Diuretics in management of ht

56% Kenyans have never been
measured for raised blood pressure
Among those reported to be
previously diagnosed with HT only
22.3% were on medication
8 people out of every hundred
suffer from severe hypertension
Ref: www.the-star.co.ke

• 30% - pooled prevalence of HT
• 27% - patients aware of their HT status
• 18% - receiving treatment
• 7% - BP controlled
Data from 33 surveys, n = 110,414 Hypertension. 2015;65:291-298.

Importance of treating HT
% Risk reduction by SBP/DBP lowering of 10/5 mmHg
 Stroke by 36%
 Heart failure by 43%
 CHD by 16%
 CV mortality by 18%
 All-cause mortality by 11%
Thomopoulos C et al. J Hypertens. 2014 Dec;32(12):2285–95.

Importance of treating HT
Lewington et al. Lancet 2002;360:1903–13

So, it is critical to control HT…
… but are all anti-hypertensives the same?

Diuretics vs. Other Classes
Psaty BM, et al. JAMA. 2003;289:2534-44.Meta-analysis of 42 RCTs, n = 192478

The First-line Agents: Evolution from JNC 1 to 7
Diuretics
Diuretics
Diuretics
-blockers
-blockers
CCB
ACE-i
DiureticsDiuretics
-blockers
-blockers
Diuretics
ACE-inhibitors
CCB
α-blockers
αblockers
JNC 1 (1977); 2 (1980) JNC 3 (1984) JNC 4 (1988)
JNC 5 (1993) JNC 6 (1997) JNC 7 (2003)
Diuretics
-blockers
Diuretics
-blockers
Diuretics
-blockers
Diuretics

Diuretic classes
Thiazide-type Chlorothiazide
Hydrochlorothiazide
Thiazide-like Chlorthalidone
Indapamide
Loop Diuretics Furosemide; Torsemide
K+-sparing Diuretics Amiloride, Spironolactone
Carbonic Anhydrase
Inhibitors Acetazolamide
Anti
Hypertensive
Edema,
Resistant HT

Are all thiazide-diuretics the same ??

Thiazide-like
(Chlorthalidone, Inda)
vs. Thiazide-type
(HCTZ) diuretics in
lowering BP
J Cell Mol Med. 2017 Jun 19.
12 RCTs, n = 1580

Variance of SBP Reduction
Variance of DBP Reduction
J Cell Mol Med. 2017 Jun 19.

Thiazide-like vs.
Thiazide-type
diuretics in lowering
CV Risk
Am J Hypertens. 2015 Dec;28(12):1453-63.
19 RCTs, n = 112,113

Thiazide-type vs. Thiazide-like
22% reduction in risk of
Cardiac Events
with Thiazide-like
No significant
reduction with
Thiazide-type

Heart Failure
with Thiazide-like
No significant
reduction with
Thiazide-type

Stroke
with Thiazide-like
No significant
reduction with
Thiazide-type

Stroke with
Thiazide-like
No significant
reduction with
Thiazide-type

Which Anti-hypertensive is
recommended by
Guidelines ?

• Chlorthalidone is preferred on the basis of prolonged
half-life and proven trial reduction of CVD
• In Africans, thiazide diuretics (esp. chlorthalidone) or
CCBs are the best initial choice for single-drug therapy
• Chlorthalidone superior to CCB and ACEi in preventing
HF, a BP-related outcome of increasing importance

References to Chlorthalidone
In Recommendation for HT in African-Americans:
“ For optimum endpoint protection, the thiazide
chlorthalidone should be administered at a dose of
12.5 to 25 mg/day ”
“ Amlodipine is as effective as chlorthalidone in
reducing BP, CVD, and stroke events but less
effective in preventing HF ”

Indications for drug therapy for adults with diastolic
and with or without systolic hypertension
Although thiazide as well as thiazide-like diuretics remain initial
treatment options, preference is now given to the longer-
acting, thiazide-like diuretics (eg, chlorthalidone)

Pharmacological Treatment of HT with Ischemic Heart Disease
Rosendorff C et al. J Am Soc Hypertens.2015 Mar 30. pii: S1933-1711(15)00097-2.

