- Email: [email protected]
Effectiveness of indapamide versus enalapril as second-step therapy of systemic hypertension
The pattern for women was very similar to that reported by Doring and Loddenkemper,’ although we found that a reanalysis of their data for women aged <60 years was not statistically significant (x2 = 8.78; p >0.05). The reasons for the different patterns found betWeeU men and women are UUknOWII and merit further research.
1. Diiring H, Loddenkemper R. Statistische Untersuchungen giber den Herzinfarkt. Z Kreislauffomh 1962;5 I:40 I-442. 2. World Health Organization. Myccardial infarction community registers. Pub lit Health in Europe No. 5. Copenhagen:’ World Health Organization, 1976. 3. Macfarlane A, White G. Deaths: the weekly cycle. Population Trends No. 7. London: Her Majesty’s Stationery Oftice, 1977. 4. Ndyhe S. Short and medium-term variations in mortality in Finland. &and/ sot ,ued 1981(suppl):21-101. . 5. Massing W, Angermeyer MC. Myocardial infarction on various days of the week. Psycho/ Med 1985;15:851-857.
Effectiveness of lndapamide Versus Enalapril as sedond-Step Therapy of Systemic Hypertension Richard Ames, MD, George Griffing, MD, Thomas Marbury, MD, Eugene Miller, MD, James Schoenberger, MD, Bruce Glenn, MS, Vincent Benn, PhD, and Donna Wilkinson, RN
ngiotensin-converting enzyme inhibitors are recomA mended and increasingly used as the initial drug for the treatment of hypertension.lv2 When hypertension is
5 mg;lday. Those with higher or lower blood pressure were removedfrom the study. If diastolic blood pressure remained between 95 and I20 mm Hg after 2 weeks of not fully controlled by an initial dose of an agent of this enalapril, the patient qualified for randomization. Randrug class, it is unclear whether upward titration is as domization separated patients into 3 add-on treatment effective as adding a second drug. This issue was exam- regimens: (I) indapamide (2.5 mglday), (2) enalapril(5 ined by studying patients unresponsive to an initial dose mgfday), or (3) matchingplacebo. All patients continued of enalapril. We compared the effectiveness of the up to take the open treatment of 5 mg of enalapril daily ward titration of enalapril with that of adding the diuretic during the double-blind phase. indapamide. Because there are data to suggest a flat doseVisits were weekly before randomization and monthresponse curve for enalapril > 10 to 20 mg/day?q4 pa- ly after it. At each visit vital signs and weight were tients uncontrolled with 5 mg/day, a dose presumably recorded before the daily dose of medication. Blood was drawn for a complete cell count and multisystem chemnear the steep portion of the curve, were studied. This was a prospective randomized, double-blind, istry testing at the screening visit, at the randomization visit and at each of the 4 monthly double-blind visits. placebo-controlled parallel study of indapamide as addon therapy in comparison with upward titration of enala- Measurements recorded at the randomization visit (i.e., pril in mild to moderate hypertension. Patients remainafter 2 weeks of enalapril therapy) served as the baseing hypertensive after receiving enalapril (5 mgjday) line. were randomized to supplemental treatment with an adAdherence to the drug rep-men was assessed by pill ditional 5 mg of enalapril, indapamide (2.5 mglday) or counts. Patients not taking 80% of their medication on 2 consecutive visits were withdrawn from the study. No placebo. Ambulatory patients with a history of hypertension dietary advice was given. Blood testing was performed by were recruited by 5 investigators who used a common a central laboratory, namely, Scicor Laboratory of Indiprotocol. The patients were men and women aged be- anapolis, Indiana. tween 21 and 75 years who were free of clinically evident With regard to statistical methods, mean changes in concomitant disease. Patients were also excluded for blood pressure among the treatment regimens at 4,8,12 obesity or use of other drug treatments including insulin, and 16 weeks, and the last visit were compared using 2lithium and nonsteroidal antiinflammatory drugs. way analysis of variance. The ‘last visit” designation After written consent was signed, patients