Evidence for the efficacy of low-dose diuretic monotherapy

Evidence for the Efficacy of Low-Dose Diuretic Monotherapy John M. Flack, MD, MPH, Winston-Salem, worth Carolina, William C. Cushman, MD, Memphis, Tennessee

Diuretic monotherapy has been recommended by the fifth report of the Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V) as a preferred initial treatment for hypertension. Thiazide diuretics are commonly used to treat hypertension because of their demonstrated efficacy, favorable safety profile, low acquisition cost, and their proven ability to reduce blood pressure-related morbidity and mortality. Oncedaily low-dose hydrochlorothiazide (12.5 mg/ day) or chlorthalidone (15 mg/day) effectively reduces blood pressure in patients with stage 1 or stage 2 hypertension in comparison with placebo. Blood pressure reductions with lowdose hydrochlorothiazide and chlorthalidone are comparable to that achieved with higher doses (25 and 50 mg/day). Additional blood pressure reductions can be attained with concomitant use of once-daily low-dose hydrochlorothiazide or chlotthalidone with an angiotensin-converting enzyme (ACE) inhibitor, a p blocker, or a calcium antagonist. Once-daily low-dose hydrochlorothiazide provides clinically meaningful blood pressure lowering while minimizing adverse effects, such as electrolyte disturbances, cholesterol elevations, and increases in serum uric acid levels. Am J Med. 1996; lOl(suppl3A):53S-60s.

From the Departments of Surgical Sciences, Sciences. Bowman Grav School of Medicine Winston-Salem, North Carolina (J.M.F.), and Veterans Affairs Medical Center, Memphis, Requests for reprints should be addressed Hypertension Center, Bowman Gray School Medical Center Boulevard, Winston-Salem,

01996 by Excerpta All rights reserved.

Medica,

Inc.

Medicine and Public Health of Wake Forest University, the Hypertension Section, Tennessee (W.C.C.). to John M. Flack, MD, MPH, of Medicine, 5th Floor, CSB, North Carolina 27157.

A

pproximately 50 million U.S. citizens have elevated blood pressure defined as systolic blood pressure (SBP) 2 140 mm Hg and/or diastolic blood pressure (DBP) 290 mm Hg, or are currently taking antihypertensive medication.’ The prevalence of high blood pressure increases with age, is greater for blacks than whites with an earlier age of onset in the former, and in both races is more prevalent among less educated individuals.’ As SBP and DBP increase, the incidence of nonfatal and fatal cardiovascular-renal disease, as well as all-cause mortality, progressively rises. l-4 Blood pressure r’eductions with diuretic-based pharmacotherapy decrease the incidence of the progression to more severe hypertension, stroke, coronary events, congestive heart failure, and all-cause mortality.” In epidlemiologic studies the incidence of stroke is 42% lower for each 5-6 mm Hg reduction in DBP.5 A 13-27% reduction in coronary artery disease (CAD) was documented in older hypertensive patients when blood pressure was lowered with diuretic-based treatment regimens.6-8 Clearly, there is compelling evidence to support the treatment of hypertension. The primary goal of hypertension treatment is to prevent or delay the onset of blood pressure-related morbidity and mortality. If lifestyle modifications, such as weight reduction, increased physical activity and moderation of dietary sodium and alcohol intake, do not result in achievement of target blood pressure goals (usually <140/90 mm Hg), then drug therapy should be added to ongoing lifestyle modifications. When drug therapy is initiated for stage 1 or stage 2 hypertension (previously referred to as “mild-to-moderate” hypertension), monotherapy with diuretics or ,f3blockers is recommended as preferred therapy by the Fifth Joint National Committee on Detection, Evaluation and Treatment of High Blood Pressure (JNC-V) unless these drugs are contraindicated, or there are specific reasons to use a different class of agent.’ Diuretics or /I blockers are recommended as preferred initial therapy, because they are the only two drug classes that have been shown to reduce cardiovascular morbidity and mortality, as well as all-cause mortalil;y in longterm controlled clinical trials~~6-s A prudent, therapeutic approach to selecting an antihypertensive agent is the prescription of the lowest effective dose. The primary goal of this strategy is to obtain the o~ptimal balance of blood pressure-lowering efficacy with a minimum of drug-related adverse events.’ OOOZ-9343/96/$15.00 PII !NOO2-9343( 96)00268.9

