107 ± 26 versus 102 ± 20 µmol/liter) and potassium (3.8 ± 0.4 versus 3.7 ± 0.3mmol/liter) were higher, cough was more common (scored on a scale of 0-8: 1.7 ± 2.1 versus 1.4 ± 1.8), and blood pressure was lower (systolic, 112 ± 14 versus 117 ± 13 mm Hg; diastolic, 66 ± 9 versus 69 ± 11 mm Hg) on the highest than on the lowest enalaprilat trough level (all p < .05). Highly variable enalaprilat trough levels and the fact that adverse effects were more common on high enalaprilat trough levels provide a rationale for individually adjusting ACE-inhibitor dose in case of adverse effects.
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Introduction |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Despite
the clear evidence that angiotensin-converting enzyme (ACE) inhibitors
improve survival, only 30 to 50% of patients with chronic heart
failure (CHF) actually receive these drugs (Philbin et al., 1996
;
Stafford et al., 1997; Barron et al., 1998). Of those receiving ACE
inhibitors, the majority in clinical practice receive doses lower than
the dosage used in the large clinical trials (Luzier et al., 1998). The
reasons for this underuse are not clear but may be related to a lack of
familiarity with the use of ACE inhibitors in CHF and concerns about
their safety and adverse reactions, especially hypotension, renal
failure, hyperkalemia, and cough (Bart et al., 1997; Deedwania, 1997;
Houghton and Cowley, 1997). Similar concerns seem to be the reason for
the use of low doses of ACE inhibitors, even though this has not yet
been addressed directly.
One possible reason for ACE-inhibitor intolerability may be higher
plasma levels in some patients than in others because of differences in
pharmacokinetics. It is well known that renal function is a major
determinant of plasma levels for most ACE inhibitors and their active
metabolites, which are excreted mainly by the kidneys (Kelly et al.,
1986). In addition, age may play an important role in the elimination
of ACE inhibitors (Hockings et al., 1986).
However, it is largely unknown whether there is a relationship between
plasma levels of ACE inhibitors and their adverse events during chronic
therapy of patients with CHF. In recent years, some studies found a
relationship between blood pressure and ACE-inhibitor dosage even
though orthostasis was not related to dosage in these studies (Davidson
et al., 1996; Pacher et al., 1996). Creatinine clearance was lower on a
high dose than on a low dose of lisinopril (Davidson et al., 1996). On
the other hand, changes in serum creatinine were not related to dosage
in long-term treatment with enalapril (Pacher et al., 1996). Similarly,
reports on the dose-effect relationship of ACE inhibitors with respect
to cough are conflicting (Yesil et al., 1994; Yeo et al., 1995).
Therefore, we conducted a within-patient, crossover study with different doses of enalapril in patients with stable, mild to moderate CHF who had been treated previously with the drug for at least 3 months. It was investigated whether plasma trough levels of enalaprilat could be predicted by different clinical and biochemical variables. Additionally, we tested whether there was a relationship between enalaprilat plasma level and adverse effects.
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Materials and Methods |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Patient Population.
The study comprised 45 patients (43 male, 2 female) aged 33 to 74 years (mean, 55 ± 10 years) with
mild to moderate CHF secondary to coronary artery disease in 26 (58%),
dilated cardiomyopathy in 16 (35%), and valvular heart disease in 3 (7%) patients. All patients had an ejection fraction 
40% (mean
28 ± 7%) and were in stable condition for at least 3 months. ACE
inhibition had been started at least 3 months before inclusion into the
study. Drug therapy was unchanged for at least 1 month. Serum
creatinine level had to be lower than 150 µmol/liter to be included
in the study. The protocol was approved by the local Ethics Committee, and patients gave informed consent to participate in the study.
Study Design.
Patients were divided into three groups
according to the dose of enalapril they were receiving before inclusion
into the study: the first group (E10, n = 16) was
receiving 5 mg enalapril b.i.d., the second (E20, n = 18) was being treated with 10 mg b.i.d., and the third (E40,
n = 11) was on 20 mg b.i.d. As illustrated in Fig.
1, patients were assessed four times by
clinical examination, and serum levels of creatinine, electrolytes, and
enalaprilat were determined. Additionally, spiroergometry and
measurement of various neurohormones were performed. Thus, the first
examination (baseline) was carried out while patients received their
initial enalapril dose. Thereafter, the dosages were changed twice in a
single blinded manner using identical-looking capsules prepared by the
hospital pharmacy to treat all patients with the two other dosages for
4 weeks each (Fig. 1). At the end of each period, examinations were
repeated. Finally, the initial dose was restored, and, after another 4 weeks of open therapy, the last examination was performed.