discontinrepresents the last study visit that patients who received ued taking any prior antihypertensive drug treatment. double-blind treatment were seen, whether or not they Placebo capsules were given in open fashion during a 3- completed the 16-week protocol. Changes in blood week washout period. At the end of the placebo period, chemistry from baseline were analyzed within each patients whose supine diastolic blood pressure was be- treatment group by Student’s paired t test at each of the tween 95 and I I5 mg Hg were given enalapril in a dose of double-blind visits. Only the l&week laboratory values are reported. Statistical significance was taken as p From Columbia University, College of Physicians and Surgeons, and <0.05 (2-tailed). St. Luke&Roosevelt Hospital Center, 428 West 59th Street, New Informed consent was signed by I87 patients. TwenYork, New York 10019. This report was supported by a grant from ty-seven (14%) were withdrawn from the study during Rhone Poulenc Rarer, Inc., Fort Washington, Pennsylvania. Manuscript received January 3, 1991; revised manuscript received and ac- the 3-week washout period (23patients because of blood cepted August 30, 199 1.. pressures not meeting protocol requirements and 4 pa-
BRIEF REPORTS 267
r
TABLE
I Clinical
Features
No. of pts. Women/men Black, hispanic, white Age tyr) Weight (Ibs) Body mass index Supine blood pressure Systolic (mm Hg) Diastolic (mm Hg)
of Protocol-Eligible
Patients
Placebo
Enalapril
lndapamide
39 18/21
30 15/15
29 14115
9, 1,29 54 k 11* 192 2 43*
19 12 29 3.5
4, 2, 23 55 + 10 182 f 32 27.8 f 3.5
156 ‘- 18*
157 ‘- 14
154 -t 20
101 z!z 5*
101 +L 5
100 k 5
29.7 2 5.9*
5, 6, 57 + 176 ‘27.3 ”
-I
Group mean blood pressures in the supine and standing positions at the end of washout, baseline, the 4 monthly double-blind visits, and the last visit are depicted in Figures I and 2. Diastolic blood pressure decreased significantly from baseline in both the supine and standing positions at each visit in all 3 treatment groups. However, the decrease in the group taking combination therapy was significantly greater at all visits (p
*Mean T standard deviation. Hispanics were unevenly distributed among the groups.
tients for other reasons). After the 3-week washout period, 16Opatients qualified with a diastolic bloodpressure between 95 and 1 I5 mm Hg and were entered into a 2week treatment period with enalapril(5 mglday). At the end of the 2-week period, 32 patients (20%) were not randomized because of a diastolic blood pressure <95 mm Hg and 5 (3%) for other reasons. Thus, 123 patients were randomized to the 16-week double-blind add-on treatment period. However, 18 patients with diastolic blood pressure <95 mm Hg were erroneously randomized. These subjects were eliminated from the efficacy analysis because their baseline blood pressure would be too low to judge response. Seven of the properly randomized patients failed to complete 21 days of double-blind treatment and were excluded from the primary analysis. Hence, 98 subjects were properly evaluable for effects of the double-blind treatment on blood pressure and blood chemistry. The demographic features of these 98 patients are displayed in Table I. All 123 randomized patients were included in the analysis of adverse experiences. Enalapril 5mg
t
T
160 T
Enalapril IO mg
T
Enalapril lndapamide
5 mg 2.5 mg
158
155
136 T
cpde
135
pressure mmHg 115
95 85
268
THE AMERICAN
88t
38 39 39 35 28 26
“ISIT,MONTFl
30 30 30 26 26 24 WB1234
WB1234
JOURNAL
I
OF CARDIOLOGY
VOLUME
69
JANUARY
15. 1992
2:
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L
bination group, but the group mean value remained within the normal range. Five of 22patients (23%) in the combination group had serum potassium levels <3.5 mEq/liter at the sixteenth week of treatment. The lowest value recorded was 3.0 mEq/liter in the combination group. Uric acid increased significantly with the combination regimen. Total cholesterol increased 4.5% with combination therapy, but this change did not reach statistical significance. Uric acid and urea nitrogen increased significantly in the enalapril 10 mg group. Serum potassium was unchanged by enalapril therapy. Symptomatic side effects were similar in the 3 treatment groups.
