Abstract

Background:

Hyperuricemia may counter benefits of blood pressure (BP) reduction, although this is controversial.

Methods:

We examined the effects of candesartan and losartan on uric acid, creatinine, and fibrinogen. Patients with hypertension and serum uric acid ≥0.42 mmol/L (7 mg/dL) associated with diuretics were randomized to receive losartan 50 to 100 mg or candesartan 8 to 16 mg for 24 weeks. At randomization and after 24 weeks, systolic and diastolic BP, serum uric acid, creatinine, and fibrinogen were measured.

Results:

A total of 59 patients were entered into the study (30 in the losartan and 29 in the candesartan group). Mean systolic and diastolic BP were reduced in the candesartan group, from 156 mm Hg at baseline to 132 mm Hg at 24 weeks, and from 90.9 to 80.8 mm Hg respectively, P < .0001), and in the losartan group from 150.3 to 132 mm Hg and from 89.6 to 77.6 respectively, P < 0001). Overall mean values of fibrinogen levels were again reduced from 4.39 g/L at baseline to 4.01 g/L at 24 weeks (P < .02). Mean values of serum uric acid in the losartan and candesartan groups wre similar at baseline (0.44 and 0.46 mmol/L, respectively), but they were lower in the losartan group after 24 weeks (0.39 and 0.48 mmol/L, P = .01). Twelve patients (44%) in the candesartan group had a 10% increase in serum creatinine compared with four patients (14.2%) in the losartan group (P < .02).

Conclusions:

Candesartan and losartan lowered BP, but only losartan reduced uric acid. The lowering of fibrinogen in both groups may explain the reduction in stroke with angiotensin receptor blockers. The effect of persistent hyperuricemia on renal function requires further study.

Hyperuricemia is common in patients with essential hypertension.1 Diuretics are the preferred first-line therapy for uncomplicated essential hypertension,2 but may cause hyperuricemia or exacerbate pre-existing hyperuricemia.3,4 Untreated hyperuricemia may predispose to gout, leading to poor patient compliance or withdrawal of diuretic therapy. However, the effect of long-term hyperuricemia on cardiac and renal outcomes remains controversial. Several studies have shown that hyperuricemia is a risk factor for the development of cardiovascular disease.5–7 This has not been confirmed by other large studies,8,9 and there is no published evidence to support the view that lowering uric acid improves cardiovascular outcomes. Reyes and Leary have also argued that thiazide-induced hyperuricemia could provide one explanation of the apparent benefit of diuretics over other classes of antihypertensive agents in lowering cardiovascular risk because uric acid may function as a potent antioxidant.10 More recent evidence suggests that hyperuricemia may lead to proteinuria and declining renal function in animal models, which may be modified by lowering uric acid.11 An elevated uric acid predicts renal insufficiency in individuals with normal renal function,12 progression of IgA nephropathy,13,14 and type 2 diabetic nephropathy.15 The possible detrimental effects of hyperuricemia and the possible beneficial effects of diuretic-induced increases in serum uric acid have recently been discussed.16,17

Hypertension is associated with increased fibrinogen. Prospective studies have shown that fibrinogen is an independent marker for future cardiovascular events,18 including ischemic stroke19; but no data have been published on the effect of uric acid on fibrinogen.

Angiotensin receptor blockers (ARB) are highly specific antagonists of the angiotensin II type 1 (AT1) receptor; and they effectively treat hypertension, particularly in combination with diuretics. Losartan is the only ARB that is uricosuric, which is independent of AT1 receptor blockade.20 The reduction in uric acid may be as much as 25%.4

There are no clear guidelines in the literature in regard to continuation of diuretic therapy in patients who develop asymptomatic hyperuricemia. In the Systolic Hypertension in the Elderly Program (SHEP) the benefits of chlorthalidone were nullified in subjects whose serum uric acid increased by >1 mg/dL during treatment.21 In the Losartan Intervention for Endpoint reduction in hypertension (LIFE) study, in which losartan was shown to be superior to atenolol for preventing cardiovascular events, a recent subanalysis demonstrated that 29% of the benefits could be attributed to the ability of losartan to lower uric acid.22 On the other hand, in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), chlorthalidone, which is known to raise serum uric acid, was associated with a lower risk for stroke, heart failure, and coronary revascularization than was lisinopril.23 To reach target blood pressure (BP), combinations are often needed, including diuretics with an ARB. To date there have been no studies comparing the uricosuric effects of losartan versus another ARB on renal function and fibrinogen in patients with hypertension and hyperuricemia associated with diuretic therapy.