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Thiazide diuretics are commonly used for treatment of hypertension because of their demonstrated blood pressure-lowering efficacy, proven ability to prevent strokes, myocardial infarction, and congestive heart failure, and their low acquisition cost.4+-g The dosage recommendations of thiazides have changed dramatically over the past 30 years. Hydrochlorothiazide doses as high as 200 mglday were recommended in the 1960s but have progressively decreased over time with a better understanding of the relationship of daily dose to both blood pressure-lowering efficacy, as well as the incidence of adverse effects. The utility of higher doses of hydrochlorothiazide (>25 mg/day) has been limited by the relatively flat blood pressure dose-response curve l”,il and by the increasing likelihood of adverse metabolic effects, such as hypokalemia, hypomagnesemia, and hyperuricemia. “,“-i5 However, hypomagnesemia appears much more common with high-dose loop diuretic therapy than during therapy with low-to-moderate doses of thiazide diuretics in uncomplicated hypertensives.14 The incidence of these side effects has decreased as lower daily doses of 25-50 mg have been used. At present, a daily dose of 12.5-50 mg of hydrochlorothiazide is recommended in the JNC-V guidelines.’ Larger doses of hydrochlorothiazide may provide additional antihypertensive effect in some patients. However, further blood pressure reductions with increasing hydrochlorothiazide dose are minimal, at least partly because of activation of the renin-angiotensin-aldosterone system. lB,17 The purpose of this review is to present clinical evidence that supports the efficacy of low-dose hydrochlorothiazide (12.5 mg/day) and chlorthalidone (12.5-15 mg/day) for the treatment of hypertension including confirmation of efficacy versus placebo. Further, this review will provide a rationale regarding why, in many clinical situations, there should be some limitation in the maximum diuretic dose.

REVIEW OF PUBLISHED TRIALS WITH LOW-DOSE (12.5 mg) HYDROCHLOROTHIAZIDE The efficacy of hydrochlorothiazide 12.5 mg/day has been evaluated in comparison to placebo, larger daily doses of hydrochlorothiazide, and in combination with p blockers and calcium antagonists. The studies reviewed below demonstrate the effectiveness of this low-dose therapy in patients with stage 1 and stage 2 hypertension.

Placebo-Controlled

Trials

The efficacy of hydrochlorothiazide 12.5 mg/day for treatment of stage 1 and stage 2 hypertension has been documented in nine placebo-controlled trials 3A-54s

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that included 460 patients who received hydrochlorothiazide and 453 patients who received placebo (summarized in Table I) .10~n~18-23a Baseline seated or supine systolic blood pressure (SBP) in these studies was 152-174 mm Hg and seated or supine DBP was 92- 110 mm Hg prior to hydrochlorothiazide therapy. After 4-12 weeks of hydrochlorothiazide 12.5 mg/day, SBP decreased an average of 9.8 mm Hg (range, 3.9- 17.4 mm Hg) and DBP decreased an average of 6.8 mm Hg (range, 2.0-98 mm Hg). With placebo, SBP decreased O-6.0 mm Hg and DBP decreased O-6.9 mm Hg. A daily dose of hydrochlorothiazide 12.5 mg was significantly superior to placebo in decreasing SBP and DBP in six of the nine pi,&