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Evaluation Criteria. Patients were examined in the morning between 7 and 9 AM. All drugs were withheld on the morning of examination. Patients were advised to take enalapril in the morning between 7 and 9 AM and in the evening between 7 and 9 PM. Adverse effects due to enalapril therapy were assessed by a standard questionnaire referring to the period of 4 weeks before each examination. Cough (dry and productive) and orthostasis defined as dizziness felt by the patients upon standing were considered to be ACE-inhibition-related adverse events. Cough was rated by the patients (questionnaire) on an arbitrary scale from 0 (no) to 8 (very severe). Angioedema was not observed. Blood pressure was measured while supine and standing. Blood samples were taken in the supine position.
Ergospirometry. Exercise testing was performed on a treadmill using a ramp protocol. ECG was monitored continuously with a CASE 12 monitor (Marquette Corporation, Milwaukee, WI), and blood pressure was measured before, during, and after the exercise test by standard sphygmomanometer. Gas exchange was assessed, breath by breath, using a CPX/D system (Medical Graphics Corporation, St. Paul, MN). Oxygen was analyzed by a rapidly responding zirconia fuel cell and carbon dioxide was analyzed by an infrared analyzer. Flow measurements were performed using a disposable pneumotachograph.
Patients started walking after reaching a steady state of gas exchange for at least 1 min while standing quietly on the treadmill. Initially, they walked at a speed of 1.0 mph with an elevation of 6% for 6 min corresponding to approximately 0.5 W/kg b.wt. Thereafter, both speed and elevation were increased to augment work load by 0.15 W/kg b.wt./min until exhaustion. Work load was assessed by calculating the power to overcome the elevation (speed × tan[grade] × g) and to cover the distance. Horizontal energy exposure was estimated by rearrangement of the formula by the American College of Sports Medicine (American College of Sports Medicine, 1986).
Laboratory Measurements.
Venous blood was collected into
chilled tubes containing EDTA and aprotinin (500 kU/ml blood) for
measurement of natriuretic peptides and into tubes containing
lithium-heparin for determination of potassium, creatinine,
norepinephrine, and enalaprilat. Plasma was separated immediately using
a refrigerated centrifuge and stored at 
80°C until measurement.
Potassium and creatinine were measured within 1 h after blood had
been taken. All analyses were performed by individuals who were blinded
to the treatment.
). In
brief, the extraction system makes use of the complex formation in
alkaline medium between diphenylborate and the diol group of
norepinephrine in combination with ion-pair formation. The
concentration of plasma norepinephrine was determined by HPLC using a
nucleoside 7-C18 column and electrochemical detection.
Enalaprilat Assay. Analysis of enalaprilat was performed by the Clinical and Biochemical Pharmacology Laboratory (University of Glasgow, Glasgow, Scotland). Enalaprilat was measured by means of a nonspecific, indirect HPLC-UV method. The endogenous ACE activity of 100 µl of plasma was inactivated by heating at 60°C for 1 h. Then, 50 µl of diluted rabbit sera, i.e., exogenous ACE, was added and the mixture was incubated with 400 µl of the ACE substrate hippuryl-histidyl-leucine (5 mM in 100 mM phosphate buffer, pH 8.3). After 45 min of incubation at 37°C, the enzymatic reaction was terminated by the addition of 100 µl of HCl. The hippuric acid produced was extracted using 1 ml of ethyl acetate, after the addition of 100 µl of internal standard (500 µM phthalic acid) and 50 mg NaCl. After centrifugation, 500 µl of the organic phase was separated into clean tubes and evaporated to dryness at 50°C under a stream of air. The desiccated extracts were reconstituted with 150 µl of mobile phase consisting of 20 mM KH2PO4, pH 4.0, and methanol, in a ratio of approximately 95:5, transferred to appropriate vials, and injected into HPLC for analysis.