In this study we tested our hypotheses that losartan, compared with candesartan, would lower serum uric acid in hypertensive patients with hyperuricemia associated with diuretics, and produce a reduction of fibrinogen (a marker of future cardiovascular events).

Methods

This was an open-label, randomized, controlled, two–parallel group study with blinded endpoints. Adult patients were eligible for the study if they were receiving thiazide or either thiazide-like or loop diuretics, had uncontrolled mild to moderate essential hypertension, had systolic blood pressure (SBP) between 140 and 180 mm or diastolic blood pressure (DBP) between 90 and 110 mm Hg, and had uric acid ≥0.42 mmol/L (7 mg/dL). The 0.42 mmol level was chosen, as this is the upper limit of normal of serum uric acid used by our laboratory and others.24 The dose of diuretics was required to be stable for the past 12 weeks before study entry, and women of childbearing potential were required to be using an effective form of contraception. Exclusion criteria were as follows: secondary, severe, or malignant hypertension; poorly controlled diabetes mellitus; compelling indications for an angiotensin-converting enzyme (ACE) inhibitor use; regular use of steroids, nonsteroidal anti-inflammatory drugs, allopurinol, or colchicine; class III or IV heart failure according to the New York Heart Association criteria; recent myocardial infarction; coronary revascularization in the last 6 months; unstable angina or significant cardiac arrhythmia; stroke or transient ischemic attack in the past 6 months; acute or chronic liver disease with aspartate aminotransferase or alanine aminotransferase twice the upper limit of normal; serum creatinine >200 μmol/L; and known hypersensitivity or contra-indication to losartan or candesartan. The University of Cape Town Research Ethics Committee approved the study.

After informed consent, eligible patients underwent a 2-week run in period (Fig. 1) before randomization. All patients received standard dietary advice regarding sodium, fat, and carbohydrate intake, which was reinforced at each visit. Therapy with ACE inhibitors was withdrawn. Patients were then randomized to either losartan 50 mg or candesartan 8 mg daily. Medication could be up-titrated to losartan 100 mg and candesartan 16 mg daily respectively if BP remained >140/90 mm Hg at 6 weeks. After 12 weeks, if BP remained uncontrolled and losartan and candesartan had been up-titrated, open-label therapy (excluding an ACE inhibitor or ARB) could be used. Each patient was required to continue taking a constant dose of diuretics for the duration of the study.

Design of trial comparing the effects of losartan versus candesartan on uric acid, renal function, and fibrinogen in patients with hypertension and hyperuricemia associated with diuretics.

Blood pressure was measured at each visit using a mercury spyghmomanometer according to standard guidelines.2 This was done in the sitting position after a 5-min rest with the arm supported at heart level. The mean of last two stable readings was recorded. Blood was taken for serum uric acid, creatinine, and fibrinogen at randomization and at week 24. Urinary sodium excretion was not measured.

The primary outcome of the study was the difference in serum uric acid between the candesartan and losartan groups at week 24. The sample size was estimated at n = 24 in each group, taking a 20% difference at week 24, with α = 0.05 and a power of 80%. Secondary outcomes were the differences in BP, fibrinogen, and creatinine between the groups. Results of the study were analyzed by the Student t and Mann-Whitney tests for baseline demographics and the Fisher exact test for nonparametric data. Changes in BP, serum uric acid, and fibrinogen were evaluated for differences over time and between the groups by analysis of variance for repeated measurements, and the differences in mean fibrinogen and serum uric acid at week 24 were analyzed by the Student t test. The numbers of patients in each group with a 10% increase in serum creatinine were analyzed using the Fisher exact test (two-tailed). The level of significance was set at P < .05.