“ Clinical outcome benefits have been best
established with chlorthalidone…
Chlorthalidone has more powerful effects on blood
pressure than HCTZ and has a longer duration of action ”
J Clin Hypertens (Greenwich). 2014 Jan;16(1):14-26.

“ If diuretic treatment is to be initiated or changed,
offer a thiazide-like diuretic, such as chlorthalidone
(12.5 mg–25.0 mg once daily) or indapamide in
preference to a conventional thiazide diuretic such as
bendroflumethiazide or hydrochlorothiazide”
NICE 2011
states

Which Anti-hypertensive is
recommended by
Experts ?

Recommended by Experts
“ In a nutshell, HCTZ has lousy antihypertensive efficacy, there are
no outcomes data for it, and it should not be used as initial
therapy” Am J Med. 2011 Oct;124(10):896-9.
“ The calamity of millions of patients being
exposed to an inefficacious drug could have
been avoided if the NHLBI simply had stated
the facts - that Chlorthalidone and not HCTZ or
a ‘thiazide’ was the drug that time and again
reduced morbidity and mortality in all studies”
Hypertens J. 2016;2(4):209-10.
Prof. Franz H. Messerli, MD

Recommended by Experts
“Chlorthalidone is the best diuretic for the
treatment of HT, both in BP–lowering efficacy
and in prevention of HT related morbidity and
mortality” Hypertension. 2011;58:994-5.
“ best available evidence.. favors Chlorthalidone
in most patients with uncomplicated HT. Also,
Chlorthalidone is a reasonable choice for use in
combination with other agents for most
patients” J Clin Hypertens. 2011 Dec;13(12):867-9.
Prof. Norman M. Kaplan, MD
Prof. Clive Rosendorff, MD

What do Textbooks say about
Chlorthalidone ?

“ The drug class best documented to reduce morbidity
and mortality in hypertension, when compared with
either placebo or active therapy, remains the thiazide
diuretics, specifically chlorthalidone ”

“ In light of the considerable clinical trial data supporting
chlorthalidone to diminish adverse CV events – vs. that
available for currently used low doses of HCTZ – there is a
growing concern that chlorthalidone may be an
underutilized drug in hypertensives ”

“ Chlorthalidone has the advantage of better 24-hour
blood pressure control than hydrochlorothiazide ”

Why is Chlorthalidone
the preferred and recommended
anti-hypertensive ?

Chlorthalidone
Preferred 1st Line Anti-hypertensive
 Long half life and high potency
 Unique Pleiotropic Benefits
 Sustained 24 hour BP control
 Critical night-time BP control
 Evaluated and proven in landmark government
funded RCTs
 Recommended by Guidelines, Experts and Textbooks

Pharmacokinetic Differences
Preferentially taken up by the red blood cells
and released slowly  long half-life
Diuretics Half life (hrs) Duration of Action
HCTZ 5-14 12-16
Indapamide 14-16 20-24
Chlorthalidone 40-60 48-72

Chlorthalidone – High Potency
Chlorthalidone is 2x as potent as HCTZ
HCTZ 50mg 25mg
Chlorthalidone 25mg 12.5mg
Carter BL et al. Hypertension. 2004;43:4-9.

Pleiotropic Effects
Carbonic anhydrase
Cl / HCO3 exchange
Catecholamine &
thrombin mediated
platelet
aggregation
Vascular
contrac-
tility
TGF-βAngiogenesis
Inhibition Stimulation
Vascular
Resistance
Hypertension: 2010;56:463-70, J Cardiovasc Pharmacol Ther. 2005 Dec;10(4):265-72,
Proc Natl Acad Sci. 2000 Mar 28;97(7):3479-84.
Role in Stroke, MI
Endothelial
Function
LVH, Vascular
Remodelling
Albumin
Permeation
ESRD
TGF-β3: Transforming Growth Factor-β
Chlorthalidone

VEGF-C
Role in Pulmonary Edema & CHF
Vascular
permeability
Inhibition
Stimulation
Vascular
Resistance
Woodman et al; Hypertension: 2010, 56: 463-70VEGF-C: Vascular endothelial growth factor C
Pleiotropic Effects
Chlorthalidone