10,18,21-23a

In one report, a significant decrease in DBP was noted after 4 weeks of treatment with hydrochlorothiazide 12.5 mg/day as compared wit.h placebo, with further reductions observed by the completion of the 8-week study.23 Approximately 44% of the patients taking low-dose hydrochlorothiazide reached the target blood pressure goals.23 In another study ‘I the antihypertensive effects of hydrochlorothiazide 6.25 mg/day were not significantly different from placebo, while the decrease in SBP with 12.5 mg/day was significant. The authors recommended initiating treatment for systolic hypertension with hydrochlorothiazide 12.5 mg/day. However, at this time there are not enough studies with 6.25 mglday to assess adequately the utility of this dose as a monotherapy. The mean age of the patients enrolled i:n these placebo-controlled trials was approximatel,y 50 years. The study populations were approximately 40% female and 60% male. One study was performed exclusively in blacks,‘l but the majority of the patients included in these trials were white. In the single trial that provided results by age and race, hydrochlorothiazide 12.5 mg/day decreased diastolic blood pressure by 8.4 mm Hg in blacks and 12.9 mm Hg in the elderly, as compared with 8.9 mm Hg in the study group as a whole. Thus, this study provides little information as to the blood pressure-lowering efficacy of low-dose hydrochlorothiazide in younger Caucasian patients.23 The primary goal of these trials was to document blood pressure changes with low-dose hydrochlorothiazide therapy. Four of the trials assessed achievement of blood pressure control.“~20X23~23” Blood pressure was deflned as being “controlled” or “normalized” when the DBP was 590 mm Hg,11.20,23a or there was a decrease in SBP of 10 mm Hg from baseline.23 These goals were achieved in 16% of black patients in one study, l1 in 42% of white patients in another study, 2o in 34.3% of patients in a third study,23a and in 44.3% of the predominant1.y white patients in the final study.23 101

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I

48.2 53 56.2 54

6 8 8 8 8 53

48.2

6

12

49.2

4

Randomized, double-blind, cross-over Randomized, double-blind, crossover Randomized, double-blind, parallel-group Randomized, double-blind, parallel-group Randomized, double-blind parallel-group Randomized, double-blind, parallel-group Double-blind, parallel-group

Randomized, double-blind, parallel-group

46.3

6

Treatment Period (weeks)

166 110 174 104 157-164 106-108 92-109

155 103 152 101

SuDBP

SeSBP: SeDBP: SeSBP: SeDBP:

= supine

SeDBP: 95-l 10

SeDBP: loo-115

SeSBP: SeDBP: SuSBP: SuDBP: SuSBP: SuDBP: SeDBP:

diastolic

blood

140

81

17

29’

66

45”

19

16

pressure:

SeSBP

-4.1

-6.09

-2.7

-3.2’

Od

-2.4

-3.8

+2.0b

= seated

-2.0

-6.09

-6.9

-2.9’

-3.gd

-3.9

-2.9

Ob

systolic

blood

142

87

17

29’

65

45”

19

16

pressure;

SeDBP

= seated

-8.5 (p
-16.0b (p
diastolic

bloom

-9.3 (p
-7.0b (p 0.05) -6.3 (p 0.05) -6.0’

12.5 mg/day: Comparative Changes in Systolic and Diastolic Blood Pressure Placebo Hydrochlorothiazide 12.5 mg Mean Change Mean Change Mean Baseline Blood (mm Hg) in (mm Hg) in Pressure Number of Number of Age Patients DBP Patients SBP SBP DBP (years) (mm W SuSBP: 157 52.8 40 -1.0 -1.0 40 -5.0 -2.0 SuDBP: 101 (p to.051 (p co.051

Trials with Hydrochlorothiazide

Randomized, double-blind, cross-over

Study Design

Placebo-Controlled

SBP = systolic blood pressure; DBP = diastolic blood pressure; S&BP = supine systolic blood pressure; pressure. a P value versus placebo. b The first placebo period was used for baseline values. c The number of patients was calculated as the average of the 42-48 patients per treatment group. d Changes were estimated from the author’s Figures 1 and 2 at week 8. e The number of patients was calculated as the average of the 26-31 patients per treatment group. r Changes were estimated from the author’s Figure 4 at the last visit. g Changes were estimated from the author’s Figure 1 at week 12.

