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Comparison of the effects of prazosin versus propranolol on plasma lipoprotein lipids in patients receiving hemodialysis
Comparison of the Effects of Prazosin versus Propranolol on / Plasma Lipoprotein Lipids in Patients Receiving Hemodialysis
HERSCHEL R. HARTER, M.D. VICTOR N. MELTZER, M.D. CAROL A. TINDIRA, R.N. ANNA D. NAUMOVICH, M.D. ANDREW P. GOLDBERG, M.D. St. Louis,
A prospective, crossover study was used to evaluate the effects of prazosin and propranolol on lipid metabolism in 10 hypertensive patients receiving long-term hemodialysis therapy. Adequate blood pressure control was achieved with either agent (mean predialysis blood pressure was 144i77 mm Hg). Total triglyceride levels increased by ,27 f 4 percent during propranolol therapy but decreased during prazosln therapy by 8 f 2 percent (p ~0.05). These changes were accounted for by a 21 + 1.5 percent increase in very low-density lipoprotein triglyceride during propranolol therapy and a 8 f 2 percent decrease in very-low-density lipoprotein triglyceride during prazosin therapy (p ~0.05). Although no change in total cholesterol occurred with either agent, a significant decrease (19 f 1 percent, p ~0.01) in high-density lipoprotein cholesterol occurred with propranolol therapy and an increase of 18 + 4 percent occurred during treatment with prazosin (not significant). The highdensity lipoprotein, cholesterol levels decreased by 22 +I 4 percent after treatment with propranolol and increased by 4 percent after prazosin therapy. Propranolol reduced high-density lipoprotein3 cholesterol levels by 18 +- 2 percent, whereas prazosin increased these values by 19 -+ 2 percent (p ~0.01). These changes were associated with a reduction in tissue lipoprotein lipase activity after propranolol therapy (2.4 + 0.3 percent) and. an increase after prazosin therapy (2.5 f 1 percent, p ~0.05). These data suggest that treatment with propranolol may be associated with unfavorable changes in the lipid profile that are not observed after treatment with prazosin.
Missouri
From the Chromalloy American Kidney Center and Renal Division, and the Lipid Research Center, Department of Medicine, of Washington University School of Medicine, St. Louis, Missouri. Requests for reprints should be addressed to Dr. Herschel R. Harter, 711 Wcod Street, Monroe, Louisiana 71201.
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Journal
The long-term survival of patients with end-stage renal disease receiving chronic hemodialysis therapy is limited because of atherosclerotic complications induced by hypertension, smoking, and abnormalities in lipid metabolism [l-5]. In one study, more than 50 percent of hemodialysis patients were hypertensive at some time during their treatment course [6]. The mechanisms responsible for hypertension vary, but the hypertension of many patients with end-stage renal disease is sodium dependent and can be controlled by maintenance of normal body sodium and water levels [7]. A smaller group of patients are hypertensive because of high plasma renin and angiotensin II concentrations [a], and most often hypertension is the etiology for their end-stage renal disease [6,9]. A third group of patients undergoing hemodialysis has been described that is thought to be hypertensive’ because of autonomic nervous system dysfunction [IO]. Those patients are usually elderly or diabetic, present with pradialysis hypertension, and often have a hypotensive episode early in
of Medicine
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TABLE I
the course of dialysis therapy [lO,ll]. Regardless of etiology, hypertension in hemodialysis patients requires prompt and effective control to reduce the incidence of cerebrovascular and cardiovascular complications. An accelerated rate of atherogenesis seems to be the primary mechanism for the early deaths of many dialysis patients [1,12]. It probably occurs primarily as a result of the synergistic interaction of the many risk factors for atherosclerosis that are prevalent in these patients, including abnormalities in lipid and glucose metabolism, hypertension, cigarette smoking, and a low level of physical fitness [l-5,1 3-l 51. Between 30 to 50 percent of all hemodialysis patients have significant abnomialities in lipid metabolism [12]. These abnormalities are especially prevalent in white males, who typically have hypertriglyceridemia with an increase in very-low-density lipoprotein triglyceride levels and reduced levels of high-density lipoprotein cholesterol, particularly the high-density lipoprotein2 subfraction
ET AL
Characteristics of Study Population While
Black
Number of patients Mean age (years) Sex Male Female Duration of dialysis (months) Disease category Nephrosclerosis Chronic glomerulonephritis PyelonephritisAnterstitial nephritis
5 55 2 8
5 52 k 7
4
2 3
1 11
68k
50r 18
2
2 3 0
1 2
lipid or glucose metabolism. All patients were receiving standard medications for renal failure, including phosphate-binding agents, calcium carbonate, iron supplementation, and multivitamins. Nandrolone decanoate was discontinued for a minimum of six weeks before initiation of the study. The patients were carefully counseled on their diet to assure a constant intake of 35 to 40 percent fat, 45 to 50 percent carbohydrates, 15 percent protein, and 300 to 400 mg of cholesterol, to maintain a polyunsaturated to saturated fat ratio of 0.5 to 0.8 (saturated fats being less than 10 percent of total fat intake), and to limit monosaccharides and disaccharides throughout the observation period. This advice was also given lo assure weight maintenance. To document compliance, patients were asked to complete a bimonthly questionnaire regarding their dietary intake over a three-day period. Experimental Design. Patients were randomly assigned to antihypertensive treatment with either propranolol or prazosin for 12 weeks. Twelve patients receiving prazosin and eight receiving propranolol completed this phase of the study [I 91. Two patients refused to participate after initial recruitment and three were excluded because of severe hypertension during the washout phase (blood pressure equal to or greater than 180/l 10 mm Hg). Of those 20 patients, 10 agreed to complete a crossover treatment phase, during which time they received the other drug for an additional 12 weeks, followed by a washout period of one month. The clinical characteristics of this study group are depicted in Table I. Clinical and biochemical tests included a chest roentgenogram, electrocardiogram, measurement of serum electrolytes, liver function tests, and a complete blood cell count at the start of therapy and thereafter on a monthly basis during the course of the study. Patients who had been previously treated for hypertension stopped their drugs for one month before initiation of either study medication (washout phase). During this phase, blood pressures were monitored daily, and an increase in systolic blood pressure to a level greater than 170 mm Hg or an increase in diastolic blood pressure to a level greater than 105 mm Hg necessitated reihstitution of medication and disqualification from the protocol. Lipid measurements at baseline and during active drug therapy were obtained after a 12-hour overnight fast; these were done in duplicate one week apart on the day representing the longest interdialysisinterval. Measurements included total plasma tri-
A number of drugs that are commonly prescribed in the treatment of hemodialysis patients elevate very-lowdensity lipoprotein triglyceride levels and reduce highdensity lipoprotein cholesterol concentrations, including the synthetic androgen preparations [16], corticosteroids [5], and propranolol [17]. Cross-sectional data from our dialysis center indicate that when used alone or in combination with each other, propranolol and nandrolone decanoate are associated with an adverse lipid profile (higher very-low-density lipoprotein triglyceride and lower high-density lipoprotein cholesterol levels). This profile is potentially more atherogenic than the one that occurs with the use of prazosin alone or in combination with an androgen preparation [18]. Any agent that adversely affects lipid metabolism in the dialysis population might accelerate the rate of atherosclerosis and promote the risk of early cardiovascular mortality. Our study was designed, therefore, to evaluate the effects of both prazosin and propranolol on lipid metabolism in a selected group of hypertensive patients receiving hemodialysis. PATIENTS AND METHODS Patients. Twenty-five hypertensive dialysis patients with end-stage renal disease were selected for study from a large group of patients treated at the Chromalloy American Kidney Center at Washington University School of Medicine, St. Louis, Missouri. The patients underwent dialysis three times per week, four to five hours per session, with a standard hollow fiber dialyzer, and had a residual creatinine clearance of less than 1 ml per minute. Only untreated patients with a diastolic blood pressure of 90 mm Hg or greater were selected for study. Also excluded from the study were patients over 70 years of age or less than 18 years of age, those with insulindependent diabetes mellitus or symptomatic coronary artery disease, those having had a cerebrovascular accident or myocardial infarction within six months of the initiation of the study, and those receiving treatment with drugs that affect
14, 1966
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b121.