Results

A total of 59 patients were entered into the study (30 in the losartan and 29 in the candesartan group). Patients were well matched at randomization, with no significant differences in mean baseline demographics (Table 1). The number of patients with underlying diabetes (28% v 33.3%, P = .63), previous cardiovascular events (17.3% v 23.3%, P = .51), and prior use of ACE inhibitors (62% v 60%, P = .87) was similar in the candesartan and losartan groups respectively. Two patients, both in the losartan group, had a history of gout. A total of 55 patients successfully completed the 24-week study. Four patients did not complete the study: one in each group was lost to follow-up, one in the candesartan group was withdrawn because of hypotension at week 6, and one in the losartan group was withdrawn at 18 weeks because of noncompliance. The type of diuretics received by each group was very similar and is shown in Table 2. No patient developed gout, and there were no other serious adverse events.

Table 1

Mean baseline demographics of study subjects

Parameter Losartan (SD) Candesartan (SD) P value* 
Number 30 29  
Men (%) 40 41 0.91 
Systolic BP (mm Hg) 151 (8.4) 157 (16.7) 0.07 
Diastolic BP (mm Hg) 89.2 (8.4) 90.5 (7.840) 0.57 
Creatinine (μmol/L) 88.5 (56–123) 95 (63–155) 0.56 
Prior antihypertension 2.7 2.8 0.87 
Parameter Losartan (SD) Candesartan (SD) P value* 
Number 30 29  
Men (%) 40 41 0.91 
Systolic BP (mm Hg) 151 (8.4) 157 (16.7) 0.07 
Diastolic BP (mm Hg) 89.2 (8.4) 90.5 (7.840) 0.57 
Creatinine (μmol/L) 88.5 (56–123) 95 (63–155) 0.56 
Prior antihypertension 2.7 2.8 0.87 

BP = blood pressure.

*

Student t test;

Median and range;

Mann-Whitney test.

Table 2

Dose and type of diuretics used by study subjects

Diuretic Losartan Candesartan 
Hydrochlorothiazide (12.5–25 mg) 26 26 
Indapamide (2.5 mg) 
Furosemide (40–160 mg) 
Diuretic Losartan Candesartan 
Hydrochlorothiazide (12.5–25 mg) 26 26 
Indapamide (2.5 mg) 
Furosemide (40–160 mg) 

The differences over time (weeks 0 and 24) and between the groups were evaluated by analysis of variance for repeated measurements. In the overall study (both groups combined), the mean systolic BP, diastolic BP, and fibrinogen levels decreased (Table 3), without change in mean potassium between randomization and week 24. There were no differences between the losartan and candesartan groups in mean systolic and diastolic BP, potassium, and fibrinogen at week 24 (Table 3). Only the serum uric acid decreased in the losartan group at week 24, which was significantly different from the values noted with candesartan (P = .01). In the losartan and candesartan groups, four patients (14.2%) and 12 patients (44%) experienced 10% increases in serum creatinine at week 24 (P = .02, Fisher exact test, two-tailed) respectively. Because of the effect of renal function on uric acid, we used creatinine as a covariate in the analysis of repeated measurements, and the power of the study to detect a 10% change in creatinine was 54%.

Table 3

Change in mean blood pressure (BP), uric acid, potassium, and fibrinogen from week 0 compared with week 24 in the overall study and, in the candesartan (C) and losartan (L) groups

