clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage i...

CURRENT MEDICAL RESEARCH AND OPINION�

VOL. 24, NO. 6, 2008, 1771–1779

0300-7995

doi:10.1185/03007990802118071

� 2008 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted

ORIGINAL ARTICLE

Clinical effectiveness oflow-dose chlorthalidone(6.25 mg)Yatenololcombination in stage Ihypertensive patients: amulticenter, randomized,controlled studyA. Pareeka, N. Karnikb, S. B. Salagrec, S. D. Zaward,V. K. Joglekare, N. Chandurkara and G. S. Naika

a Ipca Laboratories Ltd, Mumbai, Indiab LTMM College & LTMG Hospital, Mumbai, Indiac Seth G.S. Medical College & KEM Hospital, Mumbai, Indiad Indira Gandhi Government Medical College, Nagpur, Indiae Grant Medical College & St. George Hospital, Mumbai, India

Key words: Amlodipine – Atenolol – Chlorthalidone – Stage I essential hypertension

ABSTRACT

Objective: To compare the efficacy and safety of low-dose

chlorthalidoneþ atenolol combination with atenolol and

atenololþ amlodipine combination in stage I hypertensive

patients uncontrolled on active run-in monotherapy.

Methods: Newly diagnosed stage I hypertensive patients

were randomized to active run-in monotherapy either

with atenolol 25 mg (98/300) or chlorthalidone 6.25 mg

(100/300) or amlodipine 2.5 mg (102/300). A total of

282/300 patients (atenolol 92, chlorthalidone 91,

amlodipine 99) completed the active run-in phase

successfully. Patients uncontrolled on active run-in

monotherapy (atenolol 33, chlorthalidone 45, amlodipine

47) received the study treatment, namely atenolol 50 mg

alone, chlorthalidone 6.25 mgþ atenolol 25 mg and

atenolol 25 mgþ amlodipine 2.5 mg, respectively. Efficacy

of the therapy was evaluated by BP measurement at

weeks 12 and 20 post-therapy.

Results: Post-active run-in monotherapies, the study

treatment groups showed a significant fall in mean SBP

and DBP from baseline ( p50.05). The mean fall in SBP

and DBP was comparable for study treatments (atenolol

50 mg, atenolol 25 mgþ chlorthalidone 6.25 mg and

atenolol 25 mgþ amlodipine 2.5 mg) ( p¼ 0.337 for SBP

and p¼ 0.054 for DBP) at week 12 and ( p¼ 0.744 for

SBP and p¼ 0.855 for DBP) at week 20; also, the

percentage of responders was comparable for the three

study treatment groups ( p¼ 0.799) indicating that the

low-dose chlorthalidoneþ atenolol combination is non-

inferior to the high-dose atenolol alone and atenololþ

amlodipine combination. No serious laboratory/clinical

adverse events were reported in this study.

Conclusion: Chlorthalidone 6.25 mg in combination with

atenolol 25 mg is effective and safe in stage I (JNC 7)

essential hypertensive patients. This low dose of

chlorthalidone could reduce dose-related concerns

over metabolic adverse effects and may lead to

wider usage of this proven antihypertensive agent in

combination therapy.

Address for correspondence: Anil Pareek, Medical Affairs and Clinical Research, IpcaLaboratories Ltd, 142 AB, Kandivli Industrial Estate, Kandivli (West), Mumbai 400 067, India.Tel.: þ91 022 66474747; Fax: 91 022 28686954; [email protected]

Paper 4517 1771

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Introduction

Hypertension is an increasingly important public health

issue. In 1990 there were about 5.2 million deaths from

cardiovascular disease in economically developed

regions and about 9.1 million deaths in economically

developing countries. It has been predicted that by the

year 2020 there will be an increase of almost 75% in

global cardiovascular disease burden. Of the number of

risk factors responsible for the increase in cardiovascular

morbidity and mortality, high blood pressure is one of

the most important and independent risk factors,

affecting 24–36% of the adult population in developed

countries1. Hypertension is a well known risk factor for

causing acceleration of atherosclerosis. Recent guide-

lines for controlling hypertension emphasize greater

concerns for the prevention of cardiovascular diseases.

The Joint National Committee on Prevention,

Detection, and Treatment of High Blood Pressure

(JNC 7) guideline has now coined a new terminology,

‘pre-hypertension’, for individuals whose systolic blood

pressure is in the range 120–139 mmHg and diastolic

blood pressure in the range of 80–89 mmHg, as there is

a significant risk of atherosclerosis even at these blood

pressure levels. Hence there is a need for wider usage of

evidence-based therapies in patients with stage I

hypertension.

