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Hydrochlorothiazide vs Chlorthalidone
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Peer Feedback:
“chlorthalidone - thiazde diuretic with evidence to supports its use, covered by ODB, supports
evidence based care”
Literature Review Question:
Is chlorthalidone a more efficacious thiazide diuretic then hydrochlorothiazide?
Literature Search:
eCPS – Hypertension
ODB
Cochrane - Hydrochlorothiazide OR Chlorthalidone
Pubmed – “Hydrochlorothiazide AND Chlorthalidone AND meta-analysis/review”
Misconceptions about Treating HTN (2015)
Hydrochlorothiazide is one of the weakest antihypertensive agents available. In head-to-head
comparison by 24-hour ambulatory monitoring, the antihypertensive efficacy was shown to be
inferior to other drug classes, such as angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers, beta-blockers, and calcium channel blockers.5 Moreover, hydrochlorothiazide’s
antihypertensive effect does not last 24 hours, thereby leaving the critical early morning hours
unprotected.5-7 2.
Hydrochlorothiazide in its usual dose of 12.5 to 25 mg per day has never been shown to reduce
the risk of myocardial infarction, stroke, or death.4 In fact, higher doses have been shown to
increase the risk of sudden cardiac death in a dose-dependent fashion.8 3.
Even in combination with an angiotensin-converting enzyme inhibitor, hydrochlorothiazide has
been shown to be inferior to a calcium channel blocker, such as amlodipine. In the Avoiding
Cardiovascular Events through Combination Therapy in Patients Living with Systolic
Hypertension trial, despite identical blood pressure reduction, the amlodipine-based combination
reduced cardiovascular events by 20% better than the hydrochlorothiazide combination, a fact
that led to a prematuretermination of the study.9 4.
All efficacy and outcome data for thiazides are solely derived from chlorthalidone and
indapamide. Antihypertensive therapy based on both of these drugs have been shown repeatedly
to decrease the risk of heart attack, stroke, heart failure, and even death in several prospective
randomized trials, such as Systolic Hypertension in the Elderly Program, Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), Hypertension in the Very
Elderly Trial, and Perin-dopril Protection against Recurrent Stroke Study.10-13 However, both of
these drugs, chlorthalidone and indapamide, are distinctly different from hydrochlorothiazide and
have been documented to exert pleiotropic effects that may account for their superior
efficacy.4,14
It is clear that hydrochlorothiazide should be avoided as the first-line therapy for hypertension. If a
thiazide is deemed to be appropriate, our choice should be chlorthalidone or indapamide, as is
stated in the British National Institute for Health and Clinical Excellence guidelines.15
Argulian, Edgar, Ehud Grossman, and Franz H. Messerli. "Misconceptions and Facts About
Treating Hypertension." The American journal of medicine 128.5 (2015): 450-455.
Cochrane (2014)
In 33 trials with a baseline blood pressure of 155/100 mmHg, hydrochlorothiazide lowered blood
pressure based on dose, with doses of 6.25 mg, 12.5 mg, 25 mg and 50 mg/day lowering blood
pressure compared to placebo by 4 mmHg (95% CI 2 to 6, moderatequality evidence)/2 mmHg
(95% CI 1 to 4, moderate-quality evidence), 6 mmHg (95% CI 5 to 7, high-quality evidence)/3
mmHg (95% CI 3 to 4, high-quality evidence), 8 mmHg (95% CI 7 to 9, high-quality evidence)/3
mmHg (95% CI 3 to 4, high-quality evidence) and 11 mmHg (95% CI 6 to 15, low-quality
evidence)/5 mmHg (95% CI 3 to 7, low-quality evidence), respectively.
Direct comparison of doses did not show evidence of dose dependence for blood pressurelowering for any of the other thiazides for which RCT data were available: bendrofluazide,
chlorthalidone, cyclopenthiazide, metolazone or indapamide.
In seven trials with a baseline blood pressure of 163/88 mmHg, chlorthalidone at doses of 12.5
mg to 75 mg/day reduced average blood pressure compared to placebo by 12.0 mmHg (95% CI
10 to 14, low-quality evidence)/4 mmHg (95% CI 3 to 5, low-quality evidence).