Berglund and Andersson, 1976” Lorimer et al, 198318 Stein et al, 1992” Scholze et al, 199319 Mersey et al, 1993’O Canter et al, 19942’ Fernandez et al, 199422 Chrysant et al, 199423 Mackay et al, 1 99623”

Reference

TABLE

SYMPOSIUM ON HYPERTENSION/FLACK

AND CUSHMAN

Serum potassium levels decreased significantly during hydrochlorothiazide treatment (12.5 mg daily) as compared with placebo in one study.” However, the level did not drop below 3.3 mEq/L in any patient. Three other investigators found a trend toward a greater effect by hydrochlorothiazide than placebo on lowering serum potassium levels, although the differences were not statistically significmt

20,21,23,23a

Studies of 12.5 mg Versus 25 mg Daily The efficacy of hydrochlorothiazide 12.5 mg/day was compared with 25 mg/day in six trials that included a total of 455 patients.‘0~“~‘g~21~23~24 In general, doubling the daily dose to 25 mg did not result in further reduction in blood pressure compared with 12.5 mg/day. Data from these trials are summarized in Table II. The mean reduction in SBP was 3.9-17.4 mm Hg and 2.0-9.0 mm Hg in DBP with hydrochlorothiazide 12.5 mg/day. Patients who received hydrochlorothiazide 25 mg/day had a mean reduction in SBP of 5.0-19.1 mm Hg and DBP of 3.0-11.0 mm Hg. The difference in blood pressure reductions between the two doses of hydrochlorothiazide was not signiflcant. These studies further demonstrate the flat dose-response with hydrochlorothiazide and conlirm the efficacy of a 12.5 mg daily dose in patients with stage 1 or stage 2 hypertension. The effects of the two hydrochlorothiazide dose levels on metabolic parameters were evaluated by several authors.‘0,‘g~2’*23,24 Although serum potassium was decreased during hydrochlorothiazide therapy, three studies showed no difference between the two whereas two others found that doses studied, 1oz3,24 as the hydrochlorothiazide dose was increased, the reduction in serum potassium was greater.‘gz21In one study, a mean serum potassium decrease of 0.47 mmol/L was observed in the 25 mg/day group compared with a 0.05 mmol/L decrease in the 12.5 mgl day group.lg In another study, as the daily dose of hydrochlorothiazide increased, a greater percentage of patients experienced 0.5 mmol/L decreases from baseline in serum potassium.21 Although there were small differences in the mean reductions in DBP and SBP with the 12.5 and 25 mg doses, Stein and associates” found that as the dose of hydrochlorothiazide increased, the number of patients whose DBP was <90 mm Hg (“controlled”) also increased. Of the patients receiving 50 mg/day, 47% were controlled, as compared with 32% of the patients receiving 25 mg/day and 16% of those receiving 12.5 mg/day. However, the number of patients in each group was small, and differences between doses were not significant. Chrysant,23 in a larger study, found no difference in the antihyper3A-56s

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tensive efficacy of 12.5 mg and 25 mg, with 44.3%and 46.8% of the patients in each group achieving a decrease in sitting DBP to 590 mm Hg or a decrease by 2 10 mm Hg from baseline at the end of 12 weeks, respectively. The relationship between plasma concentrations of hydrochlorothiazide and antihypertensive effect was evaluated.24 No correlations were found among the changes in SBP, DBP, or mean blood .pressure in any position and the plasma concentrations drawn just prior to the morning dose or 5 houm after the morning dose.