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glyceride,
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lected for study had significant hypertension (160/90 mm Hg in the sitting position) that was not controlled by ultrafiltration alone. Blood pressure control was considered adequate if predialysis values were less than 145/90 mm Hg. Antlhypertensive medications were taken just prior to initiation of dialysis. All patients accepted for the study gave voluntary consent according to the procedures outlined by the Human Studies Committee, Washington University School of Medicine. All data are presented as mean values 2 standard error of the mean. Statistical analysis involved using a paired Student t test, an analysis of covariance, and regression analysis with calculation of a correlation coefficient when appropriate.
lesterol, very-low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol. Low-density lipoprotein cholesterol was calculated [20]; plasma high-density lipoprotein, cholesterol and high-density lipoprotein, cholesterol levels were measured by precipitation [21]. Standard pools of plasma,representing high, medium, and low lipid values were run with each lipoprotein assay. If the values obtained differed from the mean of the standard by more than 8 percent, the assay was repeated. The coefficient of replicate determinations for the pool was 7 percent. Post-heparin plasma lipolytic activity was measured (221 at baseline, at the end of each treatment period, and after crossover. Plasma samples used for measurement of post-heparin lipases were collected following the intravenous injection of intestinal mucosa heparin (Upjohn, 2,280 units per square meter of body surface area). Total post-heparin lipolytic lipase activity was measured on a “C-triolein-labeled substrate. Another 14C-triolein substrate containing 1 M of sodium chloride to inhibit lipoprotein lipase activity was used in the direct measurement of hepatic lipase activity [23]. The difference between postheparin lipolytic activity and hepatic lipase activity was used as the measure of the level of tissue lipoprotein lipase activity. Samples for lipase activities from each patient were run in the same assay, using standardized post-heparin plasma pools. Interassay and intra-assay coefficients of variation for these analyses were less than 15 and 10 percent, respectively. Limited amounts of antibody to hepatic lipase prevented us from determining lipoprotein lipase activity directly on all samples, but 20 random samples were assayed using antibody, and levels of post-heparin plasma lipoprotein lipase activity were within 10 percent of the levels calculated by the method just described. Samples from each patient were measured in duplicate in the same assay. We also tested whether propranolol or prazosin altered either lipase by adding antibody to hepatic lipase plus 1 M per liter of sodium chloride to post-heparin plasma. In all instances, total activity was inhibited by more than 95 percent. Stud’y Design. The study design was a crossover technique in which 25 patients went through a 30-day washout period, after which baseline lipid and chemical determinations were performed in duplicate. Patients were then randomly assigned to receive eitlier prazosin or propranolol. Cf the initial 25 patients recruited, three patients were excluded from analysis because their blood pressure levels increased to 1801 110 mm Hg or more during the initial washout phase; two refused to continue after the initial screening. Each drug was titrated to within its therapeutic range, and patients continued with the initial agent for a minimum of three months. At the end of this period, lipid studies and standard biochemical techniques were repeated in duplicate. The agents were then slowly discontinued; a second 30-day washout period followed. Baseline lipid studies and biochemical determinations were again performed; the alternate drug was substituted and titrated to therapeutic levels. After three months with the alternate antlhypertensive agent, biochemical tests were repeated. Ten patients who completed the crossover part of the study and received both p&pranolol and prazosin are the subject of this report. Blood pressure measurements were obtained in the sitting and standing positions before and after dialysis. Those se-
a4
February
14,1926
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RESULTS The mean predialysis systolic blood pressure for all patients studied was 164 2 4 mm Hg and the mean diastolic blood pressure was 98 f 4 mm Hg. After titration oteither
agent, the mean predialysis systolic blood pressure was 150 k 4 mm Hg and the mean diastolic blood pressure was 80 + 2 mm Hg. Sustained normal blood pressures were achieved after three months with either agent and averaged 144/77 mm Hg (predialysis) for both agents. Differences in blood pressure among patients treated with either propranolol or prazosin were not statisticany signiicant and, therefore, the data for all 10 patients were combined. Prazosin therapy was initiated at 1 mg twice daily, with the first dose given at bedtime and progressively ihcreased until blood pressure was controlled. The mean dose of prazosin administered to these patients was 11 + 2 mg per day. Propranolol was initially administered at 29 mg twice daily and progressively increased until adequate blood pressure control was achieved. The mean dose of propranolol used in all patients was 132 + 12 mg per day. In patients treated with propranolol, total triglycerides increased from 192 k 23 to 231 2 46 mg/dl (not signiffcant), which was associated with a cbminensurate increase in very-low-density lipoprotein triglycerides from 125 of:13 to 168 + 9 mg/dl (p ~0.06). In patients reoeiving prazosin therapy, plasma triglyceride levels decreased slightly from 208 + 24 to 180 + 34 mg/dl (not signkant). This change in plasma triglycerides could be accounted for by reduction of very-low-density lipoprotein triglyceride levels from 153 f 39 to 127 k 29.5 mg/dl (not significant) (Figure 1). Figure 2 illustrates the percent change from baseline for the triglyceride values in patients treated with either propranolol or prazosin. Propranolol significantly increased total triglycerides by 17 + 4 percent, whereas prazosin decreased total plasma triglyceride levels by 8 k 2 percent (p ~0.05). Propranolol increased very-lowdensity lipoprotein triglycerides by 21 2 1.5 percent, and prazosin decreased very-low-density lipoprotein triglycerides by 6 f 2 percent (p ~0.05). No change in low-density lipoprotein or high-density lipoprotein triglycerides occurred.
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P= NS 200 160 160 mg/dL 140
0 Propranolol l Prazosin
120
100 60 60 40 20 0
Figwe 1. Mean triglyceride values in 10 patients duting crossover study. Total triglyceddes (T) and very-low-density lipoprotein trig/ycerides (VLDL-T) increased widh propranolol therapy and decreased with prazosin therapy.
Total T
VLDL-T
25 20 15
% A
0 Propranolol
10
n
5 0 -5 F/guns 2. Percent change from baseline for total triglycerides m and very-lowdensity lipoprotein triglycerides (VLDL-T) with propranolol therapy and pfazosin therapy.
