Effect of Captopril and Lisinopril on Circadian Blood Pressure Rhythm and Renal Function in Mild-to-Moderate Heart Failure Karl J. Osterziel,
MD,
Markus Karr,
MD,
ymptomatic arterial hypotension and functional renal impairment are important side effects in patients with heart failure during therapy with angiotensin-converting enzyme (ACE) inhibitors.1,2 Even after identification of high-risk patients and reduction of the initial dose of enalapril, symptomatic hypotension occurred in 3.2% of patients with severe heart failure (New York Heart Association [NYHA] class IV).l Minor functional renal impairment during therapy with ACE inhibitors can be found in lo-14% of patients with heart failure.2,3 Differences in plasma half-life may be responsible for observed differences in hemodynamic alterations by ACE inhibitors. 3j4With short-acting ACE inhibitors, periodic increases and decreases in blood pressure were reported, whereas blood pressure remained at nearly constant low levels during therapy with a long-acting ACE inhibitor.4 The degree of renal impairment is thought to be caused by the length of time the blood pressure is below the renal autoregulatory threshold.4 However, most studies on the effects of ACE inhibition on blood pressure and renal function have only measured arterial pressure for a few hours. To test the hypothesis that long-acting ACE inhibitors lead to a continuous decrease in arterial pressure, whereas short-acting ACE inhibitors allow recovery of blood pressure between dosing, the influence of 2 different ACE inhibitors on the 24-hour blood pressure profile was determined. Circadian blood pressure rhythm and renal function were evaluated before and after the titration period (5 days) with captopril or lisinopril.
S
METHODS
Twenty-eight hospitalized patients 3 women) with heart failure (NYHA
(25 men and class II-IV)
From Innere Medizin III (Schwerpunkt Kardiologie, Angiologie und Pulmologie), Medizinische UniversitPtsklinik Heidelberg and Zentrum der Pharmakologie, Heidelberg (K.J.0, M.K., R.D.), and J.W. Goethe-UniversitBt, Frankfurt/M (B.L.), Germany. Address for reprints: Karl J. Osterziel, MD, Innere Medizin III, Medizinische Universittitsklinik, Heidelberg, Germany
BjGrn Lemmer,
MD,
and Rainer Dietz,
MD
were examined. The diagnosis was confirmed in every patient by right and left heart catheterization and selective coronary angiography. All patients were randomized for additional therapy with either captopril or lisinopril. The 2 groups did not differ in etiology, severity of heart failure, and concomitant medication, with the exception that 5 patients in the captopril group received low doses of B blockers (Table I). One patient in each group had diabetes mellitus. During the titration period with the 2 ACE inhibitors, only changes in the diuretic therapy according to clinical needs were allowed. One patient in the captopril group previously not on diuretics received a thiazide diuretic. The diuretic dosage was reduced in 1 patient and increased in 1 patient in the lisinopril group. Blood pressure and heart rate were determined by the oscillometric method (Spacelab monitor, model 90 202) before and on day 5 of therapy with either captopril or lisinopril. The blood pressure values obtained by this method are reproducible and show a close correlation with intra-arterial measured values.5 Blood pressure and heart rate were recorded every 20 minutes from 6:00 A.M. to 10:00 P.M. and every 60 minutes from 10:00 P.M. to 6:00 A.M.. Serum electrolytes, serum creatinine, and urine creatinine were measured by an autoanalyzer method and plasma renin activity was determined at 11:00 P.M. by a radioimmunoassay. The average hourly means of blood pressure and heart rate were used to analyze for daily variations. Within groups, the alterations of blood pressure and heart rate over time were compared by analysis of variance (ANOVA). In addition, rhythm analysis was performed by non-linear fitting of the hourly data to cosine function with the PHARMFIT program.6 The fitting procedure is based on the Marquardt-Levenberg algorithm. This is performed by searching the minimum difference in the sum of squares between measured and calculated values of the dependent variable (blood pressure or heart rate). Data were fitted to a 24-hour period and to a 24-hour period overlapA SYMPOSIUM:
HEART FAILURE
MANAGEMENT
147c
TABLE I Characteristics Congestive Heart Failure
of the 2 Groups Captopril
of Patients
1
with
(n = 15)
Lisinopril (n = 13)
P Value
NYHA classification
2.8 +- 0.1
2.8 -t 0.2
NS
Etiology lschemic CMP Dilated CMP
5
4
NS
10
9
NS
Age (yr)
60 zt 3
Height(m) Weight
1.69 (kg)
? 0.02
62 zi 3 1.73
NS
f 0.02
NS
67 + 3
84 r 4
0.01
1312
12/l
NS
Gender Medication Digitalis Diuretics Potassium supplement Nitrates Molsidomine p blockers Calcium antagonists Mexiletine Quinidine NSAlDs
2 12 5 4 3 5 2 1 0 2
7
NS
10
NS
4 2 3 0
NS NS NS 0.05
1
NS
0 2 2
NS NS NS
CMP = cardiomyopathy; NS = difference not significant: NSAlDs = nonsteroidal anti-inflammatory drugs; NYHA = functional classification according to the New York Heart Association.