The compounds of interest were separated on an analytic cartridge column (10 cm × 4.6 mm i.d.) packed with Spherisorb ODS 1, with a particle size of 5 µm. The system was fitted with a precolumn packed with Lichroprep RP-18, with a particle size of 25 to 40 µm. Eluted compounds were monitored by UV at 228 nm. UV absorption to the compounds was recorded by a Shimadzu CR-3A Integrator.Statistical Analyses. Values are expressed as frequencies and means ± S.D. or S.E. as indicated. To evaluate dose dependence of enalaprilat plasma levels, multifactorial ANOVA using a hierarchical method was performed. Pearson correlation was used for comparison between continuous variables, and Spearman rank was used for ordinal variables. Comparisons between two groups were performed using unpaired Student's t test or Mann-Whitney U test, as appropriate. Within-patient comparison was performed using paired t test, or Wilcoxon rank-sum test for two measurements, and ANOVA for repeated measurements or Friedman ANOVA, as appropriate.
A two-tailed significance level of 0.05 was considered to be statistically significant. All analyses were performed using a commercially available statistical package (SPSS for Windows 6.0).| |
Results |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The baseline characteristics are summarized in Table 1. Exercise capacity and left ventricular ejection fraction were moderately impaired and neurohormones were elevated. There were no statistically significant differences between the three groups.
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Relationship Between Enalapril Dosage and Enalaprilat Trough Level
As expected, enalaprilat trough levels differed significantly
between the three groups at study entry (E10: 20.7 ± 21.9 ng/ml; E20: 25.0 ± 12.0 ng/ml; E40: 48.1 ± 33.9 ng/ml;
p < .01). However, as shown in Fig.
2, enalaprilat levels varied
markedly within each group. This was also true when only 40 (89%)
patients were considered in whom enalaprilat trough levels followed the
direction of dosage change.
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ANOVA revealed that various factors influenced the enalaprilat trough level in addition to the dosage of enalapril (Table 2). Age did not influence enalaprilat serum levels (p > .1).
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Together with dosage of enalapril, ANOVA including covariates (p < .1 in former model) explained 84% of the variance of enalaprilat levels in these patients (R2 = .84, p < .0001). Apart from dosage of enalapril (F = 30.0, p < .001), serum creatinine (increase in plasma enalaprilat of 0.74 ng/ml per 1 µmol), oxygen consumption at rest per kg body weight (decrease in plasma enalaprilat of 10.0 ng/ml per 1 ml/kg per min), body weight (decrease in plasma enalaprilat of 0.38 ng/ml per 1 kg), BNP level (increase in plasma enalaprilat of 0.23 ng/ml per 10 pg/ml), and physical signs of CHF (increase in plasma enalaprilat of 16.0 ng/ml if present) independently influenced plasma enalaprilat levels. Mean enalaprilat trough level after consideration of covariates was 14.2 ng/ml in patients taking 10 mg enalapril daily, 31.8 ng/ml in patients taking 20 mg enalapril daily, and 54.3 ng/ml in patients taking 40 mg enalapril daily (Fig. 2).
Enalapril Dosage and Adverse Effects
At baseline, there was no relationship between dosage of enalapril and blood pressure in supine or standing position, and orthostasis was equally common in all three groups. Subjective severity of cough as assessed by cough score was highest in the E40 group and lowest in the E10 group (E40: 3.1 ± 3.0; E20: 1.8 ± 1.8; E10: 0.9 ± 1.0; p < .05).
Within-patient comparisons of blood pressure, renal function, and adverse effects were performed when enalapril doses were 40 mg and 10 mg. There was no significant difference in the change of cough throughout the study on various enalapril doses; 16% of the patients had more cough on low dose and 28% had more cough on high dose of enalapril (p > .1). Orthostatis was more common on enalapril 40 mg daily. Systolic blood pressure in supine position was slightly lower on enalapril 40 mg daily than on 10 mg (Table 3).
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Changes in serum creatinine and potassium levels are depicted in Fig.
3. Doubling of enalapril (i.e., 10 mg to
20 mg and 20 mg to 40 mg) did not result in a significant increase in
serum potassium or creatinine. However, quadrupling of the dose from 10 to 40 mg per day resulted in a significant reduction of renal function
in the E40 group. Reduction of enalapril decreased serum potassium
significantly.