CHLORTHALIDONE Daily doses of chlorthalidone as low as 12.5-15 mg have been shown to lower blood pressure more effectively than placebo in hypertensive patients.2g’30 Similar to hydrochlorothiazide, chlorthahdone has a relatively flat blood pressure dose-resp’onse curve at daily doses >25 mg, 2g-31although the lblood pressure-lowering effect of 25 mg appears rsuperior to that of 12.5 mg.31In contrast, another study showed an equivalent blood pressure-lowering effect for 25 mg versus 15 mg.” At a daily dose of 12.5 mg of chlorthalidone, the fall in serum potassium appears to be quite small (0.2 mmol/L) .30Other studies have shown that the hypokalemia associated with chlorthalidone therapy is dose related and, in general, more substantial at similar dose levels in comparison to hydrochlorothiazide. Thus, utilization of the lowest possible doses of chlorthalidone, similar to the situation with hydrochlorothiazide, seemsprudent.

SELECTED LONG-TERM CLINICAIL TRIALS USING LOW-DOSE HYDROCHLOROTHIAZIDE AND CHLORTHAlilDONE Veterans Affairs Cooperative Study Group on Antihypertensive Agents Materson and coworkers32 reported data from the most recent of VA Cooperative Clinical Trials of Antihypertensive Drug Therapies. A total of 1,292 men aged 221 years with DBP 95-109 mm Hg (average, 152/99 mm Hg) received either placebo or one of six antihypertensive drugs: ( 1) hydrochlorothiazide (12.5-50 mg/day); (2) atenolol (25-100 mg/day); (3) captopril(25-100 mg/day); (4) clonidine (0.20.6 mg/day); (5) sustained-release diltiazem ( 120360 mg/day); or (6) prazosin (4-20 mg/day). All drugs were initiated at the lowest dose and were titrated every 2 weeks until a DBP <90 mm Hg on two consecutive visits or the maximum drug dose was reached. At the end of the 4-B-week titration phase, the percentage of participants attaining goal DBP at the lowest (12.5 mg/day) doses of hydrochlorothiazide was 45%. 101 (suppl

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II

48.2 53 53.5

6 8 8

patients patients

49.2

6

Randomized, double-blind cross-over Randomized, double-blind, parallel-group Randomized, double-blind, parallel-group Double-blind, parallel-group

per treatment per treatment

57.8

2

Single-blind, titration

Mean Age (years) 52.8

6

Treatment Period (weeks)

group. group.

SeSBP: 155 SeDBP: 103

SuSBP: 174 SuDBP: 104 SuSBP: 157-164 SuDBP: 106-108 DBP range: 100-115

SeSBP: 169 SeDBP: 103

Baseline Blood Pressure (mm Hg) SuSBP: 157 SuDBP: 101

12.5 mg/day versus 25 mg/day: Comparative

Randomized, double-blind, crossover

Study Design

Hydrochlorothiazide

See Table I for definitions of abbreviations. a The number of pabents was calculated as the average of the 42-48 b The number of patients was calculated as the average of the 26-31 c Changes were estimated from the author’s Figure 1 at week 12.

Reference Berglund and Andersson, 19761° Beermann and GroschinskyGrind, 197824 Stein et al, 1992’l Scholze et al, 199319 Canter et al, 1 9942’ Chrysant et al, 1 99423

TABLE

87

2gb

45”

19

9

-13.0”

-3.9

-8.5

-17.4

-15.0

-9.0’

-6.0

-6.3

-8.2

-9.0

84

29b

45”

19

9

-14.0”

-10.2

-11.9

-19.1

-10.0

-11.0’

-8.5

-8.4

-10.7

-7.0

Changes in Systolic and Diastolic Blood Pressure 12.5 mg Dose 25 mg Dose Mean Change Mean Change (mm Hg) in (mm Hg) in Number of Number of Patients SBP DBP Patients SBP DBP 40 -5.0 -2.0 40 -5.0 -3.0