 Overall (n = 55) L (n = 27) C (n = 25) C vs L 
Parameter Week 0 (SD) Week 24 (SD) P value* Week 0 (SD) Week 24 (SD) Week 0 (SD) Week 24 (SD) P value* 
Systolic BP (mm Hg) 153.9 (9.1) 132.1 (10.1) <.001 150.3 (2.7) 132 (2.2) 156 (2.7) 132 (2.1) .19 
Diastolic BP (mm Hg) 89.8 (9.1) 79.1 (8.9) <.001 89.6 (1.8) 77.6 (1.7) 90.9 (1.8) 80.8 (1.7) .71 
Uric acid (mmol/L) 0.45 (0.07) 0.43 (0.09) .21 0.44 (0.01) 0.39 (0.02) 0.46 (0.01) 0.48 (0.02) <.01 
Potassium (mmol/L) 4.13 (0.51) 4.23 (0.57) .16 4.23 4.02 4.27 4.19 .19 
Fibrinogen (g/L) 4.39 (0.95) 4.01 (0.72) <.001 4.49 (0.18) 4.12 (0.14) 4.38 (0.18) 3.9 (0.14) .41 
10% increase in creatinine — 16 (29) — — 4 (14.2) — 12 (44) .02 
 Overall (n = 55) L (n = 27) C (n = 25) C vs L 
Parameter Week 0 (SD) Week 24 (SD) P value* Week 0 (SD) Week 24 (SD) Week 0 (SD) Week 24 (SD) P value* 
Systolic BP (mm Hg) 153.9 (9.1) 132.1 (10.1) <.001 150.3 (2.7) 132 (2.2) 156 (2.7) 132 (2.1) .19 
Diastolic BP (mm Hg) 89.8 (9.1) 79.1 (8.9) <.001 89.6 (1.8) 77.6 (1.7) 90.9 (1.8) 80.8 (1.7) .71 
Uric acid (mmol/L) 0.45 (0.07) 0.43 (0.09) .21 0.44 (0.01) 0.39 (0.02) 0.46 (0.01) 0.48 (0.02) <.01 
Potassium (mmol/L) 4.13 (0.51) 4.23 (0.57) .16 4.23 4.02 4.27 4.19 .19 
Fibrinogen (g/L) 4.39 (0.95) 4.01 (0.72) <.001 4.49 (0.18) 4.12 (0.14) 4.38 (0.18) 3.9 (0.14) .41 
10% increase in creatinine — 16 (29) — — 4 (14.2) — 12 (44) .02 
*

ANOVA for repeated measurements;

Number (%);

Fisher exact test, two-tailed.

The differences between the groups in the serum uric acid and fibrinogen at 24 weeks was also analyzed by the Student t test. There was no difference in fibrinogen in the losartan and candesartan groups (4.12 v 3.9 g/L, P = .29); however, the serum uric acid was significantly lower in the losartan group (0.39 v 0.48 mmol/L, P < .008). The number of patients that went below the threshold of 0.42 mmol/L in the losartan and candesartan groups was 20 v 8 patients, and the number remaining above the threshold were 8 v 19 patients respectively (P < .003, Fisher exact test).

Discussion

In this study losartan and candesartan reduced both SBP and DBP. The drugs were well tolerated. There was only one serious adverse event in the entire study.

As anticipated, uric acid levels were significantly reduced by losartan (−0.05 mmol/L), but not candesartan. These differences were not likely caused by differences in serum potassium (Table 3), or sodium intake, as all patients received the same dietary advice. However, it is important to note that 24-h urinary sodium was not measured. The differences in renal function could have been a confounder. In the losartan group the uric acid was reduced with unchanged creatinine levels, whereas in the candesartan group uric acid was unchanged with a slight increase in creatinine. This would argue against renal function causing the changes in uric acid.

Srinivas et al.16 and Reyes and Leary17 have debated the importance of increases in serum uric acid. Briefly there are two opposing viewpoints. On the one hand, uric acid is considered to be a powerful anti-oxidant and diuretic-induced hyperuricemia may protect against future cardiovascular events, and on the other hand it may cause adverse cardiovascular events and progressive renal deterioration. In this study we were unable to show either beneficial or deleterious effects of persistent hyperuricemia on fibrinogen as a marker of future cardiovascular events; however, there was a small but significant decline in renal function in the candesartan group.

Of interest is the reduction of fibrinogen seen with both candesartan and losartan, which does not occur with all antihypertensive drugs.25–28 In general, inhibitors of the renin–angiotensin system tend to reduce fibrinogen levels. It is not known whether reducing fibrinogen levels decreases cardiovascular events. Previous studies have suggested that fibrinogen is a powerful predictor of cardiovascular events, particularly ischemic stroke.19 Thus our findings may partly explain the reduction of stroke associated with candesartan noted in the Study on COgnition and Prognosis in the Elderly (SCOPE),29 with losartan in the LIFE study,30 and with eprosartan in the Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention (MOSES) study.31

In regard to the important question of the long-term effect of hyperuricemia on renal function, significantly more patients in the candesartan group had a >10% decline in serum creatinine. The systolic BP in the candesartan group was slightly but not significantly higher; however, the achieved BP in each group was very similar. Our results would be in agreement with recent work done by Kang et al.11 The induction of hyperuricemia in rats was associated with increasing proteinuria, hypertension, and declining renal function. Lowering uric acid with allopurinol prevented these changes.

