Chlorthalidone has been shown to be more effective at lowering blood pressure than hydrochlorothiazide, especially at night, due to its longer half-life. Evidence from large clinical trials also indicates that chlorthalidone reduces cardiovascular outcomes more than hydrochlorothiazide when used for hypertension. As a result, clinical guidelines now recommend chlorthalidone as the first-line thiazide-type diuretic for treating hypertension.

1. Choosing a diuretic combination
therapy in hypertension
Follow the crowd
Or
Follow evidence?
http://www.medscape.com/viewarticle/728684

2. The agenda for discussion
• Recalling the basics
• Hypertension therapy: principles
• Diuretics
• All about Chlorthalidone
• Time reflected evidence
• Summary
• Combination

3. Recalling the basics

4. Recalling the basics

5. Recalling the basics

6. Recalling the basics

7. Hypertension therapy: principles
• Non pharmacologic
1. Sodium restriction of 70-100 mEq Sodium per day
2. Diet rich in fruits, vegetables, low fat dairy, reduced
saturated fats, moderation in alcohol
3. Weight reduction may normalize 75% of overweight
patients with mild hypertension
4. Exercise
• Pharmacologic
1. One drug approach: Thiazides, CCBs or ACE
Inhibitors/ ARBs.
2. Additional drug in case of inadequate control.

8. Hypertension therapy: principles

9. Co-morbid therapy: principles
• ACE Inhibitors with diabetes mellitus and
proteinuria
• Beta blockers or calcium channel blockers with
angina
• Alpha 1 blockers in men who have benign
prostatic hypertrophy
• Diuretics, ACE Inhibitors, ARB, or beta blocker for
heart failure
• African Americans tend to respond better to
diuretics and calcium channel blockers

10. Hypertension therapy: principles

11. Hypertension therapy: principles

12. Diuretic

13. Diuretic actions

14. Diuretics: Conclusions
• Diuretics are the only class of drugs that directly
deals with the fundamental cause of hypertension:
Sodium retention
• Considered first line therapy for most forms of
hypertension as a standard of care
• Inexpensive
• Longstanding history of use, efficacy and tolerance
• Often necessary in combination therapy with other
classes of anti hypertensives that may cause salt and
water retention as compensatory response.

15. Sodium and water regulation by the
nephron: distal convoluted tubule
• The urine flows into the distal convoluted tubule
(DCT) where another 5% of the sodium is
reabsorbed by the sodium chloride co
transporter
• Thiazide diuretics (hydrochorothiazide) inhibit
this co transporter.
• Orally absorbed well.
– Chlorothiazide is the only parenteral form.
– Indapamide is excreted by the biliary system

16. Clarity on diuretics
• Are thiazide diuretics the first-choice drug or one
of the first-choice drugs?
• Do all thiazide diuretics give the same benefit?
• Is hydrochlorothiazide (HCTZ) a better choice
than chlorthalidone for hypertension?
• Optimal dose?
• Negative effects of thiazide diuretics?

17. Thiazide diuretics - first-choice?
• Thiazide diuretics are first-line for hypertensive
patients without compelling indications for
alternate drugs.
• The advantage of HCTZ is its availability in many
combination preparations, which can improve
adherence.
• Indapamide is another thiazide-like diuretic with
good evidence for reduction in cardiovascular end
points as first- or second-line antihypertensive
therapy.

18. All about Chlorthalidone

19. Chlorthalidone - first-choice?
• Chlorthalidone has a longer half-life than HCTZ (50
to 60 vs 9 to 10 hours), which might explain the
superior BP control, especially at night time.
• Meta-analysis of 19 trials found 24-hour BP was
higher with 12.5- to 25-mg doses of HCTZ compared
with other antihypertensive drugs (systolic BP 4.5 to
6.2 mm Hg higher, diastolic BP 2.9 to 6.7 mm Hg
higher).
• Not many trials have compared HCTZ with other
thiazide diuretics in terms of cardiovascular or
mortality outcomes.
• Hence, there is a need to rely on less rigorous study
designs and other outcomes.