This multicenter protocol compared the effectiveness of different strategies for the second-step treatment of hypertension. Patients remaining hypertensive after treatment with enalapril (5 mg/day) received a higher dose of enalapril or the addition of a diuretic (i.e., indapaEnalapril 5 w
-
mide) . The addition of indapamide proved more effective in reducing blood pressure. The major effect of the increased dose of enalapril was to prevent the late rise in systolic blood pressure at week 16 and the last visit seen in the enalapril 5 mg group (Figure 2). Because of further evidence of a tendency to escape from control by low-dose therapy, 8 patients were removed from the 5 mg group due to inadequate control, whereas only 3 and 2 patients were removed for this reason from the 10 mg enalapril and the combination groups, respectively. The importance of a placebo control group in study design is highlighted in this trial. The 29% response rate in the enalapril 10 mg group (Figure 3, last visit) implies a notable effect of the increased dose. However, the 23% response rate in the placebo group changes the interpretation. The similar response rate in the 2 monotherapy groups suggests that a late response to the initial 5 mg Enalapril 10 mg
161 -
156
Enalapril lndapamide
157
155
155 -
5 mg 2.5 mg
154
t
tttt ****
t * 136
pressure mmHg 115
103
104
95 smldid”g
135 :rlr~t 85
VISIT/MONTH
N
102
100 tttt
100
t
tttt
t
36 39 39 35 28 26
39
30 30 30 26 26 23
WB1234
L
WB1234
30
**** tttt 26 29 29 29 26 24
L
WB1234
91 * t 29 L
FlGURE2.Rbod1wesswebtbedandingpesitbnbingtbe3&ugregimens.Bbedpresswewassiwificantlybwer at al do&b-bdvbRs with tbe mdbutbn et dmugs (p
100 90
1 I I I
Enalapril - 5mg Enalapril - 1Omg Enalapril 5mg +Indapamide
J
2.5mg
FIGURE 3. Meof rubjcctsineadaofthe3 -regbnnswitbsuPi---CSOllWlRg4ltthl!VdllUS
weeksefbeabmnt. b=p=O.O6 -(S lngh *p <0.02 betbdosesefemdapd.
versus
4
8
12
16
Week of Trial BRIEF
REPORTS
269
Enalapril 5w
Enalapril 1Omg
Enalapril5m lndapamide
+ 2. 9 mg
T FlGuRE4.chm5esin IWUlntadWdght
-hi--, -Ph-in thethabnent groloa tp
ttt; Visltltdonth
1234
Last
1234
Last
TABLE II Selected Blood Chemistry Values at Baseline and Changes at Week 16 by Treatment Group Baseline Mean
Change at Week 16
p Value vs Baseline
15.5 14.4 13.4
-0.3 1.6 1.2
NS 0.03 NS
4.9 5.1 5.0
0.3 0.8 1.3
NS 0.01 0.01
4.3 4.4 4.5
-0.05 -0.02 -0.53
NS NS 0.01
107 103 100
-2.7 4.5 5.3
NS NS NS
225 217 217
5 -3 10
Urea nitrogen (mg/dl) Placebo Enalapril lndapamide Uric acid (mg/dl) Placebo Enalapril lndapamide Potassium (mEq/liter) Placebo Enalapril lndapamide Glucose (mg/dl) Placebo Enalapril lndapamide Total cholesterol (mgldl) Placebo Enalapril lndapamide Triglycerides (mg/dl) Placebo Enalapril lndapamide
138 173 170
-4 -18 7
NS NS 0.08 NS NS NS
NS = not significant.
dose of enalapril or a placebo effect accounted for the additional reduction in diastolic blood pressure in the double-blind phase. Perhaps the 2 weeks of singleblind therapy was too short an interval to judge the full effect of enalapril. Enalapril(l0 mg/day) might have produced a greater antihypertensive effect if given in a divided daily schedule. We selected a once-daily regimen for its convenience of administration.