Thiazides reduced potassium, increased uric acid and increased total cholesterol and
triglycerides. These effects were dose-related and were least for hydrochlorothiazide.
Chlorthalidone increased serum glucose but the evidence was unclear for other thiazides. There
is a high risk of bias in the metabolic data. This review does not provide a good assessment of
the adverse effects of these drugs because there was a high risk of bias in the reporting of
withdrawals due to adverse effects.
This systematic review shows that hydrochlorothiazide has a dose-related blood pressurelowering effect. The mean blood pressurelowering effect over the dose range 6.25 mg, 12.5 mg,
25 mg and 50 mg/day is 4/2 mmHg, 6/3 mmHg, 8/3 mmHg and 11/5 mmHg, respectively. For
other thiazide drugs, the lowest doses studied lowered blood pressure maximally and higher
doses did not lower it more. Due to the greater effect on systolic than on diastolic blood pressure,
thiazides lower pulse pressure by 4 mmHg to 6 mmHg. This exceeds the mean 3 mmHg pulse
pressure reduction achieved by ACE inhibitors, ARBs and renin inhibitors, and the 2 mmHg pulse
pressure reduction with non-selective beta-blockers as shown in other Cochrane reviews, which
compared these antihypertensive drug classes with placebo and used similar inclusion/exclusion
criteria. Thiazides did not increase withdrawals due to adverse effects in these short-term trials
but there is a high risk of bias for that outcome. Thiazides reduced potassium, increased uric acid
and increased total cholesterol and triglycerides.
Musini, Vijaya M., et al. "Blood pressure-lowering efficacy of monotherapy with thiazide diuretics for primary
hypertension." Cochrane Database Syst Rev 5 (2014).
Is chlorthalidone better then HCTZ (2013)
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Randomized trial data show that CTDN has superior 24-h antihypertensive potency,
particularly at night (7.1 mmHg difference in systolic BP).
In an observational cohort study of MRFIT data, relative to HCTZ, CTDN was associated
with lower development of LVH.
In an observational cohort study of MRFIT data, when comparing the two drugs, CTDN
had significantly fewer CVEs by about one-fifth, P = 0.002.
In a network meta-analysis of randomized trials, relative to HCTZ, CTDN again reduced
CVEs by about one-fifth, P < 0.0001; this result was validated in a second type of
network analysis, in which CTDN was superior to HCTZ even after adjustment for
changes in office systolic blood pressure produced by the two agents.
Because HCTZ is so widely used, these results imply that millions of people are taking an
inferior diuretic.
Table 2 summarizes the differences between CTDN and HCTZ, reflecting data on more than 60
000 participants. All available evidence supports the superiority of CTDN. Relative to HCTZ, the
best estimate is that CTDN reduces CVEs by 21%. Recent guidelines are congruent with this
evidence. Because of HCTZ’s widespread use, it is likely that millions of people are taking an
inferior diuretic. Changes in prescribing practices and greater availability of CTDN-containing
pharmaceutical preparations are needed to give our patients better care.
Roush, George C., Venkata Buddharaju, and Michael E. Ernst. "Is chlorthalidone better than hydrochlorothiazide in
reducing cardiovascular events in hypertensives?." Current opinion in cardiology 28.4 (2013): 426-432.
ODB Formulary (2015)
Generic Name
Brand Name, Strength &
Dosage Form
MFR
Drug Benefit
Price
Amount
MOHLTC Pays
HYDROCHLOROTHIAZIDE
Apo-Hydro (Not a Benefit)
12.5mg Tab
APX
N/A
N/A
HYDROCHLOROTHIAZIDE
Apo-Hydro 25
25mg Tab
APX
0.0157
0.0157
HYDROCHLOROTHIAZIDE
Apo-Hydro 50
50mg Tab
APX
0.0217
0.0217
CHLORTHALIDONE
Chlorthalidone
50mg Tab
AAP
0.1242
0.1242
Accessed July 6, 2015
eCPS (2015)
Extensive evidence supports low-dose thiazide or related diuretics (e.g., indapamide) as
first-line therapy for uncomplicated hypertension. They should generally be selected
unless there are specific indications for other drugs (see Table 5). Diuretics are
inexpensive and well tolerated. They have proven antihypertensive effectiveness in
patients with isolated systolic hypertension, the elderly and black patients.