Chlorthalidone
Mechanism of Anti-hypertensive Action

Reduction in
peripheral vascular
resistance (PVR)
Reduction in
plasma volume
Chlorthalidone – High Potency

Plasma Volume Reduction
Reduction in PV
Site of Action
Kidney
Distal
Convoluted
Tubule
Excretes salt & water through kidney

Chlorthalidone
Reduces edema in
arterial walls
Reduced PVR
• Finding: Higher sodium and water content in arterial
walls in hypertensive than normotensive
Tobion L et al. Circulation. 1952;5:754.
Arterial wall edema
CHLORTHALIDO
NE
Reduction in Peripheral Vascular Resistance

Ca
Noradrenaline
Smooth muscle cell
Chlorthalidone inhibits this NA mediated intracellular calcium release
CHLORTHALIDONE
Vasodilation

Inhibition of rho kinase
• Rho kinase - enzyme responsible for providing
energy for muscle contraction
• Chlorthalidone inhibits this enzyme and thus
prevents vasoconstriction
• Reduces PVR

BP reduction with chlorthalidone
First 2-8 weeks is due to reduction in plasma volume
Long term effect is due to reduced PVR
1. Reduced arterial edema
2. Inhibition of nor - adrenaline
mediated intracellular calcium
release
3. Inhibition of rho kinase
Chlorthalidone
Anti-hypertensive Action

Importance of 24-h BP Control
Ohkubo T et al. J Am Coll Cardiol. 2005 Aug 2;46(3):508-15.

Chlorthalidone
Sustained 24 hour BP Control
• 12-week comparative, double-blind RCT
• n = 54 with Stage 1 HT
• Efficacy of CTD vs. HCTZ by 24-h ambulatory
blood pressure (ABP) monitoring
J Am Coll Cardiol. 2016;67(4):379-89.

HCTZ converts Sustained Hypertension to
Masked Hypertension
J Am Coll Cardiol. 2016;67(4):379-89.

Chlorthalidone
Better 24 hour BP control
J Am Coll Cardiol. 2016;67(4):379-89.

• Randomized, crossover study comparing
chlorthalidone 12.5 mg/day (force-titrated to 25
mg/day) and hydrochlorothiazide 25 mg/day (force-
titrated to 50 mg/day)
• n = 30 untreated hypertensive patients
• 24-hour ambulatory BP monitoring assessed at
baseline and week 8
Hypertension. 2006;47:352-358.

Chlorthalidone
Better 24-h and Nighttime SBP Control
Mean 24-h, daytime, and nighttime ambulatory SBP with change from baseline

Chlorthalidone
Sustained Nighttime SBP Control
Mean change in average hourly ambulatory systolic BP

• n = 150, > 50y, across 9 centres in USA
Outcome at 12 weeks
Chlorthalidone
(n=50)
Amlodipine
(n=48)
Placebo
(n=52)
Mean change in SBP
Standing
-14.7 mmHg -13.7 mmHg -3.3 mmHg
Reached goal BP 69% 67% 25%
Discontinuation due to
adverse effects
4% 6% 0%
Grimm RH Jr, et al; Am J Hypertens. 2002 Jan;15:31-6

Chlorthalidone
Sustained Nighttime SBP Control
Chlorthalidone resulted in a significant decline from baseline
ambulatory SBP throughout most or all of the 24-h period, with the
greatest reduction between 2:00 AM and 10:00 AM
Grimm RH Jr, et al; Am J Hypertens. 2002 Jan;15:31-6

ALLHAT
SHEP
MRFIT
TOMHS
HDFP
SPRINT

MRFIT
Multiple Risk Factor Intervention Trial
Circulation. 1990 Nov;82(5):1616-28.
8012 Hypertensive Men
Special Intervention
(n = 4019)
Chlorthalidone (6 centers) HCTZ (9 centers)
Usual Care
(n = 3993)
• NIH funded randomized trial started in 1973
• First study that allowed direct comparison between HCTZ and
CTD on CV outcomes

• HCTZ group had a 44% higher mortality vs. other centres
• In 1980, protocol changed to use chlorthalidone as agent of
choice for initial use
• Same group had a 28% lower risk with Chlorthalidone
Circulation. 1990 Nov;82(5):1616-28
MRFIT

Circulation. 1990 Nov;82(5):1616-28
MRFIT

SHEP
JAMA. 1991 Jun 26;265(24):3255-64.