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Thirty-seven patients completed the whole protocol. Three patients needed early restoration of initial high dose of enalapril because of worsening of CHF. In addition, five patients had to be withdrawn from the study for various reasons: worsening of CHF in three, two after up- and one after down-titration; temporary anuria in one after up-titration and concomitant use of nonsteroidal anti-inflammatory drug; exercise-induced ventricular tachycardia in one after down-titration. Accordingly, when considering all up-titrations, 3 of 74 (4%) were not tolerated whereas 5 of 50 (10%) down-titrations were accompanied by serious adverse events (p = 0.08). Enalaprilat trough levels at study entry were significantly higher in patients not tolerating up-titration in the E10 and E20 groups (52 ± 30 ng/ml versus 20 ± 13 ng/ml, p < .05) whereas this was not the case in patients not tolerating down-titration in the E40 group (51 ± 48 versus 46 ± 28 ng/ml, p > .1).
Relationship Between Enalaprilat Trough Level and Adverse Effects
Baseline Measurements.
There was a weak negative correlation
between enalaprilat trough level and diastolic blood pressure
(r = 0.38, p = 0.01, supine
and standing) whereas systolic blood pressure was not significantly correlated to enalaprilat trough level. Patients complaining about orthostasis tended to have higher enalaprilat trough levels (44.4 ± 33.4 ng/ml versus 24.2 ± 19.0 ng/ml, p = 0.06). There was a significant relationship between cough and
enalaprilat trough level (r = 0.42, p < .01). Patients without cough had significantly lower enalaprilat trough levels than patients with cough (any cough:
18.3 ± 15.3 versus 34.2 ± 27.3 ng/ml, p < .05; dry cough: 18.3 ± 14.4 versus 36.7 ± 28.3 ng/ml,
p < .01; productive cough 19.4 ± 15.1 versus
42.4 ± 29.7 ng/ml, p < .01). These
differences were independent of other parameters, although there was a
significant correlation between the symptoms and physical signs of CHF
and cough. Although two-thirds of the patients (n = 30) coughed, only one third of those with cough (n = 10) felt disturbed by it.
Effects of Changes in Enalaprilat Trough Level.
Within-patient
comparisons of blood pressure, renal function, and adverse effects were
performed when enalaprilat trough level was lowest (15.1 ± 16.0 ng/ml) and highest (56.2 ± 29.7 ng/ml, p < .001). Orthostasis and cough were more common on the highest than on
the lowest enalaprilat trough level. Only 12% reported more cough on
the lowest level whereas 40% had less cough (p < .05). Interestingly, neurohormones and exercise capacity changed the
most between lowest and highest enalaprilat trough levels in those 12%
of patients who showed a decrease in cough score on the highest
enalaprilat trough level compared with the other patients (ANP:
136 ± 146 versus 8 ± 82 pg/ml, p = 0.08; BNP: 127 ± 152 versus 21 ± 84 pg/ml,
p = 0.05; norepinephrine: 2.3 ± 3.1 versus
0.5 ± 1.8 nmol/liter, p = 0.20; peak
VO2: 2.1 ± 2.0 versus 0.2 ± 1.9 ml/kg/min, p < .05), indicating that the effect of
enalaprilat trough level on severity of cough possibly was attenuated
by improved cardiac function.
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Discussion |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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The results of this study indicate that enalapril dosage and enalaprilat trough level influence blood pressure, renal function, and cough in patients with CHF. A broad variation of trough levels of enalaprilat was found irrespective of the dose of orally taken enalapril. This variation could be explained largely by body weight, renal function, basal metabolic rate (oxygen consumption at rest), and severity of CHF (physical signs of CHF and plasma level of BNP). As the results demonstrate a relationship between enalapril dosage and trough levels and adverse effects, they provide a rationale for individualized adjustment of ACE-inhibitor dosage in chronic CHF patients who exhibit ACE-inhibitor-related adverse effects.
Variations in Enalaprilat Trough Level.
Enalaprilat, the
active metabolite of enalapril, is known to be excreted mainly by the
kidneys. Accordingly, the plasma level of enalaprilat is increased in
patients with renal failure (Kelly et al., 1986; Todd and Heel, 1986).
Although we excluded patients with moderate to severe renal failure,
serum creatinine level was independently related to enalaprilat trough
level. As expected, body weight also influenced enalaprilat trough
levels significantly. However, two additional factors, i.e., basal
metabolic rate and severity of CHF, influenced enalaprilat trough
levels. Together with the dosage, these four factors explained the
majority of variation in enalaprilat trough levels in this population
of patients with chronic CHF.
; Gerckens et al., 1989; Cody, 1993).