ping with its first harmonics (12 hours); improvement of fit was tested. The mesor (rhythm-adjusted mean), acrophase (peak time of rhythm), and amplitude before and after ACE inhibitor treatment were compared by t-test. Differences in other variables were evaluated by the Wilcoxon signed rank test or by the Mann-Whitney U test. The correlation coefficient of linear regressions was calculated by the method of Pearson. RESULTS Fifteen patients received captopril3 times daily at 8:00 A.M., 12:00 and 5:00 P.M. and 13 patients were treated with lisinopril once daily at 8:00 A.M.
The mean daily doses were 41 t- 4 mg captopril and 9.6 & 0.4 mg lisinopril. Before ACE inhibition, both groups showed a similar circadian blood pressure rhythm with highest values in the morning, a slight decrease in blood pressure in the early afternoon, a second peak at about 6:00 P.M. and a sustained decrease in blood pressure during the night (Figure 1; Table II). The profiles of the 24-hour heart rate showed a less consistent but similar pattern to the blood pressure curves (Figure 2; Table II). In the captopril group alterations in the circadian heart rate pattern by the concomitant p blocker therapy of 5 patients cannot be excluded. Therapy with captopril or lisinopril led to a significant decrease in the mesor of systolic and diastolic blood pressure (Table II). There was a tendency to greater blood pressure alterations by lisinopril in comparison to captopril. A slight decrease in the amplitudes of the dominant 24hour fit was observed in both groups (Table II), whereas the amplitudes of the 12-hour fit did not change. Therefore, circadian blood pressure rhythm before and during ACE inhibition was not significantly different. The increase in serum potassium in the captopril group was most likely due to a greater number of patients receiving potassium-sparing diuretics (6 vs 3 patients). Treatment with ACE inhibitors did not change serum creatinine. Captopril did not change creatinine clearance but lisinopril therapy tended to reduce creatinine clearance (p
MD,
Markus Karr,
MD,
ymptomatic arterial hypotension and functional renal impairment are important side effects in patients with heart failure during therapy with angiotensin-converting enzyme (ACE) inhibitors.1,2 Even after identification of high-risk patients and reduction of the initial dose of enalapril, symptomatic hypotension occurred in 3.2% of patients with severe heart failure (New York Heart Association [NYHA] class IV).l Minor functional renal impairment during therapy with ACE inhibitors can be found in lo-14% of patients with heart failure.2,3 Differences in plasma half-life may be responsible for observed differences in hemodynamic alterations by ACE inhibitors. 3j4With short-acting ACE inhibitors, periodic increases and decreases in blood pressure were reported, whereas blood pressure remained at nearly constant low levels during therapy with a long-acting ACE inhibitor.4 The degree of renal impairment is thought to be caused by the length of time the blood pressure is below the renal autoregulatory threshold.4 However, most studies on the effects of ACE inhibition on blood pressure and renal function have only measured arterial pressure for a few hours. To test the hypothesis that long-acting ACE inhibitors lead to a continuous decrease in arterial pressure, whereas short-acting ACE inhibitors allow recovery of blood pressure between dosing, the influence of 2 different ACE inhibitors on the 24-hour blood pressure profile was determined. Circadian blood pressure rhythm and renal function were evaluated before and after the titration period (5 days) with captopril or lisinopril.