Placebo (2371) Chlorthalidone (2365)
4736 patients aged ≥ 60 years with SBP ≥ 160 mmHg
• Longest hypertension trial ever
• Participants followed up for 22 years (1995 to 2006)
• Dose 1 – chlorthalidone (12.5 mg/d) or placebo;
dose 2 was chlorthalidone 25 mg/d

Chlorthalidone
Reduction in BP, CV events and
CV mortality

JAMA. 2002 Dec 18;288(23):2981-97.

Design
• Largest antihypertensive trial ever conducted from 1994-2002
• n = 42418 aged > 55 years with hypertension and at least 1
other CHD risk factor from 623 centers in USA
• Doxazosin arm terminated early due to clear superiority of
chlorthalidone over doxazosin
• Interventions: (n = 33357)
– Chlorthalidone, 12.5 to 25 mg/d (n = 15255)
– Amlodipine, 2.5 to 10 mg/d (n = 9048)
– Lisinopril, 10 to 40 mg/d (n = 9054)
• Follow-up of 4 to 8 years
JAMA. 2002 Dec 18;288(23):2981-97.

Effect on BP
JAMA. 2002 Dec 18;288(23):2981-97.

Heart Failure
JAMA. 2002 Dec 18;288(23):2981-97.

Heart Failure
Chlorthalidone vs. others
JAMA. 2002 Dec 18;288(23):2981-97.

Chlorthalidone vs. Amlodipine
Upto 3 times
higher risk
JAMA. 2002 Dec 18;288(23):2981-97.

Chlorthalidone vs. Lisinopril
Higher risk of Stroke
Higher risk of Heart Failure
Higher risk of Combined CVD
In African-origin participants, compared to chlorthalidone
Lisinopril had
JAMA. 2002 Dec 18;288(23):2981-97.

Chlorthalidone
Superior for African Patients
JAMA. 2002 Dec 18;288(23):2981-97.

Inferences
• Chlorthalidone should be considered first for
pharmacologic therapy in patients with HT
• Superior to CCB & ACEI in preventing one or more
major forms of CVD
• Unsurpassed in African-origin patients for lowering
BP, reducing clinical events and tolerability

N Engl J Med. 2015 Nov 26;373(22):2103-16.

Systolic Blood PRessure
INtervention Trial
N Engl J Med. 2015 Nov 26;373(22):2103-16.
• n = 9361 from 102 clinics age ≥50 years
• 1st trial to conclusively demonstrate benefit of
lowering SBP goal in a non-diabetic population
• Achievement of target SBP of 120 mm Hg as
compared to 140 mm Hg
o Reduced rates of CV events (heart attack, HF and
stroke) by almost a third
o Reduced risk of death by almost a quarter

Ex-President, ASH
Member, JNC 6 & 7
PI – SPRINT, ALLHAT
Member, JNC 6

Excerpt from the Interview…
• Dr Black: Were the antihypertensive regimens prescribed, or
was it whatever the docs wanted to do?
• Dr. Cushman: Good point… We did put a lot of emphasis on
using thiazide diuretics because of the ALLHAT results… And
it's important to point out that we actually used
chlorthalidone as the thiazide diuretic the majority of the
time that we used thiazides… So whenever a thiazide diuretic
was used in either group, overwhelmingly it was
chlorthalidone.

Chlorthalidone
Latest Evidences

Variable Response to Initial Therapy
• Understanding variation in response to different anti-
HT therapies could improve outcomes for >1 billion
people with HT
• Immediate responders: initial steep decline during
the first month, followed by a more gradual decline
• Non-immediate responders: initial increase in SBP
until about 1 month, followed by a gradual decrease
Hypertension. 2017 Jul;70(1):94-102.