-10
I
-15 c
P < 0.05
P < 0.05
Total T
VLDL-T
Total cholesterol levels were unaffected by either drug (170 + 17 mg/dl after the washout phase and 180 rf: 15 mg/dk after therapy for both groups; difference not significant). High-density lipoprotein cholesterol increased by 16 r 4 percent from baseline during prazosin therapy (from 32 k 9 to 40 f 8 mg/dl; difference not significant), and decreased by 19 2 1 percent from baseline during propranolol therapy (from 44 k 7 mg/dl after washout to 31 +- 4 mg/dl after three months of therapy: p ~0.06). Fig ure 3 depicts the changes in highdensity lipoproteinp cholesterol and high-density lipoprotein3 cholesterol after propranolol and prazosin therapy. Absolute high-density lipoproteinz cholesterol values decreased from 16 + 2 to 12 f 3 mg/dl after three months of propranolol therapy (p ~0.06) and increased from 18 + 3 to 22 + 8 mg/dl after three months of prazosin therapy (not significant). Absolute high-density lipoproteina cholesterol values decreased during propranolol therapy from 22 + 1 to 19 -c 2
Februaw
Prazosin
I
14. less: ,~
mg/dl (p ~0.05) and increased from 18 -I 2 to 24 2 4 mg/dl during prazosin therapy (p ~0.05). The percent changes from baseline for these variables are depicted in Figure 4. Although no significant changes in absolute values occurred with either prazosin or propranolol for highdensity lipoprotein, cholesterol levels, propranolol reduced high-density lipoprotein3 cholesterol levels by 18 2 2 percent, and prazosin increased these values by 19 k 2 percent (p ~0.01) from respective baseline values. Because of variations during placebo (washout) phases of the study, significant differences between groups were only noted when percent change from baseline was used for analysis. Table II depicts the absolute lipid values for patients after at least three months of treatment with either propranolol or prazosin. The ratio of low-density lipoprotein cholesterol to highdensity lipoprotein cholesterol is frequently used as a pre-
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30 28 28 24 22
mg/dL
P < 0.05
P < 0.0
20 18 18 ,4 12 10
Figure 3. Mean cholesterol
subfraction values in 10 patients during crossover study. The high-density lipoprotein2 cholesterol (HDL&) and high-density lipoprotein, cholesterol (HDL3-C) levels decreased with propranolol therapy and increased with prazosin after three months of study.
8 8 4 2 0
21
P < 0.01
P = NS
P < 0.01
18 15 12 9 6 d 0 % A
n
-63
Prazosin
I7 Propranolol
112 9 -15 -16 -21 -24 -27 HDL-C
HDL2-C
Figure 4. Percent change from baseline for high-density lipoprotein cholesterol (HDL-C), high-density lipoprotein, cholesterol (HDL,-C), and high-density lipoprotein3 cholesterol (HDL&) with propranolol therapy and prazosin therapy.
HDL3-C
dictor of coronary disease. Because significant differences occurred between the groups at baseline, percent variation from baseline was used for comparison. Figure 5 illustrates these results. Propranolol increased the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol by 4 + 1 percent, whereas no appreciable change occurred with prazosin therapy (p ~0.05). Likewise, propranolol increased the ratio of total cholesterol to high-density lipoprotein cholesterol by 6 f 1 percent, and again, no appreciable change occurred with prazosin therapy. The between-group difference for both ratios was significant (p cO.05).
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The mechanisms responsible for these observed changes in lipid metabolism are unclear. Changes in the activity of the enzymes hepatic lipas? and lipoprotein lipase may explain some of the results. Figure 6 depicts the percent changes from baseline for hepatic lipase and lipoprotein lipase with both drugs. Small but significant changes were observed between the treatment groups, although the actual change for each group was not significant. Mean hepatic lipase activity was unchanged by either drug (propranolol, 9.1 + 1.9 microequivalents of free fatty acids per milliliter per hour; prazosin, 8.5 + 1.3 microequivalents of free fatty acids per millilfler per hour).
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Propranolol decreased the activity of hepatic lipase by 1.8 ? 0.4 percent, whereas hepatic lipase activity was increased by 0.7 ? 0.2 percent with prazosin (p ~0.05). Mean lipoprotein
TABLE II
COMMENTS Improvement in long-term survival of hemodialysis patients requires more than adequate dialysis care. Although the technical aspects of dialysis have been mastered, it is apparent that correcting risk factors for accelerated atherosclerosis has been unsuccessful as rates remain
extremely
high,
approaching
Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoproteinz cholesterol High-density lipoprotein, cholesterol Total triglycerides Very-low-density lipoprotein triglycerides Low-density lipoprotein triglycerides “Data
50
shown
THERAPY-HARTER
ET AL
Mean Lipid Data for Patients Receiving Either Propranolol or Prazosin*
lipase activity was 9.9 k 0.8 microequiv-
alents of free fatty acids per milliliter per hour after treatment with propranolol and 15.0 lr 1.7 after prazosin therapy (p ~0.05). Lipoprotein lipase activity decreased during propranolol therapy by 2.4 + 0.3 percent but increased during prazosin therapy by 2.5 ? 1.O percent (p c0.05).
mortality
ON INITIAL ANTIHYPERTENSIVE
are after
at least three
Propranolol (II = 10)
Prazosin (n = 10)
211 f 30 93 -c 20
166” 97k
13 16
31 2 4
40 * 8
12 f 3
22 k 8
19 k 2
23 c 4
231 k 46 168? 9
180 k 34 127 f 30
41 k.5
32 t 3
months
of therapy.
6 5 4 3 2
% A
'
0 Propranolol
0
n
-1 -2 -3 -4 -5
Figure 5. Percent change from baseline for ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-CIHDL-C) and ratio of total cholesterol to high-density lipoprotein cholesterol (total CIHDL-C) with propran0101 therapy and prazosin therapy.
P < 0.05
P < 0.05
LDL-C/HDL-C
Total CIHDL-C
Prazosin
”
% A
Figure 6. Percent change from baseline for heparic lipase and lipoprotein lipase with propranolol therapy and prazosin therapy.
February
2.7 2.4 2.1 1.8 1.5 1.2 .9 .8 .3 O- .3 - .6 - .9 -1.2 -1.5 -1.8 -2.1 -2.4 -2.7 ’
14, 1999
-
P n
Prazosin
0 Propranolol
I
P < 0.05
Lipoprotein
Hepatic lipase
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percent at five years in some institutions [2]. Thus, effective control of hypertension, treatment of risk factors such as smoking and abnormal lipid metabolism, correction of anemia, and improvement in glucose metabolism are all necessary if survival is to be prolonged in this population. Hypertension occurs in more than 50 percent of all dialysis patients [7,24]. Adequate dialytic care with ultrafiltration to “dry weight” will reduce blood pressure to normal levels in approximately 80 percent of the patients. Vertes et al [7] described this population of patients as having volume-dependent hypertension. Antihypertensive medications may be necessary to control predialysis hypertension in some of these patients [25]. An additional 10 percent of patients have high-renin hypertension and will require potent vasodilator therapy [7,25,28], angiotensin II blockage [271, diafiltration [ll], treatment with beta blockers [8,28] and, occasionally, nephrectomy [29] for blood pressure control. The remaining patients have various causes for their hypertension, but most cases are probably related to abnormalities in the sympathetic nervous system [lO,ll]. Such patients have excessive autonomic activity with high plasma dopamine beta-hydroxylase and catecholamine levels [lO,l l] and are best treated with agents that reduce peripheral vascular resistance [10,25]. Although postdialysis blood pressures are frequently within the normal range-except possibly for those with high-renin hypertension [7,28,29]-predialysis hypertension may still be a considerable risk factor that is, as yet, unaddressed at most centers. It is our recommendation that normal blood pressures be maintained before and after the dialysis procedure. Thus, patients whose blood pressures cannot be controlled with adequate ultrafiltration should be treated with pharmacologic agents to reduce predialysis blood pressure values to within the normal range. This study demonstrates clearly that both propranolol and prazosin, in relatively modest doses, will control predialysis hypertension in patients receiving hemodialysis treatment. The symptomatic side effects of both agents were relatively minor in all patients studied, and the antihypertensive effects were acceptable.