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At the end of the titration phase the proportion of participants with SBP <140 mm Hg was clonidine (62%) ; hydrochlorothiazide (60%) ; diltiazem slowrelease (52%) ; atenolol (51%) ; prazosin (43%) ; captopril (39%) ; and placebo (30%). Only 1.1% of hydrochlorothiazide-treated patients experienced adverse effects leading to termination of treatment. In contrast, 13.8%and lO.l%, respectively, of prazosin- and clonidine-treated patients experienced adverse effects that led to discontinuation of treatment. Long-term blood pressure control was defined as a DBP <90 mm Hg during the titration phase and a DBP <95 mm Hg at 1 year. Using these criteria of success, hydrochlorothiazide controlled blood pressure in 46% of participants compared with clonidine (50%)) captopril (42%)) prazosin (42%)) diltiazem (59%)) and placebo (25%).

Systolic

Hypertension

in the Elderly

Program

The Systolic Hypertension in the Elderly Program ( SHEP)33 was a double-blind, randomized clinical trial involving 4,736 men and women (57%) aged ~60 years with isolated systolic hypertension (SBP ~160 mm Hg and DBP <90 mm Hg) comparing a low-dose ( 12.5 mg/day) chlorthalidone-based treatment regimen versus placebo. The average age of SHEP participants was 72 years. Pretreatment blood pressure averaged 170/77 mm Hg. Goal blood pressure was SBP < 160 mm Hg for individuals with pretreatment SBP 2180 mm Hg, while the therapeutic goal was a reduction in SBP of ~20 mm Hg for participants with pretreatment SBP of 160-179 mm Hg. The initial dose of chlorthalidone was doubled to 25 mg/day after a period of time in participants who did not attain goal SBP. Atenolol (25 mg/day) and reserpine (0.05 mg/day) were utilized as add-on therapy for chlorthalidone monotherapy for patients who were treatment failures. Participants were followed for an average of 4.5 years. The 5-year average blood pressure was lower in the active treatment group compared with the placebo group (143/68 vs 155/72 mm Hg). The primary study endpoint of total stroke was 36% lower in the chlorthalidone compared with the placebo group (p = 0.0003). Major cardiovascular events were also 32% lower in the chlorthalidone group. Also lower in the chlorthalidone versus the placebo group was myocardial infarction (33%)) coronary artery bypass grafting (37%)) and left ventricular failure (54%). Total mortality was 13% lower in the diuretic treatment group, an observation that was of borderline statistical significance. In SHEP, low-dose chlorthalidone therapy was well tolerated. During the 4.5-year average follow-up, slightly more patients taking placebo received a diagnosis of dementia (1.9%~~ 1.6%). Likewise, similar 3A-58s

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numbers of individuals in the chlorthalidone and placebo groups were given a diagnosis of depression. There was, however, a general trend toward a greater proportion of metabolic disturbances in the chlorthalidone compared with the placebo group. For example, hypokalemia (~3.2 mmol/L), hyperuricemia ( >595 /Imol/L) , hyperchol’esterolemia (~7.76 mmol/L), and hyponatremia (<: 130 mmol/ L) were more common in the chlorthalidone group. Nevertheless, the absolute percentage excess of all of these metabolic complications in the chlorthalidone group was low.