39,763 participants
with at least 1 SBP
measurement in the first 6
months of ALLHAT analyzed

0-6 mth cumulative incidence of outcomes
21%

6-24 mth cumulative incidence of outcomes
50%48%

Early Response – CTD vs. Others
“Chlorthalidone is associated with more favorable
initial response than other medications.. (and is) most
likely to reduce SBP and cardiovascular risk”
% of NIRs
CTD 11.4
Amlo 13.2
Lisi 18.8
NIR = Non-immediate responders

Resistant Hypertension
• Uncontrolled HT despite the use of ≥3 medication
classes or controlled HT while treated with ≥4
medication classes1
• Associated with increased risk of 2
– coronary heart disease (1.44 [1.18-1.76])
– stroke (1.57 [1.18-2.08])
– all-cause mortality (1.30 [1.11-1.52])
– heart failure (1.88 [1.52-2.34])
– peripheral artery disease (1.23 [0.85-1.79]), and
– end-stage renal disease (1.95 [1.11-3.41])
1. Circulation. 2008;117(25): e510-e526. 2. Hypertension. 2014 Nov;64(5):1012-21.

• At Year-2 follow-up visit, participants with avg. BP
≥ 140/90 on 3 anti-HT medications OR
< 140/90 on 4 anti-HT medications
• 14,684 ALLHAT participants met the criteria and were
analyzed
Am J Med. 2017 Apr;130(4):439-448.e9.

Resistant HT – Prevalence
• At 2 years, participants having Resistant HT:
Chlorthalidone – 9.6%
Amlodipine – 11.4%
Lisinopril – 19.7%
• Odds of treatment-resistant HT vs. CTD group:
Lisinopril group (OR 2.32 [1.86-2.90]; p < 0.0001)
Amlodipine group (OR 1.24 [0.98-1.56]; p = 0.07)
Am J Med. 2017 Apr;130(4):439-448.e9.

• 22,180 participants from ALLHAT followed up for 8
years (in-trial)
• 16,622 participants further followed up for 5
additional years (post-trial)
• Participants assigned to amlodipine and lisinopril
combined into 1 group and compared against CTD
• Endpoints: Hospitalized hip and pelvic fractures
JAMA Intern Med. 2017;177(1):67-76.

Results
CTD vs. amlodipine or lisinopril
• In-trial: adjusted HR 0.79 (95%CI, 0.63-0.98)
• In-trial plus post-trial: adjusted HR 0.87 (95%CI, 0.74-1.03)
JAMA Intern Med. 2017;177(1):67-76.

Superior BP control with
Dual mode of Action
Effective & Sustained
24 h BP control
Adds one more day to life with
1 month of treatment
Additional
Pleiotropic Benefits
Guidelines (ACC/AHA, CHEP,
JNC)
recommend Chlorthalidone
as 1st Choice Antihypertensive
Proven in Landmark Trials
ALLHAT, SHEP, SPRINT,
HDFP, TOMHS, MRFIT
Conclusion

In Hypertension Management
It’s Time to
Ring in the Change
Hence,

In the Management of Hypertension….It’s time
to…
CHANGE

INDICATIONS
Treatment of arterial hypertension, essential or
nephrogenic or isolated systolic
Treatment of stable, chronic heart failure of mild
to moderate degree (NYHA functional class II or
III)
Treatment of Edema

DOSAGE
Hypertension:
Monotherapy – Initial adult dosage of 12.5–25mg/day, can be
increased to 50 mg/day
Combination therapy – Dosage can be adjusted first by
administering each drug separately
Stable, Chronic Heart Failure:
The recommended starting dose is 25 to 50 mg/day, in severe
cases it may be increased up to 100 to 200 mg/day. The usual
maintenance dose is the lowest effective dose e.g. 25 to 50 mg/day
either daily or every other day
Edema:
The usual initial adult dosage of Chlorthalidone for the management
of edema is 50- 100mg daily in a single dose after breakfast

CONTRAINDICATIONS
Patients with known hypersensitivity to chlorthalidone or other
sulfonamide derived drugs
Anuria; Severe hepatic or renal failure (creatinine clearance
<30ml/min)
Refractory hypokalaemia, hyponatraemia and hypercalcaemia;
Symptomatic hyperuricaemia (history of gout or uric acid calculi)
Hypertension during pregnancy; Untreated Addison's disease;
Concomitant lithium therapy

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