In human beings, the relationship between hyperuricemia and progressive loss of renal function has not been established; however, there are several lines of emerging evidence to support this concept. Uric acid predicts renal insufficiency in individuals with normal renal function,12 progression of IgA nephropathy,13,14 and type 2 diabetic nephropathy.15 In a recent article in the Journal, Hawkins and Houston reported an association with population-wide diuretic use and end-stage renal failure; however, they were unable to establish whether this was a precipitating factor or an epiphenomenon, and they were also unable to establish an underlying mechanism.32 In the ALLHAT study there was no change in glomerular filtration rate in the chlorthalidone group compared with the effect observed with amlodipine or lisinopril32; and in the LIFE study the use of losartan was not associated with an improvement in renal function as compared with atenolol, which does not influence uric acid.22,30

There are several important limitations of the study, particularly related to changes in creatinine. First, this is a small study with a short observation period, and the study was underpowered to detect changes in creatinine after using covariate analysis. Second, the changes in uric acid associated with losartan were small. Third, the use of creatinine as a marker of renal function has several limitations, and the changes in creatinine were small. Finally, in the candesartan group, the baseline serum creatinine was higher (95 v 88.5 μmol/L) and there was greater reduction in systolic BP. The changes in creatinine in the candesartan compared with the losartan group may have been caused by underlying impairment of renal autoregulation, resulting in a greater risk for renal impairment at reduced renal perfusion pressure.

In conclusion, both candesartan and losartan lowered BP, but only losartan lowered uric acid. The reduction of fibrinogen with both candesartan and fibrinogen may in part explain the reduction in stroke seen in the MOSES, LIFE, and SCOPE studies. The long-term effect of persistent hyperuricemia on renal function requires further study.

References

1.
Selby
JV
,
Friedman
GD
,
Queensbury
CP
:
Precursors of essential hypertension: pulmonary function, heart rate, uric acid, serum cholesterol and other chemistries
.
Am J Epidemiol
 
1990
;
131
:
1017
1027
.
2.
Chobanian
A
,
Bakris
GL
,
Black
HR
,
Cushman
WC
,
Green
LA
,
Izzo
JL
Jr
,
Jones
DW
,
Materson
BJ
,
Oparil
S
,
Wright
JT
Jr
,
Roccella
EJ
,
Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee
:
The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. The JNC 7 Report.
.
J Am Med Assoc
 
2003
;
289
:
2560
2582
.
3.
Treatment of Mild Hypertension Research Group
:
Treatment of Mild Hypertension Study. A randomized, placebo-controlled trial of a nutritional-hygienic regimen along with various drug monotherapies
.
Ann Intern Med
 
1991
;
151
:
1413
1423
.
4.
Soffer
BA
,
Wright
JT
,
Pratt
JH
,
Wiens
B
,
Goldberg
AI
,
Sweet
CS
:
Effects of losartan on a background of hydrochlorothiazide in patients with hypertension
.
Hypertension
 
1995
;
26
:
112
117
.
5.
Fang
J
,
Alderman
MH
:
Serum uric acid and cardiovascular mortality the NHANES I epidemiologic follow-up study, 1971–1992. National Health and Nutrition Examination Survey
.
J Am Med Assoc
 
2000
;
283
:
2404
2410
.
6.
Puddu
PE
,
Lanti
M
,
Menotti
A
,
Mancini
M
,
Zanchetti
A
,
Cirillo
M
,
Angeletti
M
,
Panerelli
W
,
Gubbio Study Research Group
:
Serum uric acid for short-term prediction of cardiovascular disease incidence in the Gubbio population study
.
Acta Cardiol
 