Evidence from the Antihypertensive and

Lipid-Lowering to prevent Heart Attack Trial

(ALLHAT)2–4 and other pivotal hypertension studies

like Hypertension Detection and Follow-up Program

(HDFP)5, Multiple Risk Factor Intervention Trial

(MRFIT)6, Systolic Hypertension in the Elderly

Program (SHEP)7 has established that thiazide-like

diuretics confer significant reduction in stroke and

cardiovascular events8. Given their strong record of

evidence, low cost and favorable tolerability, low-dose

thiazide-like diuretics are recommended as initial

therapy in most of the hypertensive patients and as

the foundation for multiple antihypertensive drug

regimens9. Chlorthalidone was commonly used in

1970s, but its use has sharply declined in the past

20 years. It is not known why the drug has fallen out of

favor. One of the reasons for its low usage is the

concerns over metabolic adverse effects10. These

concerns can be addressed to a great extent by use of

low-dose chlorthalidone.

The largest clinical trials, including Hypertension

Detection and Follow-up Program (HDFP), MRFIT,

Systolic Hypertension in the Elderly Program (SHEP),

and ALLHAT, primarily used chlorthalidone as the

initial therapy and more consistently showed reduc-

tions in cardiovascular events than did studies that

primarily used HCTZ.10 Chlorthalidone possesses a

distinct pharmacokinetic profile, it provides more

sustained BP reduction over 24 hours, and it has been

suggested that its longer duration of action might

provide greater antihypertensive effects, particularly

throughout nighttime hours11. Due to its higher

potency and longer duration of action, chlorthalidone

is effective in providing additional protection from

stroke and myocardial infarction during the early

morning BP surge11.

In a pilot study, the substitution of chlorthalidone

for HCTZ in patients with uncontrolled blood pressure

on stable doses of HCTZ for 6 months, was found to

reduce SBP by an additional 4–7 mmHg, which led to

achieving goal BP in 6 of the 19 patients11. Similarly, a

randomized, single-blind clinical trial showed that,

after 8 weeks, patients who were taking 25 mg/day

chlorthalidone experienced a greater reduction in

blood pressure than those taking 50 mg/day of

hydrochlorothiazide11.

Since chlorthalidone appeared to be more than twice

as potent as hydrochlorothiazide10, a low dose of

chlorthalidone, i.e. 6.25 mg once daily, was thought to

be adequate in providing blood pressure control and

at the same time reducing the metabolic adverse effects.

Despite several advances in treatment of hyperten-

sion, mild-to-moderate hypertension still remains

poorly controlled. This relates to multiple factors,

including low antihypertensive efficacy of single-drug

therapies, reluctance of primary care physicians to

modify or titrate initially-chosen therapy to obtain

target blood pressure, and poor compliance with

medication12.

More than two-thirds of hypertensive individuals

cannot be controlled on one drug and require two or

more antihypertensive agents selected from different

drug classes13–17. The Joint National Committee on

Prevention, Detection, and Treatment of High Blood

Pressure (JNC 7) report9, as well as the European

Society of Hypertension and Cardiology (ESH/ESC)18

and the German Hypertension League19, have stated

that a high proportion of hypertensives will require a

combination of two or more antihypertensive agents

to achieve the desired target blood pressure (BP).

Besides better efficacy, the combination of two anti-

hypertensive agents with complementary mechanisms

of action is associated with better tolerance, improved

compliance, a simple drug regimen and lower cost.

The purpose of this study was to investigate the

antihypertensive efficacy and safety of 20 weeks

of treatment with a low-dose combination of

chlorthalidone (6.25 mg) and the �-blocker atenolol

(25 mg) in comparison with a high dose of atenolol

(50 mg) and a commonly used �-blocker–calcium

channel blocker combination (atenolol 25 mg

1772 Low-dose chlorthalidone in stage I hypertension � 2008 Informa UK Ltd - Curr Med Res Opin 2008; 24(06)

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and amlodipine 2.5 mg) in patients who were

uncontrolled on 4 weeks of active run-in on low-

dose monotherapies.

Study objective

The primary objective was to compare the mean fall in

systolic and diastolic blood pressure between the

chlorthalidone 6.25 mgþ atenolol 25 mg combination

with atenolol 50 mg alone and atenolol 25 mgþ

amlodipine 2.5 mg combination, administered once

daily in patients who were uncontrolled on 4 weeks of

active run-in monotherapies. The secondary objective

was to evaluate the number of responders in each

treatment group and to evaluate the safety of low-dose

chlorthalidone and its combination in patients with

stage I essential hypertension.

Patients and methods

Patients

Male and female patients aged 18 years and above were

eligible if they: were newly diagnosed with stage I

essential primary hypertension (BP 140–159/90–

99 mmHg as per JNC 7 criteria), were willing to sign

an informed consent form and were available for regular

follow-up. Patients with a known history of hypersen-

sitivity to chlorthalidone, atenolol, amlodipine or any

other component of the formulations were excluded

from the study. Patients with electrolyte imbalance,

abnormal hepatic and renal function were excluded

from the study. Patients with a recent cerebrovascular

accident, overt heart failure, AV block greater than first

degree, sinus bradycardia and severe aortic stenosis

were not enrolled in this study.