270
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
1
t 23
4
Last
The combination regimen produced a mild degree of hypokalemia despite the expected potassium-sparing property of enalapril. The lowest potassium level recorded was 3.0 mEq/liter; thus, few patients would require corrective measures. Total cholesterol increased nonsignificantly by 10 mg/dl (Table II). We did not obtain cholesterol fractionation to ascertain which lipoprotein components were raised. There are reports of increases in high-density lipoprotein cholesterol with indapamide.5Jj Thus, it is unclear whether this lipid modification represents an adverse effect. Using Framingham estimates, the combination regimen would lower 6-year coronary prob ability by 15% in a 55-year-old man, taking into account both cholesterol and systolic blood pressure changes.7 The 10 mg enalapril dose would produce no change from baseline in coronary probability since neither systolic blood pressure nor other risk factors changed significantly. In addition, the pressure-mediated complications of hypertension, namely stroke and heart failure, would be more favorably impacted by the combination regimen. 1. Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. The 1988 report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-1038. 2. WHO/ISH Mild Hypertension Liaison Committee. 1989 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. J Hypertenr 1989;7:689-693. 3. Salvetti A, Arzilli F. Chronic dose-response curve of enalapril in essential hypertensives. Am J Hvpertens 1989;2:352-354. 4. Sassano P, Chatellier G, Billaud E, Corvol P, Menard J. Comparison of increase in the enalapril dose and addition of hydrochlomthiazide as wxnd-step treatment of hypertensive patients not controlled by enalapril alone. J Cardiocasc Pharmacol 1989;13:314-319. 1. Meyer-Sabellek W, Gotzen R, Heitz J, Amtz HR. Schulte KL. Serum lipopm tein levels during long-term treatment of hypertension with indapamide. Hype tension 1985;7(suppl II):Il-170-11-174. 6. Print M, Beall SP, Nichoakis GE, Feldman EB, Carr AA, Feldman DS, Hames CG. Biochemical, endocrine, and mineral effects of indapamide in black women. J Clin Pharmacoi 1990;30:121-126. 7. Kannel WB. Coronary Risk Handbook. American Heart Association. Dallas, Texas: 1973.
JANUARY 15, 1992
1. Diiring H, Loddenkemper R. Statistische Untersuchungen giber den Herzinfarkt. Z Kreislauffomh 1962;5 I:40 I-442. 2. World Health Organization. Myccardial infarction community registers. Pub lit Health in Europe No. 5. Copenhagen:’ World Health Organization, 1976. 3. Macfarlane A, White G. Deaths: the weekly cycle. Population Trends No. 7. London: Her Majesty’s Stationery Oftice, 1977. 4. Ndyhe S. Short and medium-term variations in mortality in Finland. &and/ sot ,ued 1981(suppl):21-101. . 5. Massing W, Angermeyer MC. Myocardial infarction on various days of the week. Psycho/ Med 1985;15:851-857.
Effectiveness of lndapamide Versus Enalapril as sedond-Step Therapy of Systemic Hypertension Richard Ames, MD, George Griffing, MD, Thomas Marbury, MD, Eugene Miller, MD, James Schoenberger, MD, Bruce Glenn, MS, Vincent Benn, PhD, and Donna Wilkinson, RN
ngiotensin-converting enzyme inhibitors are recomA mended and increasingly used as the initial drug for the treatment of hypertension.lv2 When hypertension is
5 mg;lday. Those with higher or lower blood pressure were removedfrom the study. If diastolic blood pressure remained between 95 and I20 mm Hg after 2 weeks of not fully controlled by an initial dose of an agent of this enalapril, the patient qualified for randomization. Randrug class, it is unclear whether upward titration is as domization separated patients into 3 add-on treatment effective as adding a second drug. This issue was exam- regimens: (I) indapamide (2.5 mglday), (2) enalapril(5 ined by studying patients unresponsive to an initial dose mgfday), or (3) matchingplacebo. All patients continued of enalapril. We compared the effectiveness of the up to take the open treatment of 5 mg of enalapril daily ward titration of enalapril with that of adding the diuretic during the double-blind phase. indapamide. Because