Treatment

of Mild Hypertension

Studly

The Treatment of Mild Hypertension Study (TOMHS) 34was a randomized, double-blind clinical trial conducted in 902 men and women ages 45-69 years with stage 1 diastolic hypertension (DBP < 100 mm Hg). Eligible participants were randomized either to placebo or one of five low-to-moderate dose active drug therapies: (1) chlorthalidone, 15 mg/day; (2) acebutolol, 400 mg/day; (3) doxazosin, 2 mg/ day; (4) amlodipine, 5 mg/day; or (5) enalapril, 5 mg/day. All participants, including the placebo group, received ongoing lifestyle modification counselling, including weight loss, salt and alcohol reduction, and increased physical activity. The dose of the initial randomized treatment assignmem was doubled if DBP remained 295 mm Hg on three consecutive clinic visits or ~105 mm Hg at a single clinic visit. However, there was minimal drug dose titration during the study, mostly because there was no predesignated “goal” blood pressure level. Participant follow-up averaged 4.4 years. At baseline, blood pressure averaged 140/91 mm Hg in the overall TOMHS cohort. Using all available blood pressures during follow-up (maximum 16)) the average reduction in SBP from baseline for the 6 treatment groups was: (1) acebutolol, -17.0 mm Hg; (2) amlodipine, - 15.6 mm Hg; (3) chlorthalidone, -17.7 mm Hg; (4) doxazosin, -14.2 mm Hg; (5) enalapril, - 14.7 mm Hg; and (6) placebo, -9.1 mm Hg. Adherence to the initial randomized treatment assignment at 48 months was, however, lower in the chlorthalidone (67.5%) and doxazosin (66.1%) groups compared with the amlodipine group (82.5%). A common clinical perception exists that diuret,ics do not cause a regression in left ventricular mass. However, in TOMHS, chlorthalidone w,as the only drug that caused a larger decrease than placebo in echocardiographic left ventricular mass ( -34 vs -27 g; p = 0.03). Drug-specific clinical events were not reported, because the relatively small sample size in each of the drug groups provided little statistical power to do so reliably. 101

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DISCUSSION Thiazide diuretics interfere with the transport of sodium ions across the renal tubular epithelium, thereby enhancing the excretion of sodium, chloride, and water.“5 The cortical diluting segment of the nephron is felt to be the primary site of action, but the exact mechanism of action is unknown. In addition to enhancing the excretion of sodium and chloride, the excretion of potassium, magnesium, phosphate, bromide, and iodide are also increased. As the dose of hydrochlorothiazide is increased, the excretion of serum electrolytes increases, especially potassium. A proportional decrease in blood pressure is not observed as the dose of hydrochlorothiazide is increased above 30 mglday.‘2a1” When thiazide therapy is initiated, extracellular fluid volume, plasma volume, and cardiac output all appreciably decrease, and this may account for the initial decrease in blood pressure.36 Plasma and extracellular fluid volumes then increase after several weeks of therapy but do not return to pretreatment levels. Peripheral vascular resistance decreases and, as a result, cardiac output either returns to normal or is slightly increased. The long-term hypotensive activity of hydrochlorothiazide may be due in part to arteriolar dilation.37 This decrease in total peripheral resistance is observed in thiazide responders only; nonresponders have been shown to have a greater degree of plasma volume depletion with a resultant stimulation of the renin-angiotensin-aldosterone cascade, which probably counteracts the fall in peripheral resistance.38 Thiazide diuretics are less effective in lowering blood pressure in patients who have renal dysfunction (serum creatinine >2.5 mg/dL or creatinine clearance <30 ml/mm). 37 The endogenous organic acids that accumulate in renal insufficiency compete with thiazides for transport into the proximal tubule, leading to decreased renal responsiveness to thiazides. In patients with decreased renal function, glomerular filtration rate may actually be decreased by thiazides (presumed to be the result of a direct action on the renal vasculature) .

CONCLUSION The efficacy of both hydrochlorothiazide 12.5 mg/ day and low-dose chlorthalidone (12.5-15 mg/day) has been clearly demonstrated in both the short- and long-term studies. The use of hydrochlorothiazide 12.5 mg/day was associated with significant reductions in blood pressure as compared with placebo after 4-12 weeks of treatment. When the daily dose was increased to 25 mg, blood pressure reductions in most, but not all, studies were not significantly different from those observed with 12.5 mg. September