Pregnant and lactating women, and all females of

childbearing potential not practicing contraception

were not enrolled in this study.

Trial design

This was a randomized, comparative, multicenter,

open-label study, conducted at Seth G.S. Medical

College & KEM Hospital, Mumbai, LTMM College &

LTMG Hospital, Mumbai, Indira Gandhi Government

Medical College, Nagpur and Grant Medical College

and St. George Hospital, Mumbai. The study protocol

was approved by the hospital ethics committees of

each center. All the patients gave their written

informed consent to participate in the study

in accordance with the Declaration of Helsinki.

The execution and monitoring of the study was

conducted in accordance with the requirements of

good clinical practice. Figure 1 depicts a flow chart of

the study design.

Treatment procedures

This outpatient study consisted of three phases:

(1) screening visit and 48 hours post-screening BP

measurements, (2) 4 weeks of active run-in treatment,

and followed by (3) 20 weeks of prospective

open-label, study treatment. During the screening visit,

patients’demographyandmedicalhistorywererecorded

and patients were screened for the eligibility criteria; 48

hours after the screening visit, BP measurements were

reconfirmed and eligible patients were randomized to

receive4 weeksofactiverun-inmonotherapywitheither

atenolol 25 mg, or chlorthalidone 6.25 mg, or amlodi-

pine 2.5 mg. Subsequently patients who were uncon-

trolled (SBP�140 mmHg and DBP�90 mmHg) on run-

in therapy entered into the 20 weeks’ study treatment

phase. Those patients who were uncontrolled on

atenolol 25 mg were shifted to atenolol 50 mg; those

uncontrolled on chlorthalidone were shifted to atenolol

25 mgþ chlorthalidone 6.25 mg combination, and those

uncontrolled on amlodipine monotherapy were shifted

to amlodipine 2.5 mg þ atenolol 25 mg fixed-dose

combination for the next 20 weeks. The study drugs

were administered orally once daily. Randomization

chartswereprovidedateachcenterbythesponsor.Study

medicationswereprovidedasasingle tablet tobetaken in

the morning. Patients were examined for adverse events

and BP measurements monthly for 6 months.

At each visit, patients’ blood pressure was measured

in the morning prior to taking medications.

The patients were not allowed to take any concomi-

tant antihypertensive medication or any other drug that

could interfere with the study drugs. At each visit, study

medication compliance was assessed by counting the

used and unused strips of study medications.

Efficacy of the therapy in treated patients was

evaluated by mean changes in systolic and diastolic

blood pressure at the end of 12 and 20 weeks from

baseline (after a 4 weeks of active run-in phase). The

percentage of responders at week 12 post-therapy

was used as a secondary efficacy parameter. Blood

pressure measurements were performed at each study

visit during the study period. Measurements were

performedinduplicate,2 minapart inthesittingposition

after 10 min rest, using a sphygmomanometer. Patients

were termed as responders if systolic BP was less than

140 mmHg and diastolic BP was less than 90 mmHg.

Patients who received at least one dose of the study

medication were evaluable for the safety assessment.

Blood samples were obtained at the baseline and at the

end of 6 months’ therapy to perform hematology and

biochemistry tests including complete blood count,

urine routine, ECG, serum electrolytes (Naþ, Cl�,

Kþ), fasting and postprandial blood sugar and lipid

profile (TG, TC).

� 2008 Informa UK - Curr Med Res Opin 2008; 24(06) Low-dose chlorthalidone in stage I hypertension Pareek et al. 1773

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Safety evaluation was also based on the adverse events

reported during the study. Adverse events were

categorized by the investigator as mild, moderate or

severe and the relationship to the study drug as none,

probably not, possible, probable or definite. At every

visit during the entire study period, the reported adverse

events, the clinical state of the patients and details of

concomitant medication, if any, were captured.

Assessment

Descriptive statistics, including mean� SD and

median for continuous variables and frequency

counts and percentage for categorical variables were

used to compare treatment groups at baseline with

respect to demographic characteristics. The three

treatment groups were compared for homogeneity at

baseline by using tests like ANOVA, Kruskal–Wallis

test, chi-square test as appropriate.

Efficacy parameter, i.e. fall in systolic blood

pressures and diastolic blood pressure, was measured

from baseline to visit 6. Changes in systolic blood

pressures and diastolic blood pressure after 12 weeks of

therapy for atenolol 50 mg; chlorthalidoneþ atenolol

combination, and amlodipineþ atenolol combination

groups were compared using nonparametric tests

like Kruskal–Wallis. Response rates in each group

were compared using chi-square statistics.

Safety was evaluated by reporting adverse events and

changes in laboratory parameters. Changes in labora-

tory parameters were analyzed using the paired t-test

and the Wilcoxon signed rank test where appropriate.

Statistical analysis was performed using statistical

software MINITAB 15.