Diuretics can cause hypokalemia that may be associated with adverse cardiovascular
outcomes. Consider alternative first-line agents in those with or strongly predisposed to a
serious arrhythmia, for example, prolonged QT syndrome. Consider using a combination
product to minimize the risk of hypokalemia (hydrochlorothiazide plus a potassiumsparing diuretic—spironolactone, amiloride or triamterene). Reserve the use of high doses
(e.g., >25 mg/day of hydrochlorothiazide) for patients with resistant hypertension
unresponsive to treatment with multiple drugs or secondary to renal impairment. Consider
using a loop diuretic in patients with renal impairment. Diuretics may worsen dysglycemia,
although cardiovascular outcomes in patients with diabetes who are treated with diuretics
are similar to those treated with ACE inhibitors.
Table 6: Drugs Used for Hypertension
Class
Diuretics
Diuretics
Drug
Dosage
Adverse Effects
Drug Interactions
Comments
Cost
hydrochlorothia
zide
generics
Initial:
12.5
mg/day
Usual: 25
mg/day
Once daily
po
Hypotension,
weakness, muscle
cramps, impotence.
Hypokalemia,
hyponatremia,
hyperuricemia,
hyperglycemia,
hyperlipidemia.
Li+ excretion reduced

(monitor Li+levels,
adjust dose).
Particularly effective in ISH, the elderly and black
patients.
Monitor SCr and K+.
$
NSAIDs reduce
hypotensive efficacy.
Consider alternatives in patients with or
predisposed to arrhythmias.
Diuretic-induced
hypokalemia
increases the risk of
digoxin toxicity.
Can exacerbate gout and diabetes (biochemical
abnormalities are less frequent at low doses).
Ineffective in patients with ClCr <30 to 40 mL/min.
chlorthalidone
generics
Initial:
12.5
mg/day
Usual:
12.5–25
mg/day
Once daily
po
Rare: azotemia, blood
dyscrasias, allergic
reactions (potential
cross sensitivity with
other sulfonamide
derivatives),
photosensitivity,
fatigue.

Reduced efficacy of
antihyperglycemic
agents.


.
Lowest available tablet strength is 50 mg. Tablet (or
“pill”) splitters, widely available in pharmacies, can
be used to derive a dose of 12.5 mg (one quarter
tablet) with reasonable accuracy.
Particularly effective in ISH, the elderly and black
patients.
Monitor SCr and K+.
Consider alternatives in patients with or
predisposed to arrhythmias.
Can exacerbate gout and diabetes (biochemical
abnormalities are less frequent at low doses).
Ineffective in patients with ClCr <30 to 40 mL/min.
Legend: $<$20
$-$$ <20–40
$$ 20–40
$$$ 40–60
$$$$ 60–80
Cardiovascular Disorders: Hypertension; Norm R.C. R. C. Campbell, MD, FRCPC, Paul Gibson,
MD, FRCPC, and Ross T. Tsuyuki, PharmD, MSc, FCSHP, FACC; Date of Revision: March 2015
Medication
hydrochl
orothiazi
de
Uses
Contraindications (CI), drug
interactions (DI) or cautions
hypertensio CI: anuria, severe sulphur
n, heart
allergy, symptomatic
failure
hyperuricemia,
hyponatremia
DI: Digoxin, lithium, NSAID,
steroids
Adverse Effects
(common and severe)
Initial dose; typical
dose
increases calcium, uric
acid, glucose,
cholesterol,
triglycerides, decreases
sodium, potassium,
magnesium and zinc
12.5mg; 12.525mg one time
a day
Monitoring
BP
$