Previous studies have suggested that the treatment of mild hypertension in non-uremic persons is not associated with an improvement in the cardiovascular risk [30-321. These observations may be at least partially explained by changes in lipid metabolism (decreased high-density lipoprotein and increased very-low-density lipoprotein triglycerides) caused by the antihypertensive agents [17,30]. In non-uremic hypertensive patients, prazosin has been shown not to adversely affect lipid profiles [33]. In some studies, prazosin has been shown to decrease plasma triglyceride levels and increase high-density lipoprotein cholesterol levels [34,35]. Propranolol, on the other hand, raises plasma triglyceride levels and reduces high-density lipoproteina cholesterol levels in non-uremic subjects [35] and, in a cross-sectional study of dialysis patients, seemed to worsen their lipid profiles [18]. Such detrimental effects on lipid metabolism would be extremely important in dialysis patients who are already at risk for lipid abnormalities and accelerated atherosclerosis. A worsening of lipid profiles in these patients might increase their risk for coronary artery disease. This study demonstrated that propranolol treatment was associated with increases in plasma triglyceride levels and decreases in high-density lipoprotein cholesterol levels (predominately a decrease in high-density lipoprotein3 cholesterol). In contrast, prazosin treatment was associated with a modest decrease in total triglyceride levels, an increase in high-density lipoprotein cholesterol, and a significant increase in high-density lipoproteina cholesterol. Although the clinical significance of an increase or decrease in the high-density lipoprotein3 subfraction has not been determined, prazosin therapy was also associated with an increase in the high-density lipoprotein;! cholesterol subfraction. These changes suggest that propranolol treatment of patients receiving hemodialysis is associated with a deterioration in lipid profiles, whereas prazosin therapy does not adversely affect the lipid profiles. Determining the significance of these observed lipid changes will require long-term studies that will more clearly delineate the mechanisms involved as well as their potential effects on the survival of dialysis patients.
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Bagdade J, Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man. J Lab Clin Med 1976; 87: 37-46. Argy WP, Chester AC, Siemsen AS, Rokowski TA, Schreiner GE: Hypertension in two hemodialysis cohorts. Trans Am Sot Artif Intern Organs 1982; 28: 329-332. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end-stage renal disease. N Engl J Med 1969; 280: 978-981. Lindner A, Douglas SW, Adamson JW: Propranolol effects in long-term hemodiatysis patients with renin-dependent hypertension. Ann Intern Med 1978; 66: 457-462. Chrysanthakopoulos SG, Kastagir BK. Jubiz W, Kolff WJ: Hy-
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Goldberg A, Sherrard DJ, Brunzell JD: Adipose tissue lipoprotein lipase in chronic hemodialysis: role in plasma triglyceride metabolism. J Clin Endocrinol Metab 1978; 47: 1173-l 182. Huttunen JK, Ehnholm C, Kinnunen PKJ, Nikkila EA: An immunochemical method for the selective measurement of two triglyceride lipases in human post-heparin plasma. Clin Chim Acta 1975; 63: 335-347. Chester AC, Schreiner GE: Hypertension and hemodialysis. Trans Am Sot Artif Intern Organs 1978; 24: 36-42. Hatter HR, Delmez JA: Effects of prazosin in the control of blood pressure in hypertensive dialysis patients, J Cardiovasc Pharmacol 1979; 1 (suppl): S43-S55. Pettinger WA, Mitchell HC: Minoxidil-an alternative to nephrectomy for refractory hypertension. N Engl J Med 1973; 289: 167-l 71. MacGregor GA, Dawes PM: Angiotensin II blockade in hypertensive dialysis patients. Prog Biochem Pharmacol 1976; 12: 190-199. Maggiore Q, Zoccali C, Monzani G, Contini C: Chronic hemody namic effects of propranolol treatment in dialysis-refractory hypertension. Nephron 1978; 22: 391-398. Lee C, Neff MS, Slifkin RF, Leiter E: Bilateral nephrectomy for hypertension in patients with chronic renal failure on a dialysis program. J Urol 1978; 119: 20-22. Helgeland A: Treatment of mild hypertension: a five-year controlled drug trial. The Oslo Study. Am J Med 1980; 69: 725732. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 11431152. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA 1982; 248: 1465-1477. Havard CWH, Khokhar AM, Flax JS: Open assessment of prazosin on plasma lipids. J Cardiovasc Pharmacol 1982; 4: S238-S241. Kokubu T, ltoh I, Kurita H, Ochi T, Murata K, Yuba I: Effects of prazosin on serum lipids. J Cardiovasc Pharmacol 1982; 4: S228-5232. Neusy AJ, Lowenstein J: Effects of prazosin, atenolol, and thiazide diuretic on plasma lipids in patients with essential hypertension. Am J Med 1986; 80 (suppl 2A): 94-99.
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Journal
of Medicine
Volume
80 (suppl
2A)
89
HERSCHEL R. HARTER, M.D. VICTOR N. MELTZER, M.D. CAROL A. TINDIRA, R.N. ANNA D. NAUMOVICH, M.D. ANDREW P. GOLDBERG, M.D. St. Louis,
A prospective, crossover study was used to evaluate the effects of prazosin and propranolol on lipid metabolism in 10 hypertensive patients receiving long-term hemodialysis therapy. Adequate blood pressure control was achieved with either agent (mean predialysis blood pressure was 144i77 mm Hg). Total triglyceride levels increased by ,27 f 4 percent during propranolol therapy but decreased during prazosln therapy by 8 f 2 percent (p ~0.05). These changes were accounted for by a 21 + 1.5 percent increase in very low-density lipoprotein triglyceride during propranolol therapy and a 8 f 2 percent decrease in very-low-density lipoprotein triglyceride during prazosin therapy (p ~0.05). Although no change in total cholesterol occurred with either agent, a significant decrease (19 f 1 percent, p ~0.01) in high-density lipoprotein cholesterol occurred with propranolol therapy and an increase of 18 + 4 percent occurred during treatment with prazosin (not significant). The highdensity lipoprotein, cholesterol levels decreased by 22 +I 4 percent after treatment with propranolol and increased by 4 percent after prazosin therapy. Propranolol reduced high-density lipoprotein3 cholesterol levels by 18 +- 2 percent, whereas prazosin increased these values by 19 -+ 2 percent (p ~0.01). These changes were associated with a reduction in tissue lipoprotein lipase activity after propranolol therapy (2.4 + 0.3 percent) and. an increase after prazosin therapy (2.5 f 1 percent, p ~0.05). These data suggest that treatment with propranolol may be associated with unfavorable changes in the lipid profile that are not observed after treatment with prazosin.
Missouri
From the Chromalloy American Kidney Center and Renal Division, and the Lipid Research Center, Department of Medicine, of Washington University School of Medicine, St. Louis, Missouri. Requests for reprints should be addressed to Dr. Herschel R. Harter, 711 Wcod Street, Monroe, Louisiana 71201.