Oxygen consumption at rest was an additional factor determining
enalaprilat trough level in the study patients. Although we did not use
standardized conditions for indirect calorimetry, an effect of basal
metabolic rate on enalaprilat plasma levels might be a cause for this
relationship. To our knowledge, this was neither described nor
investigated in the past. In addition, our study design did not allow
to investigate directly such a relationship. Although a fortuitous
finding cannot be excluded, our results may be interpreted as
metabolism of enalapril and/or elimination of enalaprilat being related
to basal body metabolism. Whether this is a result of hemodynamic
changes associated with CHF remains to be investigated.
In contrast to our results, previous studies found age to be related to
enalaprilat excretion (Hockings et al., 1986). However, it has been
suggested that this relation mainly reflects decreased renal function
in older age. That most of our patients were less than 65 years of age
and there was no relationship between age and serum creatinine might be
the reason why we did not find any influence of age on enalaprilat
trough levels.
Relationship Between Enalaprilat Trough Level and Adverse
Effects.
Apart from angioneurotic edema and other rare adverse
effects, ACE inhibition can cause hypotension with associated symptoms, cough, renal dysfunction, and hyperkalemia (Moyses and Higgins, 1992;
Messner Pellenc et al., 1995). Hypotension is observed particularly during initiation of therapy. Originally, initiation of ACE inhibition with high doses in patients with CHF had led to major concerns about
tolerability of these drugs in CHF (Packer et al., 1986). In spite of
lower incidence of first-dose hypotension with low doses and avoidance
of excessive water and salt depletion (Flapan et al., 1992; Hasford et
al., 1993), these concerns may have contributed to the underuse of ACE
inhibitors in patients with CHF (Deedwania, 1997) despite the clear
benefit of these agents regarding survival (The SOLVD Investigators,
1991; Pfeffer et al., 1992; Garg and Yusuf, 1995). Although hypotension
is widely accepted to be dose-related for the first dose (The CONSENSUS
Trial Study Group, 1987), this relationship is less well defined during
long-term therapy. Our data suggest that there is a relationship
between resting blood pressure and enalaprilat trough level and
enalapril dosage, respectively, during chronic therapy. This is in
agreement with other studies: 20 mg of lisinopril led to 3- to 6-mm Hg
lower supine blood pressure than 5 mg in a recent crossover trial
(Davidson et al., 1996), and 20 mg b.i.d. enalapril lowered the supine
diastolic blood pressure more than 5 mg b.i.d. in a parallel trial
(Pacher et al., 1996).
), is another limiting factor for the use of
ACE inhibitors. Reported frequencies varied from less than 1% to more
than one-fourth of the study population (Fuller, 1989; Israili and
Hall, 1992), and 3 to 6% discontinued therapy because of cough (Yeo et
al., 1991; Desche et al., 1993; Fletcher et al., 1994; Pitt et al.,
1997). The underlying mechanism is probably the inhibition of kininase
II with accumulation of kinins, Substance P, and prostcyclin and,
therefore, a class effect (Overlack, 1996). However, the dose-effect
relationship is not well defined: although a small study reported the
severity of cough being dose-related (Yeo et al., 1995), others did not
find such a relationship (Yesil et al., 1994). In our study, cough
occurred in two-thirds of the patients and was related to enalapril
dosage and enalaprilat trough level and changed with changes in
enalapril dosage and enalaprilat trough levels. However, the finding of
a relationship between cough and the severity of CHF suggests that CHF
is an important contributor to coughing even in patients under stable
conditions. Thus, an increase in the dose of ACE inhibitor may diminish
cough by improvement of CHF in some patients whereas
ACE-inhibitor-induced cough may be decreased by a dose reduction in
others. It is important to note that in our study population, the type
of cough did not allow distinction of the underlying cause because dry
and productive cough was equally affected by enalapril dosage and
enalaprilat trough level.