there are data to suggest a flat doseVisits were weekly before randomization and monthresponse curve for enalapril > 10 to 20 mg/day?q4 pa- ly after it. At each visit vital signs and weight were tients uncontrolled with 5 mg/day, a dose presumably recorded before the daily dose of medication. Blood was drawn for a complete cell count and multisystem chemnear the steep portion of the curve, were studied. This was a prospective randomized, double-blind, istry testing at the screening visit, at the randomization visit and at each of the 4 monthly double-blind visits. placebo-controlled parallel study of indapamide as addon therapy in comparison with upward titration of enala- Measurements recorded at the randomization visit (i.e., pril in mild to moderate hypertension. Patients remainafter 2 weeks of enalapril therapy) served as the baseing hypertensive after receiving enalapril (5 mgjday) line. were randomized to supplemental treatment with an adAdherence to the drug rep-men was assessed by pill ditional 5 mg of enalapril, indapamide (2.5 mglday) or counts. Patients not taking 80% of their medication on 2 consecutive visits were withdrawn from the study. No placebo. Ambulatory patients with a history of hypertension dietary advice was given. Blood testing was performed by were recruited by 5 investigators who used a common a central laboratory, namely, Scicor Laboratory of Indiprotocol. The patients were men and women aged be- anapolis, Indiana. tween 21 and 75 years who were free of clinically evident With regard to statistical methods, mean changes in concomitant disease. Patients were also excluded for blood pressure among the treatment regimens at 4,8,12 obesity or use of other drug treatments including insulin, and 16 weeks, and the last visit were compared using 2lithium and nonsteroidal antiinflammatory drugs. way analysis of variance. The ‘last visit” designation After written consent was signed, patients discontinrepresents the last study visit that patients who received ued taking any prior antihypertensive drug treatment. double-blind treatment were seen, whether or not they Placebo capsules were given in open fashion during a 3- completed the 16-week protocol. Changes in blood week washout period. At the end of the placebo period, chemistry from baseline were analyzed within each patients whose supine diastolic blood pressure was be- treatment group by Student’s paired t test at each of the tween 95 and I I5 mg Hg were given enalapril in a dose of double-blind visits. Only the l&week laboratory values are reported. Statistical significance was taken as p From Columbia University, College of Physicians and Surgeons, and <0.05 (2-tailed). St. Luke&Roosevelt Hospital Center, 428 West 59th Street, New Informed consent was signed by I87 patients. TwenYork, New York 10019. This report was supported by a grant from ty-seven (14%) were withdrawn from the study during Rhone Poulenc Rarer, Inc., Fort Washington, Pennsylvania. Manuscript received January 3, 1991; revised manuscript received and ac- the 3-week washout period (23patients because of blood cepted August 30, 199 1.. pressures not meeting protocol requirements and 4 pa-
BRIEF REPORTS 267
r
TABLE
I Clinical
Features
No. of pts. Women/men Black, hispanic, white Age tyr) Weight (Ibs) Body mass index Supine blood pressure Systolic (mm Hg) Diastolic (mm Hg)
of Protocol-Eligible
Patients
Placebo
Enalapril
lndapamide
39 18/21
30 15/15
29 14115
9, 1,29 54 k 11* 192 2 43*
19 12 29 3.5
4, 2, 23 55 + 10 182 f 32 27.8 f 3.5
156 ‘- 18*
157 ‘- 14
154 -t 20
101 z!z 5*
101 +L 5
100 k 5
29.7 2 5.9*
5, 6, 57 + 176 ‘27.3 ”
-I
Group mean blood pressures in the supine and standing positions at the end of washout, baseline, the 4 monthly double-blind visits, and the last visit are depicted in Figures I and 2. Diastolic blood pressure decreased significantly from baseline in both the supine and standing positions at each visit in all 3 treatment groups. However, the decrease in the group taking combination therapy was significantly greater at all visits (p
*Mean T standard deviation. Hispanics were unevenly distributed among the groups.