Results

A total of 300 patients satisfying eligibility criteria

entered into 4-week active run-in phase. Out of

Patients with stage I essential hypertension

Informed consent

Screening visit (Baseline Laboratory Investigation)

48 h post-screening BP measurements

Eligible Patients (n = 300) Randomized to 4 Weeks of Active run-in Treatments

Atenolol 25 mg (n = 98) Chlorthalidone 6.25 mg (n = 100) Amlodipine 2.5 mg (n = 102)

282 patients completed active run-in

Non-responders to active run-in monotherapies after 4 weeks entered into 20 weeksprospective, open-labeled, study treatment phase

Atenolol 50 mg(n = 33)

[Chlorthalidone 6.25 mg +atenolol 25 mg]

(n = 45)

[Amlodipine 2.5 mg +atenolol 25 mg]

(n = 47)

Efficacy (blood pressure measurement) at every 4 weeks interval and safety (laboratoryinvestigation and adverse events) at the end of study period

Figure 1. Study flow chart


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300 patients, 98 patients were randomized to receive

active run-in therapy with atenolol 25 mg, 100 patients

received chlorthalidone 6.25 mg and the remaining

102 patients received amlodipine 2.5 mg.

Out of 300 patients, 282 patients (atenolol 92,

chlorthalidone 91, amlodipine 99) completed

the active run-in phase successfully. Five patients

from the atenolol group, nine patients from the

chlorthalidone group, and two patients from the

amlodipine group were lost to follow-up during

the active run-in period. One patient from the atenolol

group was withdrawn from the study due to protocol

violation, and one patient from the amlodipine group

due to adverse events.

This study enrolled 176 males (58%) and 124 females

(42%). Their ages ranged from 22 to 81 years, average

47.96� 11.87 years and an average weight

61.59� 11.4 kg. These three groups were comparable

with regard to demographic characteristics and baseline

concomitant illness, with no significant differences

between them. Table 1 provides the treatment group

wise demographic and disease characteristics of patients

entering the 4-week active run-in phase of the study.

At the end of 4 weeks of active run-in therapy, three

monotherapies showed a significant fall in mean

systolic and diastolic BP (Table 2). There was no

significant difference with respect to fall in systolic and

diastolic blood pressure across the study treatment

groups (p40.05). Similarly, the three active run-in

treatments were not significantly different in terms of

response rates.

There were a total of 125 non-responders (atenolol

33, chlorthalidone 45, amlodipine 47) at the end

of 4 weeks of active run-in therapy. These non-

responders entered into a 20-week open-label study

treatment period as per the study protocol. After

12 weeks of treatment, the three study schedules

showed a significant fall in mean systolic and

diastolic blood pressure. Although not statistically

significant, the mean fall in SBP/DBP was greater in

the low-dose chlorthalidone combination group

compared to that in the atenolol 50 mg alone or

amlodipine combination therapy groups (Table 3).

There were 82% responders to atenolol 50 mg,

84% responders to combination of chlorthalidoneþ

atenolol, and 87% in the amlodipineþ atenolol

treatment group. The study treatments were com-

parable with respect to the response rates (p40.05)

(Table 3).

In all the treatment groups the mean fall in SBP and

DBP was maximum in the first 4 weeks and subse-

quently the fall was maintained until the end of

20 weeks. The three study treatments groups were

comparable with respect to mean fall in BP as well as

response rates. Figures 2A and 2B show the blood

pressure control across three treatment groups.

Safety evaluation was carried out in patients who

had received at least one dose of the study medication.

Clinical and laboratory adverse events are summarized

in Table 4. The percentage of patients reporting

adverse events was generally similar in all the treat-

ment groups. There were no serious adverse events

reported in this study. However, one patient in the

amlodipine group reported severe pruritus that

lead to discontinuation of study medication. In the

investigator’s judgment, the reported adverse events

were of mild-to-moderate intensity, and possibly

related to the study drugs. They subsided on their

own and did not require any treatment. All the study

medications were well-tolerated and found to be safe

in this study population.

The laboratory evaluations were carried out at

baseline and at the end of therapy. Mean changes

from baseline for various laboratory parameters were

evaluated at the end of 6 months for all the patients.

Although clinically significant changes were not

Table 1. Characteristics of patients entering the study

Characteristics Total Atenolol Chlorthalidone Amlodipine p-value

Number of patients 300 98 100 102

Males 176 55 60 61 0.878

Females 124 43 40 41

Average age (SD) (years) 47.96� 11.87 48.49� 12.98 46.44� 11.79 48.98� 10.83 0.251

Average weight (SD) (kg) 61.58� 11.48 60.65� 9.92 63.56� 13.35 60.46� 10.56 0.087

Concomitant illness

Ischemic heart disease 8 2 3 3

Diabetes 48 14 17 17

Mean SBP (mmHg) (SD) 149.52� 7.27 149.47� 7.69 149.43� 6.99 149.66� 7.20 0.934

Mean DBP(mmHg) (SD) 93.51� 4.73 93.23� 3.62 93.81� 4.33 93.50� 4.48 0.492

Mean pulse rate (beats/min) (SD) 83.30� 10.00 84.83� 9.98 82.30� 11.18 82.92� 8.63 0.193


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observed across the treatment groups at the end-

of-study evaluation (Table 5), a statistically significant

fall in serum Kþ levels, along with a non-significant rise

in blood glucose levels, were observed in the chlortha-

lidone group. Though the fall in serum Kþ levels was

clinically non-significant, it was accompanied by a

minor elevation in blood glucose levels, which suggests

caution should to be exercised with regard to the

development of new-onset diabetes in the long term.