82
February
14,1986
The Amsrlcan
Journal
The long-term survival of patients with end-stage renal disease receiving chronic hemodialysis therapy is limited because of atherosclerotic complications induced by hypertension, smoking, and abnormalities in lipid metabolism [l-5]. In one study, more than 50 percent of hemodialysis patients were hypertensive at some time during their treatment course [6]. The mechanisms responsible for hypertension vary, but the hypertension of many patients with end-stage renal disease is sodium dependent and can be controlled by maintenance of normal body sodium and water levels [7]. A smaller group of patients are hypertensive because of high plasma renin and angiotensin II concentrations [a], and most often hypertension is the etiology for their end-stage renal disease [6,9]. A third group of patients undergoing hemodialysis has been described that is thought to be hypertensive’ because of autonomic nervous system dysfunction [IO]. Those patients are usually elderly or diabetic, present with pradialysis hypertension, and often have a hypotensive episode early in
of Medicine
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TABLE I
the course of dialysis therapy [lO,ll]. Regardless of etiology, hypertension in hemodialysis patients requires prompt and effective control to reduce the incidence of cerebrovascular and cardiovascular complications. An accelerated rate of atherogenesis seems to be the primary mechanism for the early deaths of many dialysis patients [1,12]. It probably occurs primarily as a result of the synergistic interaction of the many risk factors for atherosclerosis that are prevalent in these patients, including abnormalities in lipid and glucose metabolism, hypertension, cigarette smoking, and a low level of physical fitness [l-5,1 3-l 51. Between 30 to 50 percent of all hemodialysis patients have significant abnomialities in lipid metabolism [12]. These abnormalities are especially prevalent in white males, who typically have hypertriglyceridemia with an increase in very-low-density lipoprotein triglyceride levels and reduced levels of high-density lipoprotein cholesterol, particularly the high-density lipoprotein2 subfraction
ET AL
Characteristics of Study Population While
Black
Number of patients Mean age (years) Sex Male Female Duration of dialysis (months) Disease category Nephrosclerosis Chronic glomerulonephritis PyelonephritisAnterstitial nephritis
5 55 2 8
5 52 k 7
4
2 3
1 11
68k
50r 18
2
2 3 0
1 2
lipid or glucose metabolism. All patients were receiving standard medications for renal failure, including phosphate-binding agents, calcium carbonate, iron supplementation, and multivitamins. Nandrolone decanoate was discontinued for a minimum of six weeks before initiation of the study. The patients were carefully counseled on their diet to assure a constant intake of 35 to 40 percent fat, 45 to 50 percent carbohydrates, 15 percent protein, and 300 to 400 mg of cholesterol, to maintain a polyunsaturated to saturated fat ratio of 0.5 to 0.8 (saturated fats being less than 10 percent of total fat intake), and to limit monosaccharides and disaccharides throughout the observation period. This advice was also given lo assure weight maintenance. To document compliance, patients were asked to complete a bimonthly questionnaire regarding their dietary intake over a three-day period. Experimental Design. Patients were randomly assigned to antihypertensive treatment with either propranolol or prazosin for 12 weeks. Twelve patients receiving prazosin and eight receiving propranolol completed this phase of the study [I 91. Two patients refused to participate after initial recruitment and three were excluded because of severe hypertension during the washout phase (blood pressure equal to or greater than 180/l 10 mm Hg). Of those 20 patients, 10 agreed to complete a crossover treatment phase, during which time they received the other drug for an additional 12 weeks, followed by a washout period of one month. The clinical characteristics of this study group are depicted in Table I. Clinical and biochemical tests included a chest roentgenogram, electrocardiogram, measurement of serum electrolytes, liver function tests, and a complete blood cell count at the start of therapy and thereafter on a monthly basis during the course of the study. Patients who had been previously treated for hypertension stopped their drugs for one month before initiation of either study medication (washout phase). During this phase, blood pressures were monitored daily, and an increase in systolic blood pressure to a level greater than 170 mm Hg or an increase in diastolic blood pressure to a level greater than 105 mm Hg necessitated reihstitution of medication and disqualification from the protocol. Lipid measurements at baseline and during active drug therapy were obtained after a 12-hour overnight fast; these were done in duplicate one week apart on the day representing the longest interdialysisinterval. Measurements included total plasma tri-
A number of drugs that are commonly prescribed in the treatment of hemodialysis patients elevate very-lowdensity lipoprotein triglyceride levels and reduce highdensity lipoprotein cholesterol concentrations, including the synthetic androgen preparations [16], corticosteroids [5], and propranolol [17]. Cross-sectional data from our dialysis center indicate that when used alone or in combination with each other, propranolol and nandrolone decanoate are associated with an adverse lipid profile (higher very-low-density lipoprotein triglyceride and lower high-density lipoprotein cholesterol levels). This profile is potentially more atherogenic than the one that occurs with the use of prazosin alone or in combination with an androgen preparation [18]. Any agent that adversely affects lipid metabolism in the dialysis population might accelerate the rate of atherosclerosis and promote the risk of early cardiovascular mortality. Our study was designed, therefore, to evaluate the effects of both prazosin and propranolol on lipid metabolism in a selected group of hypertensive patients receiving hemodialysis. PATIENTS AND METHODS Patients. Twenty-five hypertensive dialysis patients with end-stage renal disease were selected for study from a large group of patients treated at the Chromalloy American Kidney Center at Washington University School of Medicine, St. Louis, Missouri. The patients underwent dialysis three times per week, four to five hours per session, with a standard hollow fiber dialyzer, and had a residual creatinine clearance of less than 1 ml per minute. Only untreated patients with a diastolic blood pressure of 90 mm Hg or greater were selected for study. Also excluded from the study were patients over 70 years of age or less than 18 years of age, those with insulindependent diabetes mellitus or symptomatic coronary artery disease, those having had a cerebrovascular accident or myocardial infarction within six months of the initiation of the study, and those receiving treatment with drugs that affect
14, 1966
THERAPY-HARTER
Characteristics
b121.
February
ON INITIAL ANTIHYPERTENSIVE
glyceride,
The
American
very-low-density
Journal
of Medicine
lipoprotein
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triglyceride,
60
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lected for study had significant hypertension (160/90 mm Hg in the sitting position) that was not controlled by ultrafiltration alone. Blood pressure control was considered adequate if predialysis values were less than 145/90 mm Hg. Antlhypertensive medications were taken just prior to initiation of dialysis. All patients accepted for the study gave voluntary consent according to the procedures outlined by the Human Studies Committee, Washington University School of Medicine. All data are presented as mean values 2 standard error of the mean. Statistical analysis involved using a paired Student t test, an analysis of covariance, and regression analysis with calculation of a correlation coefficient when appropriate.