Serum potassium and serum creatinine were slightly, although
significantly, higher at high than at low enalaprilat levels, which is
in agreement with some (Davidson et al., 1996) but not all previous
studies (Pacher et al., 1996). However, despite a significant worsening
of renal function in up to one-third of patients with CHF after
initiation of ACE inhibitor therapy, most patients show a only mild
increase in serum creatinine, and ACE inhibitor therapy does not have
to be discontinued in these patients (Sica and Deedwania, 1997). In
fact, a recent randomized, placebo-controlled study showed that renal
function may be significantly improved by ACE inhibition in patients
with renal dysfunction over a course of 3 years despite an initial
increase in serum creatinine of 10 to 15% (Maschio et al., 1996). In
our study, severe renal failure was observed in only one patient with
concomitant use of nonsteroidal anti-inflammatory drug, with prompt
recovery after cessation of this drug and enalapril. Nevertheless,
quadrupling the dose within 1 week led to a significant increase in
serum creatinine and doubling was generally well tolerated. An increase
in enalapril dose did not lead to hyperkalemia. In contrast,
hypokalemia was more common on the lowest than on the highest
enalaprilat level, thereby possibly augmenting the risk of serious
tachyarrhythmias (Packer and Lee, 1986). Although concomitant therapy
with diuretics can explain the relatively high frequency of
hypokalemia, reduction of ACE inhibitor doses further increased the
risk of hypokalemia in our patients.
Limitations. There are several limitations of our study. First, our patients entered into the trial on different dosages of enalapril. Thus, it could be argued that clinical indications led to different dosages. However, baseline data were comparable between the three groups.
Second, our study was single-blinded only. However, those who performed analysis of plasma samples were unaware of the actual dose of enalapril. In addition, the patients filled out the questionnaires without being influenced by study personnel. Third, it is known that basal metabolic rate is increased in patients with severe CHF (Obisesan et al., 1997). Because we investigated only
patients with mild to moderate chronic CHF, it cannot be excluded that
the relationship between basal metabolic rate as well as CHF and
enalaprilat trough level may be different in patients with more
advanced or acute CHF. Additionally, it remains unknown whether these
relations are independent of renal function because we determined serum
creatinine only rather than creatinine clearance. Nevertheless, our
results suggest that enalaprilat serum levels are predictable to a
certain extent, making dose-finding of enalapril in patients with CHF easier.
Conclusions. Our data show a relationship between enalapril dosage and enalaprilat trough level and side effects in patients with CHF under chronic ACE inhibition. Despite that, an enalapril dose of 40 mg daily was well tolerated by most patients, and serious adverse events (i.e., worsening of CHF, anuria, serious arrhythmia) tended to be more common after downward than after upward titration of enalapril. Some of these adverse effects observed during up-titration seem to be related to high enalaprilat trough levels.
The results, therefore, support an approach of individual adjustment of ACE-inhibition dosage in the chronic CHF therapy rather than discontinuation in patients suffering from ACE-inhibitor-induced adverse events, in particular, in those with an expectedly high plasma level.| |
Acknowledgments |
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We thank B. Lüll, E. Wettstein, and S. Hyvärinen, Division of Cardiology, and M. Schlumpf, Department of Internal Medicine, for their excellent technical assistance; S. Brogli, Institute of Clinical Chemistry, for determination of natriuretic peptides; and B. Küffer, Policlinic of Internal Medicine, for determination of norepinephrine.
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Footnotes |
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Accepted for publication December 3, 1998.
Received for publication August 17, 1998.
1 Current address: Baker Medical Research Institute, P.O. Box 6492, Melbourne, Victoria 8008, Australia.
Send reprint requests to: Hans Peter Brunner-La Rocca, M.D., Baker Medical Research Institute, P.O. Box 6492, Melbourne, Victoria 8008, Australia. E-mail: hanspeter.brunner{at}baker.edu.au
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Abbreviations |
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ACE, angiotensin-converting enzyme; ANP, atrial natriuretic peptide; BNP, brain natriuretic peptide; CHF, congestive heart failure; E10, patients initially treated with 5 mg b.i.d; E20, patients initially treated with 10 mg b.i.d; E40, patients initially treated with 20 mg b.i.d...
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References |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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, Values in patients with good compliance as defined
by concordant changes of enalapril doses and enalaprilat trough level;
, values in patients with bad compliance, which were excluded from
further analysis; horizontal lines, mean values (±1 S.D.); ×, mean
values after correction for covariates (serum creatinine, BNP level,
physical signs of CHF, oxygen consumption at rest, and body weight) in
ANOVA.
significant difference within one group as compared with prior
examination; 
significant difference between all three
groups as compared with first examination; § significant
difference between all three groups as compared with prior examination;
ex, examination; E40, the group initially treated with 40 mg of
enalapril per day; E20, treated with 20 mg per day; E10, treated with
10 mg per day.