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Hydrochlorothiazide 12.5-25 mg/day was well tolerated in all the studies reviewed. Six of the studies20-23~23a~2” listed the incidence of adverse drug reactions (summarized in Table III). Of the 428 patients who received hydrochlorothiazide 12.5 mg/ day, headache was the most frequently reported adverse reaction, occurring in 14% of the patients, although this was not reported as more frequent than in the placebo group. The metabolic effects of hydrochlorothiazide 12.5 mg/day were also evaluated, with particular emphasis on changes in serum potassium. Observed decreases in serum potassium were not found to be significant as compared with baseline after 2 weeks, l8 6 weeks, lg 8 weeks, 18~20,27 or 12 weeks”3J3” of hydrochlorothiazide 12.5 mg/day. Three studies found statistically significant decreases in serum potassium that were not, however, of clinical relevance.w5,26 Serum uric acid increased as compared with baseline during treatment with hydrochlorothiazide 12.5 mg/day in some studies 10,20,235r but was not altered in other studies.“3,26,27 Glucose tolerance during hydrochlorothiazide therapy appears to be a consequence of hypokalemia.‘” Serum glucose was not changed significantly from baseline in the studies in which it was measured.22~23a~27~37 Therefore, low doses of hydrochlorothiazide 12.5 mg/day or chlorthalidone (15 mg/day) lower blood pressure in patients with stage 1 and stage 2 hypertension with few adverse reactions and at low cost.

TABLE III Cumulative Reports of Adverse Reactions Observed in Patients Receiving Hydrochlorothiazide 12.5 mg/day Number of Patients, n = 428 Adverse Reaction (%I Headache 59 (13.7) Dizziness 12 (2.8) Fatigue 10(2.3) Pharyngitis 8 (1.9) Sinusitis 8 (1.9) Upper respiratory tract infection 7 (1.6) Nausea/vomiting 5 (1.2) Abdominal distention/pain 3 (il) Abnormal urination 3 (cl) Asthenia 3 (tl) Chest pain 3 (cl) Cough 3 (cl) Musculoskeletal pain 3 (cl) Stress reaction 3 (cl) Hypokalemia 1 (cl) Palpitations 1 (cl) Rash 1 (Cl) Rhinitis 1 (
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Reductions in blood pressure are comparable to those achieved with higher doses of either diuretic. Use of low-dose diuretic therapy allows for blood pressure control while minimizing adverse effects, particularly electrolyte disturbances. When initiating antihypertensive therapy in patients with stage 1 hypertension, low-dose hydrochlorothiazide (12.5 mg/ day) or chlorthalidone is an acceptable starting dose for many patients. Although 12.5 mg/day is a lower dose than what has been used previously in patients in morbidity and mortality trials, the magnitude of blood pressure lowering is similar to that obtained with higher doses of diuretics. Thus, we postulate improved long-term therapeutic compliance with the realistic expectation of at least comparable reductions in blood pressure-related risk as compared with higher-dose diuretic therapy.

REFERENCES 1. Joint

National

Committee

on Detection,

Evaluation,

Blood Pressure. The fifth report of the Joint National Evaluation, and Treatment of High Blood Pressure

and Treatment

of High

Committee on Detection, (JNC-V). Arch lntem Med.

1993;153:154-183, 2. Flack JM, Neaton JD, Daniels B, Esunge P. Ethnicity & renal disease: lessons from multrple risk factor Intervention trial and the treatment of mild hypertension study. Am J Kidney Dis. 1993;21:31-40. 3. Flack JM, Neaton

J, Grimm RH Jr, Cutler

among men with prior myocardial infarction. 4. Collins R, Peto R, McMahon S, et al. Blood

J. Blood

pressure

and mortality

Circulation. 1995;92:2437-2445. pressure, stroke, and coronary

heart

16. Wyndham RN, Gimenez L, Walker WG, Whelton PK, Russell RP. Influence of renin levels on the treatment of essential hypertension with thiazide diuretics. Arch Intern Med. 1987;147:1021-1025. 17. Leonetti ship between In hypertensive

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