20. Chlorthalidone - first-choice?
• Chlorthalidone reduces systolic blood pressure (BP)
better than HCTZ at equivalent doses with similar
effects on potassium levels:
– -25 mg of chlorthalidone, compared with 50 mg of HCTZ,
provided superior BP reduction overall (12 vs 7 mm Hg on
24-hour monitor) and at nighttime (13 vs 6 mm Hg).2
• Retrospective (and thus not definitive) analysis of
the MRFIT trial found that the chlorthalidone-based
regimen reduced mortality compared with the
HCTZ-based regimen (hazard ratio 0.79, 95% CI 0.68
to 0.92, P = .0016).

21. Chlorthalidone - first-choice?
• Large trials using chlorthalidone (like ALLHAT and
SHEP) have demonstrated reductions in
cardiovascular end points; evidence for HCTZ is less
robust.
• A network meta-analysis of 5 trials comparing
chlorthalidone with other thiazides did not find
differences in cardiovascular outcomes. However,
– These were indirect comparisons and
– The “other thiazides” were not just HCTZ, as many
reviewers assumed:
– 2 were HCTZ combined with potassium-sparing diuretics;
– 1 was indapamide (not HCTZ).

22. Chlorthalidone - first-choice?
• Patients requiring antihypertensives should be
reminded that dietary sodium restriction (< 1500
mg/d)16 remains key to BP management—
handouts could be given with each prescription.
• Available data suggest HCTZ is at best equal to
and very likely inferior to chlorthalidone for
improving BP and clinical outcomes.

23. Chlorthalidone - dosage
• Consider chlorthalidone when initiating thiazide
diuretics for hypertension.
• Prescribe 12.5 mg of chlorthalidone daily and
increase to 25 mg daily.
• Higher doses tend to cause more side effects
(including hypokalemia) but minimal further BP
reduction.
• Precautions and bloodwork monitoring for
chlorthalidone are similar to those for HCTZ.

24. Chlorthalidone - first-choice?
• One study has shown that
– Patients are more likely to persist with HCTZ than
chlorthalidone following initiation of either agent.
– However, for those who remain persistent on
chlorthalidone, there is an apparent efficacy
advantage in that they are less likely to require
further additional antihypertensives.
– Chlorthalidone 25-50 mg daily - Thiazide-like in
action, not structure
The Journal of Clinical Hypertension Vol 14 | No 9 | September 2012, The Comparative
Effectiveness of Hydrochlorothiazide and Chlorthalidone in an Observational Cohort of Veterans
by Brian C. Lund et al.

25. Chlorthalidone - first-choice?
• Mean change in
SBP (mm Hg) and
potassium (mEq/l)
by dose (mg) using
pooled data from
all studies and time
points for
– Chlorthalidone &
– HCTZ

26. Chlorthalidone - first-choice?
• Differences in
potassium loss
between HCTZ and
chlorthalidone
appear greatest for
doses between 50
and 75 mg.

27. Chlorthalidone - first-choice?

28. Chlorthalidone – usage over time

29. Current medical diagnosis and
treatment
• Chlorthalidone has
the advantage of
better 24-hour BP
control than
hydrochlorthiazide

30. Cardiovascular Therapeutics - A
Companion to Braunwald's Heart Disease , 4th Edition
• The pharmacokinetic and
pharmacodynamic profile
of chlorthalidone is
distinctly different from
that of hydrochlorthiazide.
• On a milligram-per-milligram
basis,
chlorthalidone is 1-5-2
times more potent.
• In recommended doses,
chlorthalidone is more
effective in loweing systolic
BP than HCTZ.

31. Cardiovascular Therapeutics - A
Companion to Braunwald's Heart Disease , 4th Edition
• This is likely because
chlorthalidone has a
longer half life than
HCTZ. [50-60 hours
vs. 9-10 hours]

32. Cardiovascular Therapeutics - A
Companion to Braunwald's Heart Disease , 4th Edition
• Chlorthalidone has had a
more consistent pattern
of favorable outcomes.
• Chlorthalidone has more
favorable pleiotropic
effects relating to platelt
aggregation and
angiogenesis than does
the thiazide diuretic,
bendroflumethiazide.

33. Summary
Longer half
life
More
favorable
Outcomes &
↓ mortality
More
favorable
pleiotropic
effects
More
favorable
Outcomes
More
effective in
lowering
systolic BP
More
potent
Better 24-
hour BP
control

34. Combination therapy
• Ideal ARB – Telmisartan
• Ideal diuretic for hypertension – Chlorthalidone
• Ideal combination – Telmisartan + Chlorthalidone