lesterol, very-low-density lipoprotein cholesterol, and highdensity lipoprotein cholesterol. Low-density lipoprotein cholesterol was calculated [20]; plasma high-density lipoprotein, cholesterol and high-density lipoprotein, cholesterol levels were measured by precipitation [21]. Standard pools of plasma,representing high, medium, and low lipid values were run with each lipoprotein assay. If the values obtained differed from the mean of the standard by more than 8 percent, the assay was repeated. The coefficient of replicate determinations for the pool was 7 percent. Post-heparin plasma lipolytic activity was measured (221 at baseline, at the end of each treatment period, and after crossover. Plasma samples used for measurement of post-heparin lipases were collected following the intravenous injection of intestinal mucosa heparin (Upjohn, 2,280 units per square meter of body surface area). Total post-heparin lipolytic lipase activity was measured on a “C-triolein-labeled substrate. Another 14C-triolein substrate containing 1 M of sodium chloride to inhibit lipoprotein lipase activity was used in the direct measurement of hepatic lipase activity [23]. The difference between postheparin lipolytic activity and hepatic lipase activity was used as the measure of the level of tissue lipoprotein lipase activity. Samples for lipase activities from each patient were run in the same assay, using standardized post-heparin plasma pools. Interassay and intra-assay coefficients of variation for these analyses were less than 15 and 10 percent, respectively. Limited amounts of antibody to hepatic lipase prevented us from determining lipoprotein lipase activity directly on all samples, but 20 random samples were assayed using antibody, and levels of post-heparin plasma lipoprotein lipase activity were within 10 percent of the levels calculated by the method just described. Samples from each patient were measured in duplicate in the same assay. We also tested whether propranolol or prazosin altered either lipase by adding antibody to hepatic lipase plus 1 M per liter of sodium chloride to post-heparin plasma. In all instances, total activity was inhibited by more than 95 percent. Stud’y Design. The study design was a crossover technique in which 25 patients went through a 30-day washout period, after which baseline lipid and chemical determinations were performed in duplicate. Patients were then randomly assigned to receive eitlier prazosin or propranolol. Cf the initial 25 patients recruited, three patients were excluded from analysis because their blood pressure levels increased to 1801 110 mm Hg or more during the initial washout phase; two refused to continue after the initial screening. Each drug was titrated to within its therapeutic range, and patients continued with the initial agent for a minimum of three months. At the end of this period, lipid studies and standard biochemical techniques were repeated in duplicate. The agents were then slowly discontinued; a second 30-day washout period followed. Baseline lipid studies and biochemical determinations were again performed; the alternate drug was substituted and titrated to therapeutic levels. After three months with the alternate antlhypertensive agent, biochemical tests were repeated. Ten patients who completed the crossover part of the study and received both p&pranolol and prazosin are the subject of this report. Blood pressure measurements were obtained in the sitting and standing positions before and after dialysis. Those se-
a4
February
14,1926
The
American Journal
of Mdiclna
RESULTS The mean predialysis systolic blood pressure for all patients studied was 164 2 4 mm Hg and the mean diastolic blood pressure was 98 f 4 mm Hg. After titration oteither
agent, the mean predialysis systolic blood pressure was 150 k 4 mm Hg and the mean diastolic blood pressure was 80 + 2 mm Hg. Sustained normal blood pressures were achieved after three months with either agent and averaged 144/77 mm Hg (predialysis) for both agents. Differences in blood pressure among patients treated with either propranolol or prazosin were not statisticany signiicant and, therefore, the data for all 10 patients were combined. Prazosin therapy was initiated at 1 mg twice daily, with the first dose given at bedtime and progressively ihcreased until blood pressure was controlled. The mean dose of prazosin administered to these patients was 11 + 2 mg per day. Propranolol was initially administered at 29 mg twice daily and progressively increased until adequate blood pressure control was achieved. The mean dose of propranolol used in all patients was 132 + 12 mg per day. In patients treated with propranolol, total triglycerides increased from 192 k 23 to 231 2 46 mg/dl (not signiffcant), which was associated with a cbminensurate increase in very-low-density lipoprotein triglycerides from 125 of:13 to 168 + 9 mg/dl (p ~0.06). In patients reoeiving prazosin therapy, plasma triglyceride levels decreased slightly from 208 + 24 to 180 + 34 mg/dl (not signkant). This change in plasma triglycerides could be accounted for by reduction of very-low-density lipoprotein triglyceride levels from 153 f 39 to 127 k 29.5 mg/dl (not significant) (Figure 1). Figure 2 illustrates the percent change from baseline for the triglyceride values in patients treated with either propranolol or prazosin. Propranolol significantly increased total triglycerides by 17 + 4 percent, whereas prazosin decreased total plasma triglyceride levels by 8 k 2 percent (p ~0.05). Propranolol increased very-lowdensity lipoprotein triglycerides by 21 2 1.5 percent, and prazosin decreased very-low-density lipoprotein triglycerides by 6 f 2 percent (p ~0.05). No change in low-density lipoprotein or high-density lipoprotein triglycerides occurred.
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P= NS 200 160 160 mg/dL 140
0 Propranolol l Prazosin
120
100 60 60 40 20 0
Figwe 1. Mean triglyceride values in 10 patients duting crossover study. Total triglyceddes (T) and very-low-density lipoprotein trig/ycerides (VLDL-T) increased widh propranolol therapy and decreased with prazosin therapy.
Total T
VLDL-T
25 20 15
% A
0 Propranolol
10
n
5 0 -5 F/guns 2. Percent change from baseline for total triglycerides m and very-lowdensity lipoprotein triglycerides (VLDL-T) with propranolol therapy and pfazosin therapy.
-10
I
-15 c
P < 0.05
P < 0.05
Total T
VLDL-T
Total cholesterol levels were unaffected by either drug (170 + 17 mg/dl after the washout phase and 180 rf: 15 mg/dk after therapy for both groups; difference not significant). High-density lipoprotein cholesterol increased by 16 r 4 percent from baseline during prazosin therapy (from 32 k 9 to 40 f 8 mg/dl; difference not significant), and decreased by 19 2 1 percent from baseline during propranolol therapy (from 44 k 7 mg/dl after washout to 31 +- 4 mg/dl after three months of therapy: p ~0.06). Fig ure 3 depicts the changes in highdensity lipoproteinp cholesterol and high-density lipoprotein3 cholesterol after propranolol and prazosin therapy. Absolute high-density lipoproteinz cholesterol values decreased from 16 + 2 to 12 f 3 mg/dl after three months of propranolol therapy (p ~0.06) and increased from 18 + 3 to 22 + 8 mg/dl after three months of prazosin therapy (not significant). Absolute high-density lipoproteina cholesterol values decreased during propranolol therapy from 22 + 1 to 19 -c 2
Februaw
Prazosin
I
14. less: ,~
mg/dl (p ~0.05) and increased from 18 -I 2 to 24 2 4 mg/dl during prazosin therapy (p ~0.05). The percent changes from baseline for these variables are depicted in Figure 4. Although no significant changes in absolute values occurred with either prazosin or propranolol for highdensity lipoprotein, cholesterol levels, propranolol reduced high-density lipoprotein3 cholesterol levels by 18 2 2 percent, and prazosin increased these values by 19 k 2 percent (p ~0.01) from respective baseline values. Because of variations during placebo (washout) phases of the study, significant differences between groups were only noted when percent change from baseline was used for analysis. Table II depicts the absolute lipid values for patients after at least three months of treatment with either propranolol or prazosin. The ratio of low-density lipoprotein cholesterol to highdensity lipoprotein cholesterol is frequently used as a pre-
The
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of Medicine
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80 l*~nnl \-..rr.