S
METHODS
Twenty-eight hospitalized patients 3 women) with heart failure (NYHA
(25 men and class II-IV)
From Innere Medizin III (Schwerpunkt Kardiologie, Angiologie und Pulmologie), Medizinische UniversitPtsklinik Heidelberg and Zentrum der Pharmakologie, Heidelberg (K.J.0, M.K., R.D.), and J.W. Goethe-UniversitBt, Frankfurt/M (B.L.), Germany. Address for reprints: Karl J. Osterziel, MD, Innere Medizin III, Medizinische Universittitsklinik, Heidelberg, Germany
BjGrn Lemmer,
MD,
and Rainer Dietz,
MD
were examined. The diagnosis was confirmed in every patient by right and left heart catheterization and selective coronary angiography. All patients were randomized for additional therapy with either captopril or lisinopril. The 2 groups did not differ in etiology, severity of heart failure, and concomitant medication, with the exception that 5 patients in the captopril group received low doses of B blockers (Table I). One patient in each group had diabetes mellitus. During the titration period with the 2 ACE inhibitors, only changes in the diuretic therapy according to clinical needs were allowed. One patient in the captopril group previously not on diuretics received a thiazide diuretic. The diuretic dosage was reduced in 1 patient and increased in 1 patient in the lisinopril group. Blood pressure and heart rate were determined by the oscillometric method (Spacelab monitor, model 90 202) before and on day 5 of therapy with either captopril or lisinopril. The blood pressure values obtained by this method are reproducible and show a close correlation with intra-arterial measured values.5 Blood pressure and heart rate were recorded every 20 minutes from 6:00 A.M. to 10:00 P.M. and every 60 minutes from 10:00 P.M. to 6:00 A.M.. Serum electrolytes, serum creatinine, and urine creatinine were measured by an autoanalyzer method and plasma renin activity was determined at 11:00 P.M. by a radioimmunoassay. The average hourly means of blood pressure and heart rate were used to analyze for daily variations. Within groups, the alterations of blood pressure and heart rate over time were compared by analysis of variance (ANOVA). In addition, rhythm analysis was performed by non-linear fitting of the hourly data to cosine function with the PHARMFIT program.6 The fitting procedure is based on the Marquardt-Levenberg algorithm. This is performed by searching the minimum difference in the sum of squares between measured and calculated values of the dependent variable (blood pressure or heart rate). Data were fitted to a 24-hour period and to a 24-hour period overlapA SYMPOSIUM:
HEART FAILURE
MANAGEMENT
147c
TABLE I Characteristics Congestive Heart Failure
of the 2 Groups Captopril
of Patients
1
with
(n = 15)
Lisinopril (n = 13)
P Value
NYHA classification
2.8 +- 0.1
2.8 -t 0.2
NS
Etiology lschemic CMP Dilated CMP
5
4
NS
10
9
NS
Age (yr)
60 zt 3
Height(m) Weight
1.69 (kg)
? 0.02
62 zi 3 1.73
NS
f 0.02
NS
67 + 3
84 r 4
0.01
1312
12/l
NS
Gender Medication Digitalis Diuretics Potassium supplement Nitrates Molsidomine p blockers Calcium antagonists Mexiletine Quinidine NSAlDs
2 12 5 4 3 5 2 1 0 2
7
NS
10
NS
4 2 3 0
NS NS NS 0.05
1
NS
0 2 2
NS NS NS
CMP = cardiomyopathy; NS = difference not significant: NSAlDs = nonsteroidal anti-inflammatory drugs; NYHA = functional classification according to the New York Heart Association.
ping with its first harmonics (12 hours); improvement of fit was tested. The mesor (rhythm-adjusted mean), acrophase (peak time of rhythm), and amplitude before and after ACE inhibitor treatment were compared by t-test. Differences in other variables were evaluated by the Wilcoxon signed rank test or by the Mann-Whitney U test. The correlation coefficient of linear regressions was calculated by the method of Pearson. RESULTS Fifteen patients received captopril3 times daily at 8:00 A.M., 12:00 and 5:00 P.M. and 13 patients were treated with lisinopril once daily at 8:00 A.M.
The mean daily doses were 41 t- 4 mg captopril and 9.6 & 0.4 mg lisinopril. Before ACE inhibition, both groups showed a similar circadian blood pressure rhythm with highest values in the morning, a slight decrease in blood pressure in the early afternoon, a second peak at about 6:00 P.M. and a sustained decrease in blood pressure during the night (Figure 1; Table II). The profiles of the 24-hour heart rate showed a less consistent but similar pattern to the blood pressure curves (Figure 2; Table II). In the captopril group alterations in the circadian heart rate pattern by the concomitant p blocker therapy of 5 patients cannot be excluded. Therapy with captopril or lisinopril led to a significant decrease in the mesor of systolic and diastolic blood pressure (Table II). There was a tendency to greater blood pressure alterations by lisinopril in comparison to captopril. A slight decrease in the amplitudes of the dominant 24hour fit was observed in both groups (Table II), whereas the amplitudes of the 12-hour fit did not change. Therefore, circadian blood pressure rhythm before and during ACE inhibition was not significantly different. The increase in serum potassium in the captopril group was most likely due to a greater number of patients receiving potassium-sparing diuretics (6 vs 3 patients). Treatment with ACE inhibitors did not change serum creatinine. Captopril did not change creatinine clearance but lisinopril therapy tended to reduce creatinine clearance (p