tients for other reasons). After the 3-week washout period, 16Opatients qualified with a diastolic bloodpressure between 95 and 1 I5 mm Hg and were entered into a 2week treatment period with enalapril(5 mglday). At the end of the 2-week period, 32 patients (20%) were not randomized because of a diastolic blood pressure <95 mm Hg and 5 (3%) for other reasons. Thus, 123 patients were randomized to the 16-week double-blind add-on treatment period. However, 18 patients with diastolic blood pressure <95 mm Hg were erroneously randomized. These subjects were eliminated from the efficacy analysis because their baseline blood pressure would be too low to judge response. Seven of the properly randomized patients failed to complete 21 days of double-blind treatment and were excluded from the primary analysis. Hence, 98 subjects were properly evaluable for effects of the double-blind treatment on blood pressure and blood chemistry. The demographic features of these 98 patients are displayed in Table I. All 123 randomized patients were included in the analysis of adverse experiences. Enalapril 5mg
t
T
160 T
Enalapril IO mg
T
Enalapril lndapamide
5 mg 2.5 mg
158
155
136 T
cpde
135
pressure mmHg 115
95 85
268
THE AMERICAN
88t
38 39 39 35 28 26
“ISIT,MONTFl
30 30 30 26 26 24 WB1234
WB1234
JOURNAL
I
OF CARDIOLOGY
VOLUME
69
JANUARY
15. 1992
2:
WB1234
L
bination group, but the group mean value remained within the normal range. Five of 22patients (23%) in the combination group had serum potassium levels <3.5 mEq/liter at the sixteenth week of treatment. The lowest value recorded was 3.0 mEq/liter in the combination group. Uric acid increased significantly with the combination regimen. Total cholesterol increased 4.5% with combination therapy, but this change did not reach statistical significance. Uric acid and urea nitrogen increased significantly in the enalapril 10 mg group. Serum potassium was unchanged by enalapril therapy. Symptomatic side effects were similar in the 3 treatment groups.
This multicenter protocol compared the effectiveness of different strategies for the second-step treatment of hypertension. Patients remaining hypertensive after treatment with enalapril (5 mg/day) received a higher dose of enalapril or the addition of a diuretic (i.e., indapaEnalapril 5 w
-
mide) . The addition of indapamide proved more effective in reducing blood pressure. The major effect of the increased dose of enalapril was to prevent the late rise in systolic blood pressure at week 16 and the last visit seen in the enalapril 5 mg group (Figure 2). Because of further evidence of a tendency to escape from control by low-dose therapy, 8 patients were removed from the 5 mg group due to inadequate control, whereas only 3 and 2 patients were removed for this reason from the 10 mg enalapril and the combination groups, respectively. The importance of a placebo control group in study design is highlighted in this trial. The 29% response rate in the enalapril 10 mg group (Figure 3, last visit) implies a notable effect of the increased dose. However, the 23% response rate in the placebo group changes the interpretation. The similar response rate in the 2 monotherapy groups suggests that a late response to the initial 5 mg Enalapril 10 mg
161 -
156
Enalapril lndapamide
157
155
155 -
5 mg 2.5 mg
154
t
tttt ****
t * 136
pressure mmHg 115
103
104
95 smldid”g
135 :rlr~t 85
VISIT/MONTH
N
102
100 tttt
100
t
tttt
t
36 39 39 35 28 26
39
30 30 30 26 26 23
WB1234
L
WB1234
30
**** tttt 26 29 29 29 26 24
L
WB1234
91 * t 29 L
FlGURE2.Rbod1wesswebtbedandingpesitbnbingtbe3&ugregimens.Bbedpresswewassiwificantlybwer at al do&b-bdvbRs with tbe mdbutbn et dmugs (p
100 90
1 I I I
Enalapril - 5mg Enalapril - 1Omg Enalapril 5mg +Indapamide
J
2.5mg
FIGURE 3. Meof rubjcctsineadaofthe3 -regbnnswitbsuPi---CSOllWlRg4ltthl!VdllUS
weeksefbeabmnt. b=p=O.O6 -(S lngh *p <0.02 betbdosesefemdapd.