~1 ---,
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30 28 28 24 22
mg/dL
P < 0.05
P < 0.0
20 18 18 ,4 12 10
Figure 3. Mean cholesterol
subfraction values in 10 patients during crossover study. The high-density lipoprotein2 cholesterol (HDL&) and high-density lipoprotein, cholesterol (HDL3-C) levels decreased with propranolol therapy and increased with prazosin after three months of study.
8 8 4 2 0
21
P < 0.01
P = NS
P < 0.01
18 15 12 9 6 d 0 % A
n
-63
Prazosin
I7 Propranolol
112 9 -15 -16 -21 -24 -27 HDL-C
HDL2-C
Figure 4. Percent change from baseline for high-density lipoprotein cholesterol (HDL-C), high-density lipoprotein, cholesterol (HDL,-C), and high-density lipoprotein3 cholesterol (HDL&) with propranolol therapy and prazosin therapy.
HDL3-C
dictor of coronary disease. Because significant differences occurred between the groups at baseline, percent variation from baseline was used for comparison. Figure 5 illustrates these results. Propranolol increased the ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol by 4 + 1 percent, whereas no appreciable change occurred with prazosin therapy (p ~0.05). Likewise, propranolol increased the ratio of total cholesterol to high-density lipoprotein cholesterol by 6 f 1 percent, and again, no appreciable change occurred with prazosin therapy. The between-group difference for both ratios was significant (p cO.05).
88
February
14,1986
The American
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of Medlclne
The mechanisms responsible for these observed changes in lipid metabolism are unclear. Changes in the activity of the enzymes hepatic lipas? and lipoprotein lipase may explain some of the results. Figure 6 depicts the percent changes from baseline for hepatic lipase and lipoprotein lipase with both drugs. Small but significant changes were observed between the treatment groups, although the actual change for each group was not significant. Mean hepatic lipase activity was unchanged by either drug (propranolol, 9.1 + 1.9 microequivalents of free fatty acids per milliliter per hour; prazosin, 8.5 + 1.3 microequivalents of free fatty acids per millilfler per hour).
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Propranolol decreased the activity of hepatic lipase by 1.8 ? 0.4 percent, whereas hepatic lipase activity was increased by 0.7 ? 0.2 percent with prazosin (p ~0.05). Mean lipoprotein
TABLE II
COMMENTS Improvement in long-term survival of hemodialysis patients requires more than adequate dialysis care. Although the technical aspects of dialysis have been mastered, it is apparent that correcting risk factors for accelerated atherosclerosis has been unsuccessful as rates remain
extremely
high,
approaching
Total cholesterol Low-density lipoprotein cholesterol High-density lipoprotein cholesterol High-density lipoproteinz cholesterol High-density lipoprotein, cholesterol Total triglycerides Very-low-density lipoprotein triglycerides Low-density lipoprotein triglycerides “Data
50
shown
THERAPY-HARTER
ET AL
Mean Lipid Data for Patients Receiving Either Propranolol or Prazosin*
lipase activity was 9.9 k 0.8 microequiv-
alents of free fatty acids per milliliter per hour after treatment with propranolol and 15.0 lr 1.7 after prazosin therapy (p ~0.05). Lipoprotein lipase activity decreased during propranolol therapy by 2.4 + 0.3 percent but increased during prazosin therapy by 2.5 ? 1.O percent (p c0.05).
mortality
ON INITIAL ANTIHYPERTENSIVE
are after
at least three
Propranolol (II = 10)
Prazosin (n = 10)
211 f 30 93 -c 20
166” 97k
13 16
31 2 4
40 * 8
12 f 3
22 k 8
19 k 2
23 c 4
231 k 46 168? 9
180 k 34 127 f 30
41 k.5
32 t 3
months
of therapy.
6 5 4 3 2
% A
'
0 Propranolol
0
n
-1 -2 -3 -4 -5
Figure 5. Percent change from baseline for ratio of low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-CIHDL-C) and ratio of total cholesterol to high-density lipoprotein cholesterol (total CIHDL-C) with propran0101 therapy and prazosin therapy.
P < 0.05
P < 0.05
LDL-C/HDL-C
Total CIHDL-C
Prazosin
”
% A
Figure 6. Percent change from baseline for heparic lipase and lipoprotein lipase with propranolol therapy and prazosin therapy.
February
2.7 2.4 2.1 1.8 1.5 1.2 .9 .8 .3 O- .3 - .6 - .9 -1.2 -1.5 -1.8 -2.1 -2.4 -2.7 ’
14, 1999
-
P n
Prazosin
0 Propranolol
I
P < 0.05
Lipoprotein
Hepatic lipase
The
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P < 0.05 lipase
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percent at five years in some institutions [2]. Thus, effective control of hypertension, treatment of risk factors such as smoking and abnormal lipid metabolism, correction of anemia, and improvement in glucose metabolism are all necessary if survival is to be prolonged in this population. Hypertension occurs in more than 50 percent of all dialysis patients [7,24]. Adequate dialytic care with ultrafiltration to “dry weight” will reduce blood pressure to normal levels in approximately 80 percent of the patients. Vertes et al [7] described this population of patients as having volume-dependent hypertension. Antihypertensive medications may be necessary to control predialysis hypertension in some of these patients [25]. An additional 10 percent of patients have high-renin hypertension and will require potent vasodilator therapy [7,25,28], angiotensin II blockage [271, diafiltration [ll], treatment with beta blockers [8,28] and, occasionally, nephrectomy [29] for blood pressure control. The remaining patients have various causes for their hypertension, but most cases are probably related to abnormalities in the sympathetic nervous system [lO,ll]. Such patients have excessive autonomic activity with high plasma dopamine beta-hydroxylase and catecholamine levels [lO,l l] and are best treated with agents that reduce peripheral vascular resistance [10,25]. Although postdialysis blood pressures are frequently within the normal range-except possibly for those with high-renin hypertension [7,28,29]-predialysis hypertension may still be a considerable risk factor that is, as yet, unaddressed at most centers. It is our recommendation that normal blood pressures be maintained before and after the dialysis procedure. Thus, patients whose blood pressures cannot be controlled with adequate ultrafiltration should be treated with pharmacologic agents to reduce predialysis blood pressure values to within the normal range. This study demonstrates clearly that both propranolol and prazosin, in relatively modest doses, will control predialysis hypertension in patients receiving hemodialysis treatment. The symptomatic side effects of both agents were relatively minor in all patients studied, and the antihypertensive effects were acceptable.
Previous studies have suggested that the treatment of mild hypertension in non-uremic persons is not associated with an improvement in the cardiovascular risk [30-321. These observations may be at least partially explained by changes in lipid metabolism (decreased high-density lipoprotein and increased very-low-density lipoprotein triglycerides) caused by the antihypertensive agents [17,30]. In non-uremic hypertensive patients, prazosin has been shown not to adversely affect lipid profiles [33]. In some studies, prazosin has been shown to decrease plasma triglyceride levels and increase high-density lipoprotein cholesterol levels [34,35]. Propranolol, on the other hand, raises plasma triglyceride levels and reduces high-density lipoproteina cholesterol levels in non-uremic subjects [35] and, in a cross-sectional study of dialysis patients, seemed to worsen their lipid profiles [18]. Such detrimental effects on lipid metabolism would be extremely important in dialysis patients who are already at risk for lipid abnormalities and accelerated atherosclerosis. A worsening of lipid profiles in these patients might increase their risk for coronary artery disease. This study demonstrated that propranolol treatment was associated with increases in plasma triglyceride levels and decreases in high-density lipoprotein cholesterol levels (predominately a decrease in high-density lipoprotein3 cholesterol). In contrast, prazosin treatment was associated with a modest decrease in total triglyceride levels, an increase in high-density lipoprotein cholesterol, and a significant increase in high-density lipoproteina cholesterol. Although the clinical significance of an increase or decrease in the high-density lipoprotein3 subfraction has not been determined, prazosin therapy was also associated with an increase in the high-density lipoprotein;! cholesterol subfraction. These changes suggest that propranolol treatment of patients receiving hemodialysis is associated with a deterioration in lipid profiles, whereas prazosin therapy does not adversely affect the lipid profiles. Determining the significance of these observed lipid changes will require long-term studies that will more clearly delineate the mechanisms involved as well as their potential effects on the survival of dialysis patients.