In the chlorthalidoneþ atenolol combination, fall in

serum Kþ levels were not significant, possibly due to the

anti-renin effects of atenolol, as �-blockers are known to

inhibit renin secretion. In this short-duration

therapy, no significant changes were observed in

serum Kþ and blood glucose levels in the

atenololþ chlorthalidone combination therapy. Two

patients reported changes in the laboratory parameters.

Total cholesterol was increased in one patient each

treated with chlorthalidone 6.25 mg and atenolol 25 mg.

There was no serious laboratory abnormality

reported in any patient in this study.

Discussion

This is probably the first study that has evaluated

the safety and efficacy of low-dose chlorthalidone,

i.e. 6.25 mg in combination with atenolol 25 mg in

patients with stage I essential hypertension. This study

evaluated a combination of once-daily low-dose

chlorthalidone with atenolol, keeping in mind the

concerns over dose-related metabolic adverse effects of

thiazide-like diuretics.

The study compared low-dose chlorthalidoneþ

atenolol combination with high-dose atenolol 50 mg,

as well as with atenolol 25 mgþ amlodipine 2.5 mg

fixed-dose combination.

Atenolol 25 mg alone once daily and amlodipine

2.5 mg in combination with atenolol 25 mg are widely

used as first-line antihypertensive therapies in Indian

stage I hypertensive patients in clinical practice. The

patients who do not respond to atenolol 25 mg are

stepped-up either to atenolol 50 mg OD or to a

combination of atenolol 25 mgþ amlodipine 2.5 mg.

Table 3. Comparisons of mean fall in blood pressure and response rates after 12 and 20 weeks of active study treatments

Efficacy parameters ATN 50 mg

(n¼ 33)

CTNþATN

(n¼ 45)

AMLþATN

(n¼ 47)

p-value

Mean baseline SBP (mmHg) 145.94� 0.967 147.24� 1.37 147.47� 0.72 0.592

Mean SBP (mmHg) after 12 weeks 135.18� 1.08 133.20� 1.42 135.23� 1.01 0.387


Mean baseline DBP (mmHg) 89.75� 0.960 92.4� 0.523 90.36� 0.85 0.055

Mean DBP (mmHg) after 12 weeks 85.15� 1.18 84.66� 0.974 84.97� 0.847 0.942


Mean fall in SBP (mmHg) after 12 weeks �10.76� 1.08 �14.04� 1.93 �12.23� 1.20 0.337

Mean fall in SBP (mmHg) after 20 weeks �13.27� 1.58 �14.09� 1.91 �15.21� 1.64 0.744

Mean fall in DBP (mmHg) after 12 weeks �4.60� 0.776 �7.73� 1.03 �5.38� 0.885 0.054

Mean fall in DBP (mmHg) after 20 weeks �7.45� 1 �7.68� 0.932 �6.96� 1 0.855

Responders 27 (82%) 38 (84%) 41 (87%) 0.799

Non-responder 6(18%) 7 (16%) 6 (13%)

Table 2. Comparisons of mean fall in blood pressure and response rates after 4 weeks of active run-in therapy

Efficacy parameters ATN (n¼ 92) CTN (n¼ 91) AML (n¼ 99) p-value

Mean screening SBP (mmHg) 149.42� 7.63 149.35� 6.86 149.67� 7.13 0.929


Mean screening DBP (mmHg) 93.14� 5.23 93.74� 4.24 93.47� 4.44 0.481


Mean fall in SBP (mmHg) �12.34� 9.38* �10.52� 11.35* �11.18� 10.30* 0.337

Mean fall in DBP (mmHg) �7.68� 6.35* �6.16� 7.17* �6.87� 6.16* 0.292

Responders 59 (64%) 46 (51%) 52 (53%) 0.133

Non-responders 33 (36%) 45 (49%) 47 (47%)

ATN¼ atenolol; CTN¼ chlorthalidone; AML¼ amlodipine*Significant fall from screening visit p50.05


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Hence in our study we decided to compare the novel

combination of chlorthalidone 6.25 mgþ atenolol

25 mg with atenolol 50 mg, as well as with the

commonly prescribed atenololþ amlodipine combina-

tion in patients who were uncontrolled on active

run-in monotherapies. Thiazide and thiazide-like

diuretics have shown good efficacy as well as long--

term benefits in terms of morbidity and mortality in

hypertensive patients. One of the major reasons for

the low usage of these drugs in clinical practice is

concern regarding adverse metabolic effects, such as

hypokalemia, hyperuricemia and impaired glucose

tolerance. By reducing the dose of diuretics, these

concerns are reduced but not completely eliminated.