2001
;
56
:
243
251
.
7.
Feig
DI
,
Johnson
RJ
:
Hyperuricemia in childhood primary hypertension
.
Hypertension
 
2003
;
42
:
247
252
.
8.
Sakata
K
,
Hashimoto
T
,
Ueshima
H
,
Okayama
A
,
NIPPON DATA 80 Research Group
:
Absence of an association between serum uric acid and mortality from cardiovascular disease: NIPPON DATA 80, 1980–11994. National Integrated Projects for Prospective Observation of Non-communicable Diseases and its Trend in the Aged
.
Eur J Epidemiol
 
2001
;
17
:
461
468
.
9.
Moriarity
JT
,
Folsom
AR
,
Iribarren
C
,
Nieto
FJ
,
Rosamond
WD
:
Serum uric acid and risk of coronary heart disease: Atherosclerosis Risk in Communities (ARIC) Study
.
Ann Epidemiol
 
2000
;
10
:
136
143
.
10.
Reyes
AJ
,
Leary
WP
:
The increase in serum uric acid induced by diuretics could be beneficial to cardiovascular prognosis in hypertension: a hypothesis
.
J Hypertens
 
2003
;
21
:
1775
1777
.
11.
Kang
DH
,
Nakagawa
T
,
Feng
L
,
Watanabe
S
,
Han
L
,
Mazzali
M
,
Truong
L
,
Harris
R
,
Johnson
RJ
:
A role for uric acid in the progression of renal disease
.
J Am Soc Nephrol
 
2002
;
13
:
2888
2897
.
12.
Beck
L
:
Requiem for gouty nephropathy
.
Kidney Int
 
1986
;
30
:
280
287
.
13.
Syrijänen
J
,
Mustonen
J
,
Pasternak
A
:
Hypertriglyceridemia and hyperuricaemia are risk factors for progression of IgA nephropathy
.
Nephrol Dial Transplant
 
2000
;
15
:
34
42
.
14.
Ohno
I
,
Hosoya
T
,
Gomi
H
,
Ichida
K
,
Okabe
H
,
Hikita
M
:
Serum uric acid and renal prognosis in IgA nephropathy
.
Nephron
 
2001
;
87
:
333
339
.
15.
Bo
S
,
Cavallo-Perin
P
,
Gentile
R
,
Repetti
E
,
Pagano
G
:
Hypouricemia and hyperuricaemia in type 2 diabetes: two different phenotypes
.
Eur J Clin Invest
 
2001
;
31
:
318
321
.
16.
Srinivas
TR
,
Herrera-Acosta
J
,
Feig
DI
,
Kang
D-H
,
Segal
MS
,
Johnson
RI
:
Diuretic-induced hyperuricaemia does not decrease cardiovascular risk
.
J Hypertens
 
2004
;
22
:
1415
1417
.
17.
Reyes
AJ
,
Leary
WP
:
Diuretic-induced hyperuricaemia does not decrease cardiovascular risk. Reply
.
J Hypertens
 
2004
;
22
:
1417
1419
.
18.
Kannel
WB
,
Wolf
PA
,
Castelli
WP
,
D’Agostino
RB
:
Fibrinogen and risk of cardiovascular disease. The Framingham Study
.
J Am Med Assoc
 
1987
;
258
:
1183
1186
.
19.
Kofoed
SC
,
Wittrup
HH
,
Silleson
H
,
Nordestgaard
BG
:
Fibrinogen predicts ischaemic stroke and advanced atherosclerosis but not echolucent, rupture-prone carotid plaques. The Copenhagen City Heart Study
.
Eur Heart J
 
2003
;
24
:
567
576
.
20.
Schmitt
F
,
Natov
S
,
Martinez
F
,
Lacour
B
,
Hannedouche
T
:
Renal effects of angiotensin I-receptor blockade and angiotensin convertase inhibition in man
.
Clin Sci
 
1996
;
90
:
205
213
.
21.
Franse
LV
,
Pahor
M
,
Di Bari
M
,
Shorr
RI
,
Wan
JY
,
Somes
GW
,
Applegate
WB
:
Serum uric acid, diuretic treatment and risk of cardiovascular events in the Systolic Hypertension in the Elderly Program (SHEP)
.
J Hypertens
 