versus
4
8
12
16
Week of Trial BRIEF
REPORTS
269
Enalapril 5w
Enalapril 1Omg
Enalapril5m lndapamide
+ 2. 9 mg
T FlGuRE4.chm5esin IWUlntadWdght
-hi--, -Ph-in thethabnent groloa tp
ttt; Visltltdonth
1234
Last
1234
Last
TABLE II Selected Blood Chemistry Values at Baseline and Changes at Week 16 by Treatment Group Baseline Mean
Change at Week 16
p Value vs Baseline
15.5 14.4 13.4
-0.3 1.6 1.2
NS 0.03 NS
4.9 5.1 5.0
0.3 0.8 1.3
NS 0.01 0.01
4.3 4.4 4.5
-0.05 -0.02 -0.53
NS NS 0.01
107 103 100
-2.7 4.5 5.3
NS NS NS
225 217 217
5 -3 10
Urea nitrogen (mg/dl) Placebo Enalapril lndapamide Uric acid (mg/dl) Placebo Enalapril lndapamide Potassium (mEq/liter) Placebo Enalapril lndapamide Glucose (mg/dl) Placebo Enalapril lndapamide Total cholesterol (mgldl) Placebo Enalapril lndapamide Triglycerides (mg/dl) Placebo Enalapril lndapamide
138 173 170
-4 -18 7
NS NS 0.08 NS NS NS
NS = not significant.
dose of enalapril or a placebo effect accounted for the additional reduction in diastolic blood pressure in the double-blind phase. Perhaps the 2 weeks of singleblind therapy was too short an interval to judge the full effect of enalapril. Enalapril(l0 mg/day) might have produced a greater antihypertensive effect if given in a divided daily schedule. We selected a once-daily regimen for its convenience of administration.
270
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 69
1
t 23
4
Last
The combination regimen produced a mild degree of hypokalemia despite the expected potassium-sparing property of enalapril. The lowest potassium level recorded was 3.0 mEq/liter; thus, few patients would require corrective measures. Total cholesterol increased nonsignificantly by 10 mg/dl (Table II). We did not obtain cholesterol fractionation to ascertain which lipoprotein components were raised. There are reports of increases in high-density lipoprotein cholesterol with indapamide.5Jj Thus, it is unclear whether this lipid modification represents an adverse effect. Using Framingham estimates, the combination regimen would lower 6-year coronary prob ability by 15% in a 55-year-old man, taking into account both cholesterol and systolic blood pressure changes.7 The 10 mg enalapril dose would produce no change from baseline in coronary probability since neither systolic blood pressure nor other risk factors changed significantly. In addition, the pressure-mediated complications of hypertension, namely stroke and heart failure, would be more favorably impacted by the combination regimen. 1. Joint National Committee on the Detection, Evaluation, and Treatment of High Blood Pressure. The 1988 report of the Joint National Committee on the Detection, Evaluation and Treatment of High Blood Pressure. Arch Intern Med 1988;148:1023-1038. 2. WHO/ISH Mild Hypertension Liaison Committee. 1989 guidelines for the management of mild hypertension: memorandum from a WHO/ISH meeting. J Hypertenr 1989;7:689-693. 3. Salvetti A, Arzilli F. Chronic dose-response curve of enalapril in essential hypertensives. Am J Hvpertens 1989;2:352-354. 4. Sassano P, Chatellier G, Billaud E, Corvol P, Menard J. Comparison of increase in the enalapril dose and addition of hydrochlomthiazide as wxnd-step treatment of hypertensive patients not controlled by enalapril alone. J Cardiocasc Pharmacol 1989;13:314-319. 1. Meyer-Sabellek W, Gotzen R, Heitz J, Amtz HR. Schulte KL. Serum lipopm tein levels during long-term treatment of hypertension with indapamide. Hype tension 1985;7(suppl II):Il-170-11-174. 6. Print M, Beall SP, Nichoakis GE, Feldman EB, Carr AA, Feldman DS, Hames CG. Biochemical, endocrine, and mineral effects of indapamide in black women. J Clin Pharmacoi 1990;30:121-126. 7. Kannel WB. Coronary Risk Handbook. American Heart Association. Dallas, Texas: 1973.
JANUARY 15, 1992