Available literature indicates that chlorthalidone is

twice as potent as hydrochlorothiazide. Hence, we

proposed that the low dose of chlorthalidone should

be further reduced to 6.25 mg instead of 12.5 mg

per day.

In this present study, after 4 weeks of active run-in

therapy, the low-dose chlorthalidone 6.25 mg

reported a significant fall in SBP from 149.35�6.86

to 138.84� 12.49 (p50.05) and in DBP from

93.74� 4.24 to 87.58� 6.76 (p50.05). This fall was

comparable with that observed with atenolol 25 mg

and amlodipine 2.5 mg once daily during the

active run-in treatment phase. However, the efficacy

of low-dose chlorthalidone monotherapy requires

further validation, as a prior placebo run-in period

was not administered in the studied population to

eliminate the effect of lifestyle and dietary changes.

This study demonstrated the efficacy of chlorthali-

done 6.25 mg in combination with atenolol 25 mg in

patients who were not adequately controlled on

chlorthalidone 6.25 mg monotherapy. Data from the

literature reported a fall of 16 mmHg in SBP and

13 mmHg in DBP when a similar combination was

used in mild-to-moderate hypertensive patients at

double the doses of individual components used in

this study20. Our study reported a mean fall of

Table 4. Adverse events

Adverse events ATN 25 mg

pts (%)

n¼ 64

CTN pts (%)

n¼ 53

AML pts (%)

n¼ 54

ATN 50 mg

pts (%)

n¼ 34

ATNþCTN

pts (%)

n¼ 47

ATNþAML

pts (%)

n¼ 48

Dizziness 3 (4.68) 3 (5.66) 1 (1.85) 1 (2.94) – 3 (6.25)

Fatigue 3 (4.68) 1 (1.88) 2 (3.70) 1 (2.94) 1 (2.12) 1 (2.08)

Tingling and

numbness of limbs

– 1 (1.88) 1 (1.85) – 3 (6.38) 1 (2.08)

Nausea and vomiting 3 (4.68) 1 (1.88) – – 1 (2.12) –

Bradycardia 2 (3.12) – – – 1 (2.12) 1 (2.08)

Headache – – 1 (1.85) – 1 (2.12) 1 (2.08)

Increase in TC level 2 (3.12) 1 (1.88) – – – –

Loss of appetite – 1 (1.88) – – – –

Neck pain – 1 (1.88) – – – –

Pruritus – – 1 (1.85) – – –

Loss of taste – – – – 1 (2.12) –

ATN¼ atenolol; CTN¼ chlorthalidone; AML¼ amlodipine; TC¼ total cholesterol

78

80

82

84

86

88

90

92

94

BP

(mm

Hg

)

(A)

125

130

135

140

145

150

0 4 8 16 20

BP

(mm

Hg

)

Atenolol 50

Chlorthalidone 6.25 mg + Atenolol 25 mg

Amlodipine 2.5 mg + Atenolol 25 mg

Atenolol 50

Chlorthalidone 6.25 mg + Atenolol 25 mg

Amlodipine 2.5 mg + Atenolol 25 mg

(B) Mean fall in SBP for step-up therapies

Mean fall in DBP for step-up therapies

Weeks

12

0 4 8 16 20

Weeks

12

Figure 2. Changes in mean DBP and SBP over 20 weeks of

active study treatment


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14.04 mmHg in SBP and 7.73 mmHg in DBP in

patients who received atenolol–chlorthalidone combi-

nation. This study confirmed that the combination of

atenololþ chlorthalidone was as good as the atenololþ

amlodipine combination or atenolol 50 mg in reducing

SBP and DBP with similar response rates Table 3.

There was a significant fall in mean SBP and DBP from

the baseline across the study treatment groups.

This fall was comparable and was sustained throughout

the study duration. Also, there was no significant

difference in the response rates in all the

three treatment groups, indicating that the low-

dose chlorthalidone combination is non-inferior to

atenolol 50 mg or amlodipineþ atenolol combination

therapy.

Besides the efficacy of the chlorthalidoneþ atenolol

combination, this study also demonstrated a good safety

profile of the combination. Biochemical screening did

not reveal any clinically significant changes in serum

electrolytes and blood glucose level after 6 months of

therapy with chlorthalidone and its combination. When

used in high doses, chlorthalidone causes adverse events

(like hyperuricemia, hyperglycemia, and electrolyte

imbalance) in a dose-dependent manner. However, at

this reduced dose the potential adverse events are

minimized. In our study we administered low-dose

chlorthalidone for up to 6 months, either alone or in

combination, and there were no reports of electrolyte

imbalance in the studied population.