2000
;
18
:
1149
1154
.
22.
Hoieggen
A
,
Alderman
MH
,
Kjeldsen
SE
,
Julius
S
,
Devereux
RB
,
De Faire
U
,
Fyhrquist
F
,
Ibsen
H
,
Kristianson
K
,
Lederballe-Pedersen
O
,
Lindholm
LH
,
Nieminen
MS
,
Omvik
P
,
Oparil
S
,
Wedel
H
,
Chen
C
,
Dahlof
B
,
LIFE Study Group
:
The impact of serum uric acid on cardiovascular outcomes in the LIFE study
.
Kidney Int
 
2004
;
65
:
1041
1049
.
23.
ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group
:
Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic
.
J Am Med Assoc
 
2002
;
288
:
2981
2997
.
24.
Laposata
M
:
SI Unit Conversion Guide
.
NEJM Books
 
Boston
,
1992
.
25.
Fogari
R
,
Zoppi
A
,
Malamani
GD
,
Marasi
G
,
Vanasia
A
,
Villa
G
:
Effects of different antihypertensive drugs on plasma fibrinogen in hypertensive patients
.
Br J Clin Pharmacol
 
1995
;
39
:
616
620
.
26.
Fogari
R
,
Zoppi
A
,
Lazzari
P
,
Preti
P
,
Mugellini
A
,
Corradi
L
,
Lusardi
P
:
ACE inhibition but not angiotensin II antagonism reduces plasma fibrinogen and insulin resistance in overweight hypertensive patients
.
J Cardiovasc Pharmacol
 
1998
;
32
:
616
620
.
27.
Makris
TK
,
Stavroulakis
GA
,
Krespi
PG
,
Hatzizacharias
AN
,
Triposkiadis
FK
,
Tsoukala
CG
,
Votteas
VV
,
Kyriakidis
MK
:
Fibrinolytic/hemostatic variables in arterial hypertension: response to treatment with irbesartan or atenolol
.
Am J Hypertens
 
2000
;
13
:
783
788
.
28.
Bhatia
J
,
Mahajan
P
,
Sikka
M
,
Kalra
OP
:
Effect of various antihypertensive therapies on plasma fibrinogen levels in patients with essential hypertension
.
Indian J Med Sci
 
2001
;
55
:
491
494
.
29.
Lithell
H
,
Hansson
L
,
Skoog
I
,
Elmfeldt
D
,
Hofman
A
,
Olofsson
B
,
Trenkwalder
P
,
Zanchetti
A
,
SCOPE Study Group
:
The study on cognition and prognosis in the elderly (SCOPE): principal results of a randomized double-blind intervention trial
.
J Hypertens
 
2003
;
21
:
875
886
.
30.
Lindholm
LH
,
Ibsen
H
,
Dahlöf
B
,
Devereux
RB
,
Beevers
G
,
de Faire
U
,
Fyhrquist
F
,
Julius
S
,
Kjeldsen
SE
,
Kristiansson
K
,
Lederballe-Pedersen
O
,
Nieminen
MS
,
Omvik
P
,
Oparil
S
,
Wedel
H
,
Aurup
P
,
Edelman
J
,
Snapinn
S
,
LIFE Study Group
:
Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention for Endpoint reduction in hypertension study (LIFE)
.
Lancet
 
2002
;
359
:
1004
1010
.
31.
Schrader
J
,
Luders
S
,
Kulschewski
A
,
Hammersen
F
,
Plate
K
,
Berger
J
,
Zidek
W
,
Dominiak
P
,
Diener
HC
,
MOSES Study Group
:
Morbidity and Mortality After Stroke, Eprosartan Compared with Nitrendipine for Secondary Prevention: Principal Results of a Prospective Randomized Controlled Study (MOSES)
.
Stroke
 
2005
;
36
:
1218
1226
.
32.
Hawkins
RG
,
Houston
MC
:
Is population-wide diuretic use directly associated with the incidence of end-stage renal disease in the United States?
Am J Hypertens
 
2005
;
18
:
744
749
.

Author notes

*
This study was supported by a grant from the Merck University program.