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99
Green D, Stone NJ, Krumlovsky FA: Putative atherogenic factors in patients with chronic renal failure. Prog Cardiovasc Dis 1983; 28: 133-144. Lindner A, Charra 6, Sherrard DJ, Scribner BH: Accelerated atherosclerosis in prolonged maintenance hemodialysis. N Engl J Med 1974; 290: 897-701. Lazarus JM, Lowrie EG, Hampers CL, Merrill JP: Cardiovascular disease in uremic patients on hemodialysis. Kidney Int 1975; 7: (suppl 2) 167-175. Vincenti F, Amend WJ, Abele J, Feduska NJ, Salvatierra 0 Jr: The role of hypertension in hemodialysis-associated atherosclerosis. Am J Med 1980; 68: 363-369.
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Bagdade J, Casaretto A, Albers J: Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man. J Lab Clin Med 1976; 87: 37-46. Argy WP, Chester AC, Siemsen AS, Rokowski TA, Schreiner GE: Hypertension in two hemodialysis cohorts. Trans Am Sot Artif Intern Organs 1982; 28: 329-332. Vertes V, Cangiano JL, Berman LB, Gould A: Hypertension in end-stage renal disease. N Engl J Med 1969; 280: 978-981. Lindner A, Douglas SW, Adamson JW: Propranolol effects in long-term hemodiatysis patients with renin-dependent hypertension. Ann Intern Med 1978; 66: 457-462. Chrysanthakopoulos SG, Kastagir BK. Jubiz W, Kolff WJ: Hy-
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pertension in patients on maintenance hemodialysis: evaluation of peripheral renin activity and bilateral nephrectomy. Am J Med Sci 1972; 264: 9-21. Lilley JJ, Golden J, Stone RA: Adrenergic regulation of blood pressure in chronic renal failure. J Clin Invest 1976; 57: 11901200. Mitas JA, O’Connor DT, Stone RA: Hypertension in renal insufficiency. Postgrad Med 1978; 64: 113-120. Goldberg AP, Hatter HR, Patsch W, et al: Racial differences in plasma high-density lipoproteins in patients receiving hemodialysis. N Engl J Med 1983; 308: 1245-1252. Haire HM, Sherrard DJ, Scardapane D, et al: Smoking, hypertension, and mortality in a maintenance dialysis population. Cardiovasc Med 1978; 3: 1163-l 168. Goldberg AP, Hagberg JM, Delmez JA, Haynes ME, Harter HR: Metabolic effects of exercise training in hemodialysis patients. Kidney Int 1980; 18: 754-761. Goldberg AP, Hagberg JM, Delmez JA, Florman RW, Hatter HR: Effects of exercise training on coronary risk factors in hemodialysis patients. Proc Dialysis Transpl Forum 1979; 9: 39-43. Brunzell JD, Albers JJ, Haas LB, et al: Prevalence of serum lipid abnormalities in chronic hemodialysis. Metabolism 1977; 26: 903-910. Johnson BF, Romero L, Johnson J, Marwaha R: Comparative effects of propranotol and prazosin upon serum lipids in thiazide-treated hypertensive patients. Am J Med 1984; 76 (suppl 2A): 109-l 12. Goldberg AP, Tindira CA, Harter HR: Coronary risk in patients with end-stage renal disease: interaction of hypertension with hyperlipidemia. J Cardiovasc Pharmacol 1982; 4: S257S261. Meltzer VN, Goldberg AP, Tindira CA, Naumovich AD, Harter HR: Effects of prazosin and propranolol on blood pressure and plasma lipids in patients undergoing chronic hemodialysis. Am J Cardiol 1984; 53: 40A-45A. National Institutes of Health: Manual of laboratory operations, Lipid Research Clinics Program, vol 1, lipid and lipoprotein analyses. DHEW Publication No. (NIH) 75-628 Bethesda: National Institutes of Health, 1982. Gidez LI, Miller GJ, Burstein M, Slagle S, Eder HA: Separation and quantitation of subclasses of human plasma high-density lipoproteins by a simple precipitation procedure. J Lipid Res 1982; 23: 1206-1223.
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Goldberg A, Sherrard DJ, Brunzell JD: Adipose tissue lipoprotein lipase in chronic hemodialysis: role in plasma triglyceride metabolism. J Clin Endocrinol Metab 1978; 47: 1173-l 182. Huttunen JK, Ehnholm C, Kinnunen PKJ, Nikkila EA: An immunochemical method for the selective measurement of two triglyceride lipases in human post-heparin plasma. Clin Chim Acta 1975; 63: 335-347. Chester AC, Schreiner GE: Hypertension and hemodialysis. Trans Am Sot Artif Intern Organs 1978; 24: 36-42. Hatter HR, Delmez JA: Effects of prazosin in the control of blood pressure in hypertensive dialysis patients, J Cardiovasc Pharmacol 1979; 1 (suppl): S43-S55. Pettinger WA, Mitchell HC: Minoxidil-an alternative to nephrectomy for refractory hypertension. N Engl J Med 1973; 289: 167-l 71. MacGregor GA, Dawes PM: Angiotensin II blockade in hypertensive dialysis patients. Prog Biochem Pharmacol 1976; 12: 190-199. Maggiore Q, Zoccali C, Monzani G, Contini C: Chronic hemody namic effects of propranolol treatment in dialysis-refractory hypertension. Nephron 1978; 22: 391-398. Lee C, Neff MS, Slifkin RF, Leiter E: Bilateral nephrectomy for hypertension in patients with chronic renal failure on a dialysis program. J Urol 1978; 119: 20-22. Helgeland A: Treatment of mild hypertension: a five-year controlled drug trial. The Oslo Study. Am J Med 1980; 69: 725732. Veterans Administration Cooperative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 11431152. Multiple Risk Factor Intervention Trial Research Group: Multiple Risk Factor Intervention Trial. Risk factor changes and mortality results. JAMA 1982; 248: 1465-1477. Havard CWH, Khokhar AM, Flax JS: Open assessment of prazosin on plasma lipids. J Cardiovasc Pharmacol 1982; 4: S238-S241. Kokubu T, ltoh I, Kurita H, Ochi T, Murata K, Yuba I: Effects of prazosin on serum lipids. J Cardiovasc Pharmacol 1982; 4: S228-5232. Neusy AJ, Lowenstein J: Effects of prazosin, atenolol, and thiazide diuretic on plasma lipids in patients with essential hypertension. Am J Med 1986; 80 (suppl 2A): 94-99.
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