The results of the present study confirmed the

efficacy of low-dose chlorthalidone combination

in patients with stage I essential hypertension.

Evidence of efficacy, along with low cost and favorable

tolerability profile, makes low-dose chlorthalidone

combination a useful therapeutic option for treating

patients with stage I essential hypertension.

Study limitations

This study had the following limitations:

(1) This being an outpatient study, no ambulatoryblood pressure monitoring was done to assess24-hour efficacy of study medications.

(2) The dose of chlorthalidone 6.25 mg/day wasbased on the brief review published by Carteret al.10, wherein the author had suggestedthat equivalent doses of chlorthalidone shouldgenerally be 50–75% of typical hydrochlorothia-zide doses and not based on the dose–responserelationships of chlorthalidone in such patientpopulations.

(3) Due to the short-term nature of the study (up to6 months), we were unable to study theinfluence of blood pressure reductions oncardiovascular morbidity and mortality.

(4) In this short-term study, we could not assessthe incidence of new-onset diabetes in patientstreated with thiazide-like diuretic chlorthali-done and its combination with atenolol.

Table 5. Mean changes in serum electrolytes and blood sugar from baseline to end of study (6 months)

Study groups Visit Sodium

(mEq/L)

Potassium

(mEq/L)

Chloride

(mEq/L)

FBS

(mg/dL)

PPS

(mg/dL)

Atenolol 25 Baseline 138.50� 4.41 3.99� 0.45 98.00� 2.82 103.93� 32.47 132.54� 48.25

End 138.94� 3.41 4.13� 0.44 98.50� 0.70 99.25� 18.96 123.91� 32.85

p-value 0.543 0.079 0.874 0.267 0.256

Atenolol 50 Baseline 138.89� 3.94 4.07� 0.29 102.00� 2.0 106.47� 36.82 139.72� 27.46

End 139.16� 2.40 4.13� 0.30 102.66� 2.88 104.82� 20.34 141.82� 38.99

p-value 0.730 0.322 0.529 0.721 0.760

Chlorthalidone Baseline 138.370� 4.82 4.2109� 0.55 102.50� 5.07 101.49� 26.62 137.13� 59.21

End 138.291� 3.88 3.9737� 0.50 98.75� 4.57 105.78� 38.60 135.24� 57.84

p-value 0.918 0.007 0.305 0.282 0.694

Amlodipine Baseline 139.740� 5.58 4.1654� 0.44 95.60� 4.83 108.83� 49.92 154.9� 83.3

End 138.712� 3.65 4.1288� 0.46 97.20� 7.60 104.18�27.42 142.2� 50.70

p-value 0.226 0.659 0.674 0.434 0.126

Amlodipineþ atenolol

combinations

Baseline 139.193� 3.47 4.0540� 0.39 98.95� 3.99 98.21� 12.04 127.05� 24.89

End 139.705� 2.98 4.1605� 0.39 99.66� 3.55 100.33� 8.94 129.37� 21.71

p-value 0.412 0.140 0.503 0.124 0.422

Chlorthalidoneþ

atenolol

Baseline 139.534� 3.65 4.208�0.51 98.62� 4.25 100.76� 22.24 125.88� 40.20

End 139.450� 3.24 4.1559� 0.40 100.31� 5.22 100.38� 16.01 128.70� 22.66

p-value 0.859 0.421 0.423 0.878 0.549

FBS¼Fasting Blood Sugar; PPS¼Post Prandial Blood Sugar


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Conclusion

Low-dose chlorthalidone, i.e. 6.25 mg in combination

with atenolol 25 mg, is found to be effective and

safe in patients with stage I (JNC 7) essential

hypertension. The combination of low-dose chlortha-

lidoneþ atenolol is as effective as a combination of

amlodipineþ atenolol, as well as high-dose atenolol

monotherapy. If future clinical trials using chlorthali-

done 6.25 mg confirm its efficacy, then this dose could

reduce the concerns of metabolic adverse effects and

could lead to its wider usage in clinical practice.

Acknowledgements

Declaration of interest: This study was sponsored by

Ipca Laboratories Ltd., Mumbai, India. A. Pareek

and N.B. Chandurkar, who are employees of Ipca

Labs Ltd, were involved in the conceptualization,

coordination and execution of the study, at all the

centers. N.D. Karnik, S.B. Salagre, S.D. Zawar and

V.K. Joglekar, who were study investigators, did not

receive any financial benefit and declare that they

have no conflicts of interest of a declarable nature.

The authors thank S.R Kulkarni and G.S. Naik (of

Ipca Labs Ltd) for technical assistance and S.P. Dixit

(of Ipca Labs Ltd) for statistical analysis and data

management for this study. The authors would also

like to thank C.Y. Nimkar, who served as an external

consultant for statistical analysis.

References1. Scholze J, Bida M, Hansen A, et al. Initiation of hypertension

treatment with a fixed dose combination or its monocomponents– Does it really matter? Int J Clinical Pract 2006;60:265-74

2. The ALLHAT Officers and Coordinators for the ALLHATCollaborative Research Group. Major outcomes in high riskhypertensive patients randomized to angiotensin-convertingenzyme inhibitor or calcium channel blocker vs diuretic.The Antihypertensive and Lipid-Lowering Treatment toPrevent Heart Attack Trial. JAMA 2002;288:2981–97

3. Wright JT, Dunn JK, Cutler JA, et al. For the ALLHATCollaborative Research Group. Outcomes in hypertensive blackand nonblack patients treated with chlorthalidone, amlodipine,and lisinopril. JAMA 2005;293:1595-608

4. Psaty BM, Lumley T, Furberg CD, et al. Health outcomesassociated with various antihypertensive therapies used as first-line agents: a network meta-analysis. JAMA 2003;289:2534-44

5. Five-year findings of the hypertension detection and follow-upprogram. I. Reduction in mortality of persons with high

blood pressure, including mild hypertension. Hypertension

Detection and Follow-up Program Cooperative Group. JAMA

1979;242:2562–716. The Multiple Risk Factor Intervention Trial Research Group

(MRFIT). Mortality rates after 10.5 years for hypertensive

participants in the Multiple Risk Factor Intervention Trial.

Circulation 1990;82:1616–287. SHEP Cooperative Research Group. Prevention of stroke by

antihypertensive drug treatment in older persons with isolated

systolic hypertension. Final results of the Systolic Hypertension

in the Elderly Program (SHEP). JAMA 1991;265:3255–648. Neaton JD, Grimm RH, Prineas RJ, et al. For the Treatment

of Mild Hypertension Study Research Group. Treatment of

mild hypertension study. Final results. Treatment of Mild

Hypertension Study Research Group. JAMA 1993;270:713-249. Chobanian AV, Bakris GL, Black HR, et al. Joint National

Committee on Detection, Evaluation, and Treatment of High

Blood Pressure. The seventh report of the Joint National

Committee on Detection, Evaluation, and Treatment of High

Blood Pressure (JNC 7). JAMA 2003;289:2560-7210. Barry LC, Michael EE, Jerome DC. Hydrochlorothiazide versus

chlorthalidone: evidence supporting their interchangeability.

Hypertension 2004;43:4-911. Barry LC, Chris JG, Jennifer JG, et al. Comparative anti-

hypertensive effects of hydrochlorothiazide and chlorthalidone

on ambulatory and office blood pressure. Hypertension

2006;47:352-812. Ruzicka M, Leenen FH. Combination therapy as firstline

treatment of arterial hypertension. Can J Cardiol 2002;18:

1317-2713. Cushman WC, Ford CE, Cutler JA, et al. Success and

predictors of blood pressure control in diverse North

American settings: The Antihypertensive and Lipid-Lowering

Treatment to Prevent Heart Attack Trial (ALLHAT). J Clin

Hypertens 2002;4:393-40414. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of

intensive blood-pressure lowering and low-dose aspirin in

patients with hypertension: principal results of the

Hypertension Optimal Treatment (HOT) randomized trial.

HOT Study Group. Lancet 1998;26:S80-215. Black HR, Elliot WJ, Grandits G, et al. Principal results of the

Controlled Onset Verapramil Investigation of Cardiovascular

End Points (CONVINCE) trial. JAMA 2003;289:2073-8216. Dahlof B, Devereux RB, Kjeldsen SE, et al. Cardiovascular

morbidity and mortality in the Losartan Intervention for

Endpoint Reduction in Hypertensive Study (LIFE): a rando-

mized trial against atenolol. Lancet 2002;359:995-100317. Materson BJ, Reda DJ, Cushman WC, et al. Single-drug

therapy for hypertension in men. A comparison of six

antihypertensive agents with placebo. The Department of

Veterans Affairs Cooperative Study Group on

Antihypertensive Agents. N Engl J Med 1993;328:914-2118. 2003 European Society of Hypertension – European Society

of Cardiology Guidelines for the management of arterial

hypertension. J Hypertens 2003;21:1011–5319. Zidek W. Hochdruckleitlinien iiberabeitet. Was ist

Praxisrelevant? MMW Fortschr Med 2004;1–2:16/37-8/1720. Curry RC Jr Schwartz KM, Urban PL. Atenolol and chlortha-

lidone therapy for hypertension: a double blind comparison.

South Med J 1988;81:1401-6, 1411

CrossRef links are available in the online published version of this paper:

http://www.cmrojournal.com

Paper CMRO-4517_4, Accepted for publication: 10 April 2008

Published Online: 9 May 2008

doi:10.1185/03007990802118071


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clinical effectiveness of low-dose chlorthalidone (6.25 mg) + atenolol